Does orgasm cause a dopamine crash?

There's some theory around that orgasm will cause a dopamine surge and drop, and that this can lead to a period of low mood or depression. A come down.

Is this true, does orgasm have a negative psychological consequence ?

To answer your last question, I very much doubt it's true in general. It does have unplesant effects in some people though. Form a popsci account

He [a psychoanalyst] was puzzled about a 24-year-old man whom he viewed as psychiatrically healthy except for intense depression that lasted for several hours after sex. [… ] Could it be that some patients have particularly strong rebound activity in the amygdala after orgasm that makes them feel bad?

And this post-coital dysphoria can happen to women too, for which there is some prevalence data:

Forty‐six percent of respondents reported experiencing PCD symptoms at least once in their lifetime with 5.1% experiencing PCD symptoms a few times within the past 4 weeks.

"No sex before game day" was a tenet in some sports psychology/physiology corners, but more recent research failed to find significant differences of sex acts on mental performance… at least in (healthy) athletes. A 2016 review notes

Despite the major differences found in the recovery phase, where higher values of HR [heart rate] were found 2 h after sexual intercourse, no significant differences were found in workload achieved and in mental concentration of the athletes.

And, yeah, I know sex doesn't necessarily mean orgasm, but it seems close enough to mention.

The unsexy truth about dopamine

I f there were a celebrity among brain chemicals, it would be dopamine. Supposedly released whenever we experience something pleasurable, it's forever linked to salacious stories of sex, drugs and wild partying in the popular press. The Kim Kardashian of neurotransmitters, it gives instant appeal to listless reporting and gives editors an excuse to drop some booty on the science pages.

There are too many bad examples to mention in detail, but I have some favourites. The Sun declared that "cupcakes could be as addictive as cocaine" because they apparently cause "a surge of the reward chemical dopamine to hit the decision-making area of the brain". The article was topped off with a picture of Katy Perry, apparently a "cupcake fan" and, presumably, dangerously close to spiralling into a life of frosted-sponge addiction.

The dopamine stereotype is not just reserved to the jauntier sections of the tabloid press. It can also be used as a way of making any of your views sound scientific. It's a simple formula – if you disagree with something, just say it releases dopamine and imply it must be dangerously addictive. Forbes magazine recently ran an article claiming that America's gun culture could be due to firearm addiction because dopamine is released, it claimed, when a shot is fired "meaning not only are guns addictive, but automatic weaponry is far more addictive than most". It was clearly just a smokescreen for the views of gun-hating liberals.

Now at this point, some of you may be worrying that I'm about to pour cold water on the pop science party and forever banish booty to the gossip columns, but I like to think that knowing the details is a more like putting acid in the punch bowl. When you can see how weird dopamine really is, a whole new world opens up.

Dopamine is indeed involved in addiction, but it isn't a "pleasure chemical". In fact, dopamine has lots of functions in the brain – being involved in everything from regulating movement to the control of attention. In great part, its effects depend on which of the brain's pathways it is operating in. The wonderfully named tuberoinfundibular pathway regulates hormone release and is important in stimulating the production of breast milk. This is why an unfortunate side-effect of antipsychotic medication used to treat schizophrenia, which primarily alters the dopamine system, can be lactation, even in men.

But when you hear about dopamine in the press, it's usually a vague reference to the role of dopamine in the mesolimbic pathway – a small but important brain tract that connects a deep brain area called the nucleus accumbens to the frontal lobes. Even here, however, dopamine has differing effects because while the chemical is the same, there are various forms of receptors that detect the presence of dopamine but do something different, depending on their type. The type that makes the glamour mags is the D2 family of receptors, which are affected by stimulants but are also linked to episodes of psychosis. It is no accident that too much speed or cocaine can make you paranoid.

The most widely accepted theory of what mesolimbic dopamine is supposed to do concerns its role as a feedback signal for predicting rewards. The theory goes that, a bit like me, it's the nerd at the pool party who gives a running commentary on how well you're doing with the temptations on offer. If you get lucky, a surge of dopamine signals a success, but – and this is where the "pleasure chemical" idea breaks down – it also signals when you only manage an uncomfortable near-miss.

Studies on roulette players have recorded as much activity in the nucleus accumbens when punters lose money with a miserable near-miss as when they have an enjoyable win. In this case, dopamine seems not to be signalling pleasure but indicating how close you got to the reward and encouraging another attempt. This works well when success depends on skill but falsely compels us in games of chance.

Addictive drugs alter this motivational system but, crucially, this is not the same as their pleasurable effect. Many long-term addicts report that they get little joy from their hit but that they still feel compelled to continue. Similarly, dopamine blockers don't stop drug-induced highs and only certain sorts of dopamine boosting drugs, when taken in a certain way, produce pleasure. It also seems that how the drugs affect the neurochemical signal is also key. Surging or "phasic" dopamine is more associated with reward motivation than "tonic" or background dopamine levels.

If this is making your head spin, it's worth saying that there is much more down the dopamine rabbit hole, as the brain's motivational system is complex to the point where the neurotransmitter is also involved in motivation to avoid unpleasant experiences. Traumatised war veterans, for example, show nucleus accumbens dopamine surges when they are reminded of the sounds of battle, something they find deeply aversive.

But even though science doesn't give the "dopamine is a pleasure chemical" concept a second look, I can guarantee that you won't see the end of it. Even though it's wrong, it's just too useful a media prop to be tossed aside, like some half-smoked cigarette. After all, anything that can bring Kim and Katy to the party can't be an empty high… can it?

Got Dopamine? Sex and the ADHD Woman

You think youve got sex problems? We want too much. We dont want any. Were halfway to heaven, a fly walks across the wall and weve lost it.

As if living with ADHD wasnt problematic enough, our symptoms often (or, more likely, nearly always) interfere with our sex lives as well.

If sex, as they say, is 90% in the mind, imagine my surprise when I cracked open Naomi Wolfs new book, Vagina: A New Biography (2012), to find Chapter 4 was all about the brain chemistry of sex. What really got me excited was the title: &ldquoDopamine, Opioids, and Oxytocin.&rdquo

Given that, I hoped Wolfs book might provide a few keys to unlock more satisfying sex lives for women (and possibly for men, too) by understanding our ADHD brains decreased levels of dopamine.

Wolf is not writing about women with ADHD specifically. Still, she says,

A woman with low dopamine will have low libido and depression, as we have noted.

Reading this, I couldnt help but think of the high numbers of women who are diagnosed with both ADHD and depression. It also brought to mind the women with ADHD who have told me that theyve never experienced orgasm. Could this too be related to low dopamine levels?

It&rsquos important to remember that, like other ADHD traits, were all different. Some of us (Im not naming names) have no trouble in the libido department. Still, some &ndash perhaps many &ndash suffer the double trouble of low dopamine and low libido. Perhaps the research cited in Wolf&rsquos book has twice the relevance for women with ADHD.

Get your motor running

Wolfs Chapter 4 reads almost like a treatise on ADHD treatment (prescribed and self-administered). She writes:

You activate dopamines release in various ways: aerobic exercise, taking drugs like cocaine, socializing, shopping, gambling and having good orgasmic sex.

Exercise is said to be one of the best all-time treatments for ADHD. Cocaine? It&rsquos often used unwittingly as a substitute for legal stimulants when ADHD has not yet been diagnosed.

Shopping and gambling? Both of these can become addictions for a woman with untreated ADHD looking for her next dopamine hit. Good orgasmic sex? That too has been known to be used to fulfill an ADHD woman&rsquos diet for dopamine. (Or so I hear.)

While Wolf doesnt make the connection between these behaviors and ADHD, she does cite experiments in which dopamine is given to rodents who were addicted to cocaine, morphine, or heroin. After their dopamine levels were increased, the rat addicts used less of the drug they were addicted to, and showed fewer withdrawal symptoms. In us, treating ADHD safely can circumvent addictions to unhealthy behaviors or substances.

A word of caution

It seems, from reading Wolfs chapter on dopamine, opioids, and oxytocin, that increasing our dopamine levels to normal might in fact improve sex drives and love lives.

On the other hand, we need to be careful about how we get our dopamine hit.

Of thousands of different chemicals, just a few alcohol, cocaine, and other opiates and narcotics boost dopamine.

So too, I might add, do legal ADHD stimulant medications.

Wolf also inadvertently addresses some ADHDers attraction to using intense activities to self-medicate:

Highly stimulating versions of ordinary behaviors also boost dopamine, which is why exercise and pornography can be addictive.

The jurys out

Considering most ADHD research doesnt take womens unique physiology into account, were a long way from understanding the connection between womens brain chemistry, ADHD, and sex.

In lieu of a book targeted to our special brains, Id recommend taking a look at Vagina. Wait, that didnt sound right You might as well read Naomi Wolfs well-researched book, Vagina: A Biography. If nothing else, youll appreciate your quest for dopamine on a whole new level.

What, Exactly, Is an Orgasm?

Any way you look at it, orgasm is an incredible bodily process, and one of the most intense sensory experiences our brains can go through. That goes for bodies too: blood rushes, breathing quickens, muscles contract. "It's basically all systems go at orgasm," says Barry R. Komisaruk, a professor of psychology at Rutgers University. In the name of taking some of the mystery out of one of the most interesting parts of our biology, here's how it all goes down.

Step 1: Excitement
Whether it's a sext, a caress, or a passing fantasy, some arousing experience is the first step toward potential orgasm. During this stage, the parasympathetic nervous system — known for its role in rest and recuperation — is activated. This causes the spongy tissue of the penis to become erect and is also what begins vaginal lubrication and the swelling of the labia in women. It also produces engorgement of the clitoris.

RELATED: A Guide to Multiple Orgasms for Men and Women

Step 2: Stimulation
A region of the brain located between the halves of the cortex called the genital sensory complex,is a main player in these initial stirrings. "When the stimulation starts, that part of the brain is what responds," says Komisaruk. Various sexual sensations reach this region, including penile, scrotal, and testicular touching in men. Although the extent to which the vagina and cervix are sensitive is hotly debated, Komisaruk's research has found that vaginal, cervical, and nipple stimulation all activate areas of the genital sensory complex in women. The pudendal, pelvic, hypogastric, and vagus nerves help communicate between the brain and the different genital areas.

The amygdala, hypothalamus, hippocampus, and frontal cortex also show increased activity during sexual excitement. The amygdala is involved in emotional response, the hypothalamus secretes oxytocin, and the hippocampus (which we usually associate with memory) may play a part in fantasy, along with the frontal cortex.

At some point, the sympathetic system (associated with fight or flight) kicks in and takes over. Heart rate, blood pressure, and sweating increase. Pupils dilate. During the excitement phase, women's breasts and vaginal walls swell. Men's testicles swell, the scrotum tightens, and the tip of the penis lubricates. These actions all continue into the plateau phase as well.

Step 3: Preparation
During this part of the sexual response cycle, the processes that began in the excitement stage continue. Erection and lubrication are maintained. In men, the testicles draw close to the body in preparation for ejaculation. In women, the vaginal walls darken and the increasingly sensitive clitoris often retracts under the clitoral hood to prevent direct stimulation. More areas of the brain light up. Activation of the cerebellum is responsible for muscle tension and may be the cause of muscle twitching at this stage.

Step 4: Orgasm
Climax is the shortest of all of the phases, and the one where the brain goes all out. "We see in men and women that the greatest activity in the brain occurs at orgasm," says Komisaruk. The hypothalamus, which builds in activity throughout this process, secretes oxytocin in maximum amounts during orgasm. This causes pleasurable contractions of the uterus that many women associate with orgasm and may facilitate ejaculation through contraction of the prostate and seminal vesicles. While we know oxytocin plays a role in physical functions, we are less sure about its emotional effects — contrary to what you've probably heard. "The 'cuddling hormone' idea is based on studies with rodents," says Komisaruk. "It's very controversial what oxytocin actually does perceptually in humans."

The nucleus accumbens revs up as well during this sensory explosion, contributing supreme feelings of gratification. "That has been described as the pleasure center in the brain," says Komisaruk. "It's activated by not only orgasm but also by cocaine and nicotine and caffeine and chocolate." This area receives dopamine from the ventral tegmentum. During orgasm, the dopamine system in the brain also maxes out.

One mystery of brain activity in this stage involves the insular cortex and anterior cingulate cortex. "Those two regions we see very strongly during orgasm in men and women," says Komisaruk. "Those two regions are also activated during pain." This similarity is something of a mystery. Komisaruk thinks this likeness may have to do with either the inhibition of pain or may be related to facial expressions, which are comically similar during pain and orgasm.

We know that men almost always ejaculate during orgasm. Some women do as well. This is not to be confused with squirting, which produces a chemically different fluid. As with men, female ejaculation is produced via activation of the sympathetic nervous system and the fluid comes from the female prostate gland and is chemically similar to semen.

Step 5: Resolution
After orgasm, the body does what it can to return to a pre-arousal state. Heart rate, breathing, and blood pressure slow back down. Genital swelling, including erection, reduces. Most people feel an extreme sense of relaxation, and men often get sleepy.

For the most part, the processes that go on in male and female bodies throughout orgasm look a lot alike. "The similarities between men and women during orgasm in the brain are much greater than the differences," says Komisaruk. The big caveat seems to be the refractory period. While many women can begin to build to orgasm again right after their last one, many men have to wait awhile. Komisaruk says he studied one man who was able to have six ejaculations in half an hour but, for most, a half-hour or more of rest between orgasms is necessary. Komisaruk is currently studying the refractory period to see if it has any relationship to anorgasmia, the inability to have an orgasm.

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Orgasms and endorphins

Since orgasms cause a release of endorphins into one's cerebral-spinal fluid and endorphins are also somewhat responsible for the emotion of happiness, etc., is it possible that excessive masturbation and/or intercourse would lead to a depleted level of endorphins in the system that could in turn cause one's affect to become somewhat "flat"? Could a sustained low level of endorphins in the system induce depression and/or mood disorder?

Dear Not worried, just curious,

Endorphins are a group of substances formed within the body that naturally relieve pain. They have a similar chemical structure to morphine. In addition to their analgesic, or pain-relieving, effect, endorphins are thought to be involved in controlling the body's response to stress, regulating contractions of the intestinal wall, and determining mood. They may also regulate the release of hormones from the pituitary gland, notably growth hormone and the gonadotropin hormones.

Some researchers have learned that strenuous exercise releases endorphins into the blood stream. Others have found that endorphins are released during orgasm, as well as during laughter. Endorphin release may occur with frequent sex and masturbation. On the other hand, there doesn't appear to be evidence that too much sex (or exercise or laughter, for that matter) and elevated endorphin levels deplete the body of endorphins and then result in depression, etc. In fact, the most recent thinking is that exercise, as experienced during running as "runner's high," for example (and, likely, by extension, other activities that cause the release of endorphins, such as sex), can help treat depression — and health care providers often prescribe exercise! Indeed, a Duke University study released in 2000 showed that, for some people, 45 minutes of exercising, three-times-a-week, was as effective in lessening depression as was taking the antidepressant Zoloft.

Although there is no evidence to show that too much sex leads to depression, the reverse can sometimes be true — that is, depression can lead to too much sex. Sex or masturbation can be abused, as can anything — including things we need to survive, such as food. People can also get "hooked" on masturbating or sex, similar to how they can get "hooked" on anything else that makes them feel good and helps them not to think about problems they might be having.

If you're living a satisfying life, have friends, doing well at school or in your job, getting along with people in your life, and you just happen to have a lot of sex or masturbate often, then no worries. BUT if, on the other hand, you feel lonely and unhappy and things aren't going well in your life or you feel anxious and nervous about a lot of stuff or you don't feel good about yourself and you rely on sex or masturbation to make yourself feel better or to avoid any bad feelings you might be having, then you might want to think about finding a professional you can talk with about what's happening in your life and about your feelings of loneliness or unhappiness or anxiety.

In the end, it's up to you to figure out whether or not sex (either by yourself or with someone else) is fitting into your life in a positive way. And if it isn't, the next step is to figure out why. Some resources that might give you insight are any books written by Marty Klein or Betty Dodson.

Myths and Misconceptions of Self-Injury: Part II

Self-Injury Hurts! When it comes to pain, I am a wimp. If I accidentally hit my thumb with a hammer I'm ready to call an ambulance. Like many, I had a hard time understanding how those who self-injure report experiencing little or no pain when hurting themselves. It could be that there's a huge conspiracy among self-injurers to state that the act of hurting themselves is not painful in an attempt to recruit more self-injurers. But it seems more likely that there are psychological and physiological processes that help to mask the pain associated with the physical injury.

Self-injury is cyclic in nature with factors preceding the actual act of physical injury and factors following the behavior. Dissociation is one of the factors that comes into play immediately prior to the act of self-injury. Everyone dissociates to some degree. At a benign level, dissociation may be described as "zoning out" and may result in driving past the freeway ramp on which you intended to exit. At the extreme end of the dissociative spectrum is dissociative identity disorder, a psychological phenomenon in which an individual develops, typically as the result of chronic, severe trauma, two or more distinct personalities. When people self-injure they are typically in a dissociated state, allowing them to feel little or no pain while they injure themselves.

Physiologically, endorphins are released when we are injured or stressed. Endorphins are neurotransmitters that act similarly to morphine and reduce the amount of pain we experience when we are hurt. Joggers often report experiencing a "runners high" when reaching a physically stressful period. This "high" is the physiological reaction to the release of endorphins - the masking of pain by a substance that mimics morphine. When people self-injure, the same process takes place. Endorphins are released which limit or block the amount of physical pain that's experienced. Sometimes people who intentionally hurt themselves will even say that they felt a "rush" or "high" from the act. Given the role of endorphins, this makes perfect sense.

These two dynamics, dissociation and the release of endorphins, serve to mask the physical pain that would seem to accompany self-injury. Regardless of whether the injury we sustain is accidental or intentional, our body knows how to protect itself.

Dopamine Is _________

In a brain that people love to describe as “awash with chemicals,” one chemical always seems to stand out. Dopamine: the molecule behind all our most sinful behaviors and secret cravings. Dopamine is love. Dopamine is lust. Dopamine is adultery. Dopamine is motivation. Dopamine is attention. Dopamine is feminism. Dopamine is addiction.

Dopamine is the one neurotransmitter that everyone seems to know about. Vaughn Bell once called it the Kim Kardashian of molecules, but I don’t think that’s fair to dopamine. Suffice it to say, dopamine’s big. And every week or so, you’ll see a new article come out all about dopamine.

So is dopamine your cupcake addiction? Your gambling? Your alcoholism? Your sex life? The reality is dopamine has something to do with all of these. But it is none of them. Dopamine is a chemical in your body. That’s all. But that doesn’t make it simple.

What is dopamine? Dopamine is one of the chemical signals that pass information from one neuron to the next in the tiny spaces between them. When it is released from the first neuron, it floats into the space (the synapse) between the two neurons, and it bumps against receptors for it on the other side that then send a signal down the receiving neuron. That sounds very simple, but when you scale it up from a single pair of neurons to the vast networks in your brain, it quickly becomes complex. The effects of dopamine release depend on where it’s coming from, where the receiving neurons are going and what type of neurons they are, what receptors are binding the dopamine (there are five known types), and what role both the releasing and receiving neurons are playing.

And dopamine is busy! It’s involved in many different important pathways. But when most people talk about dopamine, particularly when they talk about motivation, addiction, attention, or lust, they are talking about the dopamine pathway known as the mesolimbic pathway, which starts with cells in the ventral tegmental area, buried deep in the middle of the brain, which send their projections out to places like the nucleus accumbens and the cortex. Increases in dopamine release in the nucleus accumbens occur in response to sex, drugs, and rock and roll. And dopamine signaling in this area is changed during the course of drug addiction. All abused drugs, from alcohol to cocaine to heroin, increase dopamine in this area in one way or another, and many people like to describe a spike in dopamine as “motivation” or “pleasure.” But that’s not quite it. Really, dopamine is signaling feedback for predicted rewards. If you, say, have learned to associate a cue (like a crack pipe) with a hit of crack, you will start getting increases in dopamine in the nucleus accumbens in response to the sight of the pipe, as your brain predicts the reward. But if you then don’t get your hit, well, then dopamine can decrease, and that’s not a good feeling. So you’d think that maybe dopamine predicts reward. But again, it gets more complex. For example, dopamine can increase in the nucleus accumbens in people with post-traumatic stress disorder when they are experiencing heightened vigilance and paranoia. So you might say, in this brain area at least, dopamine isn’t addiction or reward or fear. Instead, it’s what we call salience. Salience is more than attention: It’s a sign of something that needs to be paid attention to, something that stands out. This may be part of the mesolimbic role in attention deficit hyperactivity disorder and also a part of its role in addiction.

But dopamine itself? It’s not salience. It has far more roles in the brain to play. For example, dopamine plays a big role in starting movement, and the destruction of dopamine neurons in an area of the brain called the substantia nigra is what produces the symptoms of Parkinson’s disease. Dopamine also plays an important role as a hormone, inhibiting prolactin to stop the release of breast milk. Back in the mesolimbic pathway, dopamine can play a role in psychosis, and many antipsychotics for treatment of schizophrenia target dopamine. Dopamine is involved in the frontal cortex in executive functions like attention. In the rest of the body, dopamine is involved in nausea, in kidney function, and in heart function.

With all of these wonderful, interesting things that dopamine does, it gets my goat to see dopamine simplified to things like “attention” or “addiction.” After all, it’s so easy to say “dopamine is X” and call it a day. It’s comforting. You feel like you know the truth at some fundamental biological level, and that’s that. And there are always enough studies out there showing the role of dopamine in X to leave you convinced. But simplifying dopamine, or any chemical in the brain, down to a single action or result gives people a false picture of what it is and what it does. If you think that dopamine is motivation, then more must be better, right? Not necessarily! Because if dopamine is also “pleasure” or “high,” then too much is far too much of a good thing. If you think of dopamine as only being about pleasure or only being about attention, you’ll end up with a false idea of some of the problems involving dopamine, like drug addiction or attention deficit hyperactivity disorder, and you’ll end up with false ideas of how to fix them.

The other reason I don’t like the “dopamine is” craze is because the simplification takes away the wonder of dopamine. If you believe “dopamine is,” then you’d think that we’ve got it all figured out. You begin to wonder why we haven’t solved this addiction problem yet. Complexity means that the diseases associated with dopamine (or with any other chemical or part of the brain, for that matter) are often difficult to understand and even more difficult to treat.

By emphasizing dopamine’s complexity, it might feel like I’m taking away some of the glamour, the sexiness, of dopamine. But I don’t think so. The complexity of how a neurotransmitter behaves is what makes it wonderful. The simplicity of a single molecule and its receptors is what makes dopamine so flexible and what allows the resulting systems to be so complex. And it’s not just dopamine. While dopamine has just five receptor type, another neurotransmitter, serotonin, has 14 currently known and even more that are thought to exist. Other neurotransmitters have receptors with different subtypes, all expressed in different places, and where each combination can produce a different result. There are many types of neurons, and they make billions and billions of connections. And all of this so you can walk, talk, eat, fall in love, get married, get divorced, get addicted to cocaine, and come out on top of your addiction some day. When you think of the sheer number of connections required simply for you to read and understand this sentence—from eyes to brain, to processing, to understanding, to movement as your fingers scroll down the page—you begin to feel a sense of awe. Our brain does all this, even while it makes us think about pepperoni pizza and what that text your crush sent really means. Complexity makes the brain the fascinating and mind-boggling thing that it is.

So dopamine has to do with addiction, whether to cupcakes or cocaine. It has to do with lust and love. It has to do with milk. It has to do with movement, motivation, attention, psychosis. Dopamine plays a role in all of these. But it is none of them, and we shouldn’t want it to be. Its complexity is what makes it great. It shows us what, with a single molecule, the brain can do.

Excessively Masturbating Does Damage to Your Nervous System

I like to masturbate. I like it a bit too much. Since the age of 14, I would masturbate as many as 3 times a day—each and every day of the week. I would see a pretty girl, and I would get the urge to masturbate. I would see a movie with an attractive actress, and I would want to masturbate. I would even think about porn, and I would get the urge to masturbate.

Now, I believe all my over activity has made it difficult for me to have sex with an actual partner. Each time I try to have sex with my partner, I cannot maintain an erection. If I do manage to gain an erection, I ejaculate almost instantly. As a 28-year old male, I want to feel the warmth of a woman—without the sudden need to ejaculate. Please, any advice would help.


The years of abusive masturbation have severely inflamed your body. You can no longer maintain an erection—let alone postpone an ejaculation. Your body has ejaculated for so long, the hyperactive images created during masturbation have caused you to treat sex like a session of masturbation—quick, quite, and private.

Masturbation alters your brain function. You get “turned on” by a varying degree of body types and images. Your mind now objectifies women, using their body as a source of pleasure. When you prepare to have sex with a real woman, your mind cannot signal for the proper hormones because it is not accustomed to the atmosphere. Your mind is accustomed to watching a movie, seeing a women, and gaining the urge to masturbate.

The Science Behind Your Weak Erections
Masturbation and ejaculation stimulate your acetylcholine & parasympathetic nervous functions. Over stimulation of these nerves overproduce sex hormones and neurotransmitters, such as acetylcholine, dopamine, and serotonin. As a result, your body cannot modulate your hypothalamus and adrenal functions. Instead, the body releases excessive stress hormones that overwork and exhaust varous glands in your body.

In this highly stressful state, your exhausted glands ceases to produce sufficient amount of key neuro-chemicals that are necessary to transmit nerve impulses and ensure healthy blood flow. Without the necessary chemicals and hormones (example, nitric oxide), your erections disappear. When the body produces weak erections, the result can lead to excessive precum and semen leakage during intercourse.

Regain Your Old Self Back
Weak erections and premature ejaculations can ruin your relationship. Your partner will not stay patient forever. As for your little issue, you’re going to want to refrain from masturbation and sex. Tie your hands together. Lock yourself in the basement if you have too. However you stop yourself from masturbating as often, do it! If you want to speed up the recovery time of your weak erections and premature ejaculation issues, take the right herbal treatment that will improve your endurance and erection quality.

Boston University Medical CampusSexual Medicine

Female sexual dysfunction is defined as disorders of sexual desire, arousal, orgasm and/or sexual pain, which results in significant personal distress and may have an impact on the quality of life and interpersonal relationships. Although each specific condition can be separately defined in medical terms, clinically there is significant overlap in afflicted patients. The limited available data on female anatomy, physiology, biochemistry and molecular biology of the female sexual response makes this field particularly challenging to clinicians, psychologists and basic science researchers alike.

The sexual response cycle consists of desire, arousal, orgasm and resolution (both physiologic and psychologic). Desire is the mental state created by external and internal stimuli that induces a need or want to partake in sexual activity. Desire may be said to consist of: 1) biologic roots, which in part are based on hormones such as androgen and estrogen, 2) motivational roots, which are in part based on intimacy, pleasure and relationship issues and 3) cognitive issues such as risk and wish. Arousal is the state with specific feelings and physiologic changes usually associated with sexual activity involving the genitals. Arousal may be said to consist of: 1) central mechanisms including activation of thoughts, dreams and fantasies, 2) non-genital peripheral mechanisms such as salivation, sweating, cutaneous vasodilation and nipple erection and 3) genital mechanisms such as clitoral, labial and vaginal engorgement. Orgasm is the altered state of consciousness associated with primarily genital sensory input. Orgasm consists of multiple sensory afferent information from trigger points such as clitoris, labia, vagina, periurethral glans, etc., which pass centrally to supraspinal structures likely involving the thalamic septum. Following sufficient sensory stimulation, central neurotransmitter discharge during orgasm results in repeated 1-second motor contractions of the pelvic floor (3 – 8/orgasm) followed in 2 – 4 seconds by repeated uterine and vaginal smooth muscle contraction. Pleasurable sensory information is also carried to the cortical pleasure sites.

Epidemiology of Female Sexual Dysfunction

Well-designed, random-sample, community-based epidemiologic investigations of women with sexual dysfunction are limited. Current data reveals that up to 76% of women have some type of sexual dysfuntion. U.S. population census data suggest that approximately 10 million American women ages 50-74 self-report complaints of diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieving orgasm. Recently, Laumann and Rosen found that sexual dysfunction is more prevalent in women (43%) than in men (31%) and is associated with various psychodemographic characteristics such as age, education, and poor physical and emotional health. More importantly, female sexual dysfunction is associated with negative sexual relationship experiences.

Anatomy and physiology of genital sexual arousal

There is a paucity of data concerning the anatomy, physiology, pathophysiology of sexual function in women. The female external genitalia consist of various structures. The vagina is a midline cylindrical organ that connects the uterus with the external genitalia. The vaginal wall consists of three layers: a) an inner mucous type stratified squamous cell epithelium supported by a thick lamina propia, that undergoes hormone-related cyclical changes, b) the muscularis composed of outer longitudinal smooth muscle fibers and inner circular fibers, and c) an outer fibrous layer, rich in collagen and elastin, which provides structural support to the vagina. The vulva, bounded by the symphysis pubis, the anal sphincter and the ischial tuberosities, consists of labial formations, the interlabial space, and erectile tissue. The labial formations are two paired cutaneous structures: a) the labia majora are fatty folds covered by hair-bearing skin that fuses anteriorly with the mons veneris, or anterior prominence of the symphysis pubis, and posteriorly with the perineal body or posterior commissure b) The labia minora are smaller folds covered by non-hearing skin laterally and by vaginal mucosa medially, that fuses anteriorly to form the prepuce of the clitoris, and posteriorly in the fossa navicularis. The interlabial space is composed of the vestibule, the urinary meatus, and vaginal opening and is bounded by the space medial to the labia minora, the fossa navicularis and the clitoris. The clitoris is a 7-13 cm Y shaped organ comprised of glans, body, and crura. The body of the clitoris is surrounded by tunica albuginea and consists of two paired corpora cavernosa composed of trabecular smooth muscle and lacunar sinusoids. Finally, the vestibular bulb consists of paired structures located beneath the skin of the labia minora and represents the homologue of the corpus spongiosum in the male.

There is limited understanding of the precise location of autonomic neurovascular structures related to the uterus, cervix, and vagina. Uterine nerves arise from the inferior hypogastric plexus formed by the union of hypogastric nerves (sympathetic T10-L1) and the splanchnic fibers (parasympathetic S2-S4). This plexus has three portions: Vesical plexus, the rectal plexus, and the uterovaginal plexus (Frankenhauser’s ganglion), which lies at the base of the broad ligament, dorsal to the uterine vessels, and lateral to the uterosacral and cardinal ligament. This plexus provides innervation via the cardinal ligament and uterosacral ligaments to the cervix, upper vagina, urethra, vestibular bulbs and clitoris. At the cervix, sympathetic and parasympathetic nerves form the paracervical ganglia. The larger one is called the uterine cervical ganglion. It is at this level that injury to the autonomic fibers of the vagina, labia, cervix may occur during hysterectomy. The pudendal nerve (S2-S4) reaches the perineum through Alcock’s canal and provides sensory and motor innervation to the external genitalia.

Large gaps exist in our knowledge of how the central nervous system controls female sexual function. Limited data suggest that descending supraspinal modulation of female genital reflexes emanates from: 1) brainstem structures such as the nucleus paragigantocellularis (inhibitory via serotonin), locus ceruleus (norepinephrine, nocturnal engorgement during REM sleep) and midbrain periaqueductal gray, 2) hypothalamic structures such as the medial pre-optic area, ventromedial nucleus and paraventricular nucleus and 3) forebrain structure such as the amygdala. Multiple factors interact at the supraspinal levels to influence the excitability of spinal sexual reflexes such as: 1) gonadal hormones, 2) genital sensory information via the mylenated spinothalamic pathway and the unmyelinated spinoreticular pathway and 3) input from higher cortical centers of cognition.

The sexual arousal responses of the multiple genital and non-genital peripheral anatomic structures are largely the product of spinal cord reflex mechanisms. The spinal segments are under descending excitatory and inhibitory control from multiple supraspinal sites. The afferent reflex arm is primarily via the pudendal nerve. The efferent reflex arm consists of coordinated somatic and autonomic activity. One spinal sexual reflex is the bulbocavernosus reflex involving sacral cord segments S 2,3 and 4 in which pudendal nerve stimulation results in pelvic floor muscle contraction. Another spinal sexual reflex involves vaginal and clitoral cavernosal autonomic nerve stimulation resulting in clitoral, labial and vaginal engorgement.

In the basal state, clitoral corporal and vaginal smooth muscles are under contractile tone. Following sexual stimulation, neurogenic and endothelial release of nitric oxide (NO) plays an important role in clitoral cavernosal artery and helicine arteriolar smooth muscle relaxation. This leads to a rise in clitoral cavernosal artery inflow, an increase in clitoral intracavernosal pressure, and clitoral engorgement. The result is extrusion of the glans clitoris and enhanced sensitivity.

In the basal state, the vaginal epithelium reabsorbs sodium from the submucosal capillary plasma transudate. Following sexual stimulation, a number of neurotransmitters including NO and vasoactive intestinal peptide (VIP) are released modulating vaginal vascular and nonvascular smooth muscle relaxation. Dramatic increase in capillary inflow in the submucosa overwhelms Na-reabsorption leading to 3-5 ml of vaginal transudate, enhancing lubrication essential for pleasurable coitus. Vaginal smooth-muscle relaxation results in increased vaginal length and luminal diameter, especially in the distal two-thirds of the vagina (Fig. 1). Vasoactive intestinal polypeptide is a non-adrenergic non-cholinergic neurotransmitter that plays a role in enhancing vaginal blood flow, lubrication and secretions.

Experimental models for investigation of female sexual genital arousal

I Results from in vivo animal studies:
The absence of established animal models to investigate female sexual genital arousal has hampered progress in this field. Recently, Park et al., investigated vaginal and clitoral hemodynamics in female New Zealand White rabbits in response to pelvic nerve stimulation (PNS) in order to mimic genital arousal in response to sexual stimulation. This elegant study showed that pelvic nerve-stimulation caused an increase in vaginal blood flow, vaginal wall pressure, vaginal length, clitoral intracavernosal pressure and clitoral blood flow and a decrease in vaginal luminal pressure. This study represents an approach to study genital arousal in an animal model and paved the way for the investigation of genital arousal in a laboratory setting. Using a rat model, Vachon et al., confirmed genital hemodynamic changes reported by Park et al., in the rabbit model. More recently, Giuliano et al., further demonstrated that PNS induced an increase in vaginal wall tension and a decrease in vaginal vascular resistance in the rat model. In addition, this study showed that atropine did not significantly affect vaginal blood flow response to pelvic nerve stimulation despite the fact that cholinergic fibers innervate vascular smooth muscle in the rat vagina, suggesting that acetylcholine may not be the primary neurotransmitter responsible for the increase in vaginal engorgement during sexual arousal. These studies documented that genital arousal is a neurovascular event characterized by increase in genital blood flow and smooth muscle relaxation. These hemodynamic changes are mediated by neurotransmitters and vasoactive agents and modulated by the hormonal milieu. Park et al., investigated the effects of estrogen deprivation and replacement on genital hemodynamics. They reported that ovariectomy significantly reduced vaginal and clitoral blood flow in response to pelvic nerve stimulation. We also investigated the effects of ovariectomy and estrogen and androgen treatment on genital blood flow using a novel, non-invasive laser oximetry technique. In contrast to the observations made by Park et al. we found that ovariectomy did not significantly alter genital blood flow in the rabbit model. The discrepancy may be attributed to differences in methodologies. In our studies, we determined genital blood flow two-weeks post ovariectomy, while Park et al. performed their studies six weeks after ovariectomy. The longer period of estrogen deprivation may have produced tissue structural changes that altered the engorgement response. Since the female rabbit remains in continuous diestrus until mounted, serum estrogen levels are normally low (32-38 pg/ml), and ovariectomy does not produce a dramatic decrease in estrogen levels (22-25 pg/ml). As a consequence, genital hemodynamic changes before and after ovariectomy may be minimal. In addition, laser oximetry was used in our studies to assess changes in genital blood flow, whereas Park et al., used laser Doppler-flowmetry. Further studies using other animal models that undergo menstrual cycling (e.g. rat) are necessary to investigate this discrepancy.

Park et al., also reported that estrogen replacement normalized genital hemodynamics to control levels. In our studies, treatment of ovariectomized animals with estradiol significantly increased pelvic nerve-stimulated genital blood flow above control levels (Fig.2). Interestingly, treatment with testosterone did not restore blood flow to that observed in control animals. Park et al., also noted marked thinning of the vaginal epithelial layers, decreased vaginal submucosal microvasculature, and diffuse clitoral cavernosal fibrosis in ovariectomized animals. In addition, the percentage of clitoral cavernosal smooth muscle was significantly decreased in ovariectomized animals. These studies suggest that estrogens modulate genital hemodynamics and are critical for maintaining tissue structural integrity.

Vaginal lubrication, an estrogen-dependent physiological process, is one of the indicators of genital arousal and tissue integrity. Min et al., showed that vaginal lubrication in ovariectomized animals under basal conditions and after pelvic nerve stimulation was reduced and normalized with estrogen treatment (Fig 3 and 4). In contrast, androgen treatment of ovariectomized animals with testosterone alone or in combination with estradiol did not restore vaginal lubrication to that observed in control animals. Finally, it was noted that ovariectomy caused vaginal atrophy and reduced vaginal epithelial cell maturation, which was normalized by estrogen but not androgen treatment.

In summary, data derived from in vivo animal models indicates that estrogen but not androgens modulate genital blood flow, vaginal lubrication and vaginal tissue structural integrity. It should be noted that estradiol levels used in these studies were supra-physiological with potential pharmacologic effects different from those achieved physiologically. Although estrogen replacement increases vaginal lubrication and restores vaginal epithelial integrity, this therapy may not be appropriate for all patients, due to associated risk of breast and endometrial cancer. An alternative to hormonal treatment is the utilization of P2Y2 receptor agonists, which have been shown to increase mucin production and blood flow in other systems. We investigated the effects of P2Y2 receptor agonists as a feasible non-hormonal alternative for the treatment of vaginal dryness in an animal model. P2Y2 receptors are expressed in cervical and vaginal tissues, and these agonists increased vaginal lubrication under conditions of estrogen deprivation.

II. Effects of vasoactive substances on genital blood flow
Limited data are available on the effects of vasoactive substances on genital hemodynamics. Park et al., 1997 demonstrated that injection of papaverine hydrochloride and phentolamine mesylate into the vaginal spongy muscularis layer increased vaginal wall pressure and vaginal blood flow. Sildenafil, a PDE5-selective inhibitor, has been utilized in the treatment of women with sexual arousal disorders with mixed results and pre-clinical data supporting the use of this agent in the management of female sexual dysfunction remains equivocal. We have shown that sildenafil administration caused significant increase in genital blood flow and vaginal lubrication in intact and ovariectomized animals. However, this response was more pronounced in animals treated with estradiol. These data suggested that the NO-cGMP pathway is involved, at least in part, in the physiologic mechanism of female genital arousal and that sildenafil facilitates this response in an in vivo animal model.

The effects of apomorphine, a non-selective dopamine receptor agonist, on genital blood flow were investigated by Tarcan et al., who suggested that systemic administration of apomorphine improved clitoral and vaginal engorgement by increasing clitoral intracavernosal and vaginal wall arterial inflow.

In summary, data derived from in vivo animal models indicate that vasoactive agents play a role in genital arousal. Although sildenafil and apomorphine enhanced genital blood flow in the animal model, clinical use of vasoactive agents remains controversial.
Studies in organ baths:

Physiological studies of the arousal phase of the female sexual response involve, in part, an understanding of the various local regulatory mechanisms, which modulate tone in the clitoral erectile tissue and the vaginal muscularis. Immunohistochemical studies in human vaginal tissues have shown the presence of nerve fibers containing NPY, VIP, NOS, CGRP and substance P.10 Previous studies have suggested that VIP may be involved in the regulation of clitoral and vaginal smooth muscle tone but, as yet, no conclusive experimental evidence of its functional involvement has been forthcoming. There is physiological evidence supporting a role for the alpha-adrenergic system in female sexual arousal. The alpha-2 adrenergic agonist clonidine impaired both vaginal engorgement and lubrication when administered to healthy volunteers.

There is limited data on the functional activity of the inhibitory non-adrenergic non-cholinergic transmission in the clitoral corpus cavernosum. Cellek and Moncada have shown that electrical field stimulation induces NANC relaxation responses in the clitoral corpus cavernosum of the rabbit. These responses were inhibited by NG-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) or tetrodotoxin. In addition, the inhibitory effect of L-NAME was partially reversed by L-arginine but not by D-arginine. EFS-induced relaxations were enhanced by an inhibitor of type V cyclic GMP phosphodiesterase, zaprinast. It was concluded that nitrergic neurotransmission is responsible for the NANC relaxation responses in the clitoral corpus cavernosum of the rabbit. Furthermore, the role of phosphodiesterase type 5 inhibition in the modulation of female sexual dysfunction was investigated by Vemulapalli and Kurowski. Pretreatment of clitoral corpus cavernosum strips with sildenafil enhanced the electrical field stimulation-induced relaxations, both in magnitude and duration. Thus, the NO pathway is critical for smooth muscle relaxation in the clitoris. However, in the vagina, this pathway plays only a partial role, as demonstrated by Ziessen et al. These investigators showed that in the rat and rabbit vaginal wall, NANC relaxations were partly mediated by nitric oxide. The remaining part was neurogenic since it could be inhibited by tetrodotoxin. This non-nitrergic NANC response was not associated with any known neuropeptides or purines. Thus, the nature of the non-adrenergic, non-cholinergic neurotransmitter in the vagina remains elusive.

We have carried out preliminary experiments in organ bath chambers to assess clitoral and vaginal tissue responses to: a) electric field stimulation b) alpha-adrenergic agonists c) NO donors and d) VIP. Electrical field stimulation resulted in a biphasic (contraction/relaxation) response in clitoral and vaginal tissue strips. Bretylium (inhibitor of NE release) abolished the contractile response induced by EFS in both tissues. Exogenously added norepinephrine caused a dose-dependent contraction in vaginal and clitoral tissues. These observations suggest that adrenergic nerves mediate the contractile response. Sodium nitroprusside and papaverine caused dose dependent relaxation of vaginal and clitoral strips pre-contracted with norepinephrine. Alpha-1 (prazosin and tamsulosin) and alpha-2 (delequamine) selective antagonists inhibited contraction of vaginal tissue strips to exogenous norepinephrine. Further studies using specific molecular probes and RNase protection assays have detected mRNA for both alpha 1A and alpha 2A adrenergic receptors in human clitoral and vaginal smooth muscle cells (Traish et al., unpublished data). Thus, vaginal and clitoral smooth muscle contraction is the result of activation of alpha-adrenergic receptors by norepinephrine released from adrenergic nerves. It remains to be determined if other vasoconstrictor agents, such as endothelin, neuropeptide Y (NPY), angiotensin or eicosanoids may play a role in regulating smooth muscle tone in these tissues.

Giraldi et al., have characterized the effect of experimental diabetes on neurotransmission in rat vagina. It was suggested that diabetes interferes with adrenergic-, cholinergic- and NANC-neurotransmitter mechanisms in the smooth muscle of the rat vagina.8 The changes in the nitrergic neurotransmission were attributed to reduction in NOS-activity, but may also be attributed to inhibition of various reactions in the L-arginine/NO/guanylate cyclase/cGMP system.

We investigated the effects of hormonal manipulations on vaginal smooth muscle contractility in response to electrical field stimulation (EFS) and vasoactive substances. Ovariectomy reduced norepinephrine-induced contractile response and treatment with estradiol or testosterone normalized the contractile response. Ovariectomy also attenuated EFS-induced relaxation response and treatment with testosterone facilitated EFS-induced smooth muscle relaxation. Moreover, VIP induced a dose-dependent relaxation response that was attenuated in tissues from ovariectomized animals or in animals treated with estradiol. In contrast, VIP-induced relaxation was facilitated in tissues from ovariectomized animals treated with testosterone. These observations suggest that testosterone and estradiol produce distinct physiological responses in vaginal smooth muscle and that androgens facilitate vaginal smooth muscle relaxation.

In summary, the data reported from several laboratories suggest that NO is a key pathway in mediating clitoral smooth muscle relaxation. However, in the vagina, NO appears to play only a partial role in mediating smooth muscle relaxation. VIP also induces vaginal smooth muscle relaxation yet its exact functional role remains to be determined. Functional alpha-adrenergic receptors are expressed in the vagina and mediate norepinephrine induced contraction. Hyperglycemia affects vaginal smooth muscle response to neurotransmission affecting multiple physiological pathways. We have observed that androgens but not estrogens at pharmacological doses enhanced smooth muscle relaxation. Further studies with hormonal manipulations at physiological doses are necessary to establish the role of hormones on vaginal smooth muscle relaxation.

Studies in cell culture:

Park et al. and Traish et al.recently sub-cultured and characterized human and rabbit vaginal and clitoral smooth muscle cells and investigated the synthesis of second messenger cyclic nucleotides in response to vasodilators and determined the activity and kinetics of phosphodiesterase (PDE) type 5.32,37 Cultured vaginal and clitoral cells exhibited growth characteristics typical of smooth muscle cells and immunostained positively with antibodies against alpha smooth muscle actin. The cells retained functional prostaglandin E, VIP and b adrenergic receptors as demonstrated by increased intracellular cAMP synthesis in response to PGE1, VIP or isoproterenol. The response to these vasoactive substances was augmented with forskolin, suggesting stabilization of G-protein activated adenylyl cyclases. Treatment with the nitric oxide donor, sodium nitroprusside, in the presence of sildenafil, a PDE type 5 inhibitor, enhanced intracellular cGMP synthesis and accumulation. Incubation of rabbit vaginal tissue with sildenafil, sodium nitroprusside and PGE1 or forskolin produced a marked increase in intracellular cGMP. These observations were similar to those obtained with cultured cells and suggest that sub-cultured cells retained functional characteristics exhibited in intact tissue. The cells retained phosphodiesterase type 5 expression as shown by specific cGMP hydrolytic activity. Sildenafil and zaprinast inhibited cGMP hydrolysis competitively and bound with high affinity (inhibition constants Ki= 7 and 250 nM, respectively). These observations suggest that cultured human and rabbit vaginal smooth muscle cells retained their metabolic functional integrity and this experimental system should prove useful in investigating the signaling pathways that modulate vaginal smooth muscle tone.

Investigation of the distribution of NOS in the rat vagina in response to ovariectomy and estrogen replacement was recently performed using immunohistochemical analyses with n-NOS and e-NOS antibodies. In intact cycling animals, e-NOS and n-NOS expression were found to be highest during proestrous and lowest during metestrous while in ovariectomized animals n-NOS and e-NOS expression declined substantially. Estrogen replacement resulted in significant increase in e-NOS and n-NOS expression, when compared with NOS in intact animals. It was suggested that estrogen plays a critical role in regulating vaginal NOS expression of the rat vagina and that NO may modulate both vaginal blood supply and vaginal smooth musculature. More recent studies have shown the opposite observation. They found that rabbit vaginal NOS activity was considerably reduced by treatment with estradiol or estradiol and progesterone. They also noted that progesterone treatment alone up-regulated vaginal NOS. NOS-containing nerves could be demonstrated in vagina by immunohistochemistry. Vaginal smooth muscle responded with relaxation after EFS, which was inhibited by NG-nitro-L-arginine. A tissue specific role for NOS in vagina was suggested based on NO-dependent response of vaginal smooth muscle, expression of relatively high NOS, which is down-regulation by estradiol and up-regulation by progesterone.

This discrepancy in NOS regulation by estrogen in these studies may be due to species differences or to methods for assessment of NOS expression and activity. We have used both immunochemical (Western blots) and enzymatic activity assays to determine regulation of vaginal NOS in the rabbit model. In this study we demonstrated that nitric oxide synthase was predominantly expressed in the proximal vagina. The reason for this tissue distribution is yet to be determined. We further observed that ovariectomy enhanced NOS activity in the proximal vagina suggesting specific regulation of NOS by sex steroid hormones. Treatment of ovariectomized animals with estrogens resulted in decreased expression and activity of NOS in vaginal tissue, consistent with the research by Al-Hijji et al. In contrast, treatment of ovariectomized animals with androgens resulted in increased NOS expression and activity. These observations suggest that NOS in vaginal tissue is regulated by androgens and estrogens in an opposite manner.


The psychosocial and relationship aspects of female sexuality have been extensively investigated. However, studies concerning the anatomy, physiology and pathophysiology of female sexual function and dysfunction are limited. The paucity of biological data may be attributed to lack of reliable experimental models and tools for the investigation of female sexual function, and to limited funding, which is critical for the development of experimental approaches.
Research efforts by a number of investigators in different laboratories are establishing experimental models needed for the investigation of the physiological mechanisms involved in the genital arousal response of sexual function. These experimental models have permitted assessment of genital hemodynamics, vaginal lubrication, regulation of genital smooth muscle contractility and signaling pathways, providing preliminary information on the role of neurotransmitters and sex steroid hormones in sexual function. Further research is needed to define the neurotransmitters responsible for vaginal smooth muscle relaxation, the role of sex steroid hormones and their receptors in modulating genital hemodynamics, smooth muscle contractility and neurotransmitter receptor expression. Finally, a global and integral understanding of the biologic aspects of female sexual function requires investigation of the vascular, neurological (central and peripheral) and structural components of this extremely complex physiological process.


By the time a person is sitting in front of a neurologist and being told that they have Parkinson’s disease, they will have lost half the dopamine producing cells in an area of the brain called the midbrain.

On this page we will explain what dopamine is and how it relates to Parkinson’s disease.

Dopamine being released by one cell and binding to another. Source: Truelibido

Dopamine is a chemical is the brain that plays a role in many basic functions of the brain, such as motor co-ordination, reward, and memory. It works as a signalling molecule – a way for brain cells to communicate with each other. Dopamine is released from brain cells that produce this chemical (not all brain cells do this), and it binds to target cells, initiating biological process within those cells.

It does this via five different receptors – that is to say, dopamine is released from one cell and can bind to one of five different receptors on the target cell (depending on which receptor is present). The receptor is analogous to a lock and dopamine is the key. When dopamine binds to a particular receptor it will allow something to happen in that cell. And this is how information from a dopamine neuron is passed or transmitted on to another cell. Hence the reason, dopamine is referred to as a neurotransmitter.

The five different dopamine receptors can be grouped into two populations, based on the action initiated by the binding of dopamine. Dopamine receptors 1 and 5 are considered D1-like receptors, while Dopamine receptors 2,3 and 4 are considered D2-like receptors. Through these various receptors, dopamine is influential in many different activities of the brain, especially motor co-ordination.

Dopamine in motor co-ordination

When you are planning to move your arm or leg, the process required for actually initiating that action begins in an area of the brain called the motor cortex. It runs across the very top of your brain – from just above your temple to the top of your skull. And the motor cortex is divided into regions that control specific body parts (for example the legs are controlled by the very top of the motor cortex, while mouth and tongue are controlled by regions closer to you temples.

While the idea of initiating a movement starts in the motor cortex, your ability to actually move is largely controlled by the activity in a specific group of brain regions, collectively known as the ‘Basal ganglia‘.

The location of the basal ganglia structures (blue) in the human brain. Source: iKnowledge

The basal ganglia receives signals from the overlying motor cortex, processes that information before sending the signal on down the spinal cord to the muscles that are going to perform the movement.

Think of the motor cortex as excited kids wanting to do something and the basal ganglia as the parental figures deciding if this action is a good idea.

And the most important participant in that basal ganglia ‘regulation’ of movement is a structure called the thalamus.

A brainscan illustrating the location of the thalamus in the human brain. Source: Wikipedia

The thalamus is a structure deep inside the brain that acts like the central control unit of the brain. Everything coming into the brain from the spinal cord, passes through the thalamus. And everything leaving the brain, passes through the thalamus. It is aware of most everything that is going on and it plays an important role in the regulation of movement.

The direct/indirect pathways

The processing of movement in the basal ganglia involves a direct pathway and an indirect pathway. In simple terms, the direct pathway encourages movement, while the indirect pathway does the opposite (inhibits it). The two pathways work together like a carefully choreographed symphony.

The motor features of Parkinson’s disease (slowness of movement and resting tremor) are associated with a breakdown in the processing of those two pathways, which results in a stronger signal coming from the indirect pathway – thus inhibiting/slowing movement.

Excitatory signals (green) and inhibitory signals (red) in the basal ganglia, in both a normal brain and one with Parkinson’s disease. Source: Animal Physiology 3rd Edition

Both the direct and indirect pathways finish in the thalamus, but their effects on the thalamus are very different. The direct pathway leaves the thalamus excited and active, while the indirect pathway causes the thalamus to be inhibited.

The thalamus will receive signals from the two pathways and then decide – based on those signals – whether to send an excitatory or inhibitory message to the cortex, telling it what to do (‘get excited and move’ or ‘don’t get excited and do not move’, respectively).

Where does dopamine come into the picture?

In Parkinson’s disease, we often talk about the loss of the dopamine neurons in the midbrain as a cardinal feature of the disease. When people are diagnosed with Parkinson’s disease, they have usually lost approximately 50-60% of the dopamine neurons in an area of the brain called the substantia nigra.

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

The midbrain is – as the label suggests – in the middle of the brain, just above the brainstem (see image below). The substantia nigra dopamine neurons reside there.

Location of the substantia nigra in the midbrain. Source: Memorylossonline

The dopamine neurons of the substantia nigra generate dopamine and release that chemical in different areas of the brain. The primary regions of that release are areas of the brain called the putamen and the Caudate nucleus. The dopamine neurons of the substantia nigra have long projections (or axons) that extend a long way across the brain to the putamen and caudate nucleus, so that dopamine can be released there.

The projections of the substantia nigra dopamine neurons. Source: MyBrainNotes

In Parkinson’s disease, these ‘axon’ extensions that project to the putamen and caudate nucleus gradually disappear as the dopamine neurons of the substantia nigra are lost. When one looks at brain sections of the putamen after the axons have been labelled with a dark staining technique, this reduction in axons is very apparent over time, especially when compared to a healthy control brain.

The putamen in Parkinson’s disease (across time). Source: Brain


Under normal circumstances the dopamine neurons release dopamine in the basal ganglia that excites the direct pathway and inhibits the indirect pathway. This acts as a kind of lubricant for movement.

With the loss of dopamine neurons in Parkinson’s disease, however, there is an increased amount of activity in the indirect pathway. As a result, the thalamus is kept inhibited. With the thalamus subdued, the overlying motor cortex has trouble getting excited, and thus the motor system is unable to work properly. And this is the reason why people with Parkinson’s disease have trouble initiating movement.

People with Parkinson’s disease will often be tested with a brain scan called a DAT-scan when they are diagnosed. This imaging technique results assesses the amount of dopamine being released in the putamen. It results in a horizontal image of the brain being presented on a computer screen with red (hot) regions that overlap with the location of the putamen in healthy individuals, indicating the normal release of dopamine. In people with Parkinson’s disease, however, there is a significant reduction in the release of dopamine (due to less dopamine neurons being present to generate dopamine), resulting in less red colouring on the computer screen image of the brain. In people with later stage Parkinson’s disease, there is even less colouring on the computer image (see image below).

Dopamine transporter (DAT) in normal (A), early Parkinson’s (B) and late stage Parkinsons’ (C) brains. Source: Lancet

SSRI antidepressants involve dopamine as well as serotonin signaling

SSRIs perform their antidepressant function by increasing the concentration of serotonin in the signaling junctions, called synapses, between neurons. This increase alleviates the deficiency of serotonin that causes depression.

As their name indicates, SSRIs prevent uptake of the serotonin after it has performed its task as a chemical messenger that enables one neuron to trigger a nerve impulse in a neighbor. SSRIs prevent this uptake by inhibiting the action of the molecular cargo carriers called transporters that recycle serotonin back to the neuronal storage sacs called vesicles.

Now, however, Fu-Ming Zhou (presently at the University of Tennessee) and colleagues at Baylor College of Medicine have revealed that SSRIs can have more complex effects on neurotransmitter traffic in the brain than just altering serotonin levels. They found that higher serotonin concentrations caused by SSRIs can "trick" transporters of another key neurotransmitter, dopamine, into retrieving serotonin into dopamine vesicles. Dopamine transporters have a low affinity for serotonin, but the higher serotonin levels result in its uptake by the dopamine transporters, found the scientists.

As a result, the normal dopamine-triggered firing from such neurons, in essence, launches two different types of neuronal ammunition, causing "cosignaling."

The researchers were led to study the role of dopamine signaling in SSRI action by previous evidence that dopamine was involved in depression and in the function of antidepressants in the brain. They studied the nature and machinery of serotonin and dopamine signaling by treating mouse brain slices with fluoxetine (Prozac) and other chemicals, and analyzing the effects on the dopamine-signaling machinery.

The relatively inefficient, slow process of "hijacking" of dopamine transporters by serotonin during SSRI treatment could explain why it takes many days of treatment before antianxiety effects are seen, suggested the researchers.

Also, they wrote that their findings may explain why treatment of children with fluoxetine can induce depressive symptoms in adulthood. The researchers wrote that, since serotonin plays a vital role in neuronal development, disruption by fluoxetine of the normal serotonin levels during development could be responsible for such behavioral abnormalities.

They also theorized that such corelease of dopamine and serotonin caused by SSRIs could explain cases of a "potentially life-threatening serotonin syndrome" caused by such situations as dietary overload of serotonin precursors in people taking SSRIs.

The researchers wrote that the relationship between dopamine and serotonin signaling "is likely vital for normal behavior and for the pathology that can be treated with SSRIs." The brain area involved, the ventral striatum, "is critically involved in the neuronal processes of reward and emotional functions." Thus, they wrote, enhanced participation of the striatal dopamine system in serotonin signaling during treatment with SSRIs "may contribute to the therapeutic efficacy of SSRIs."

Fu-Ming Zhou, Yong Liang, Ramiro Salas, Lifen Zhang, Mariella De Biasi, and John A. Dani: "Corelease of Dopamine and Serotonin from Striatal Dopamine Terminals"

Publishing in Neuron, Volume 46, Number 1, April 7, 2005, pages 65-74. http://www. neuron. org

The researchers include Fu-Ming Zhou of Baylor College of Medicine (presently at the University of Tennessee) and Yong Liang, Ramiro Salas, Lifen Zhang, Mariella De Biasi, and John A. Dani of Baylor College of Medicine. This work was supported by the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke, and grants from the National Alliance for Research on Schizophrenia and Depression (FMZ) and from the National Institutes of Health. John A. Dani consults for In Silico Biosciences to support drug discovery and analysis.

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