Can dopamine antagonists be used as dopamine upregulation?

Can dopamine antagonists be used as dopamine upregulation?

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Can dopamine antagonists such as Thorazine that are used to treat schizophrenia and bipolar be used to upregulate dopamine in the long term in healthy (non schizophrenic or bipolar) users to get a similar effect as a stimulant high without inducing neurotoxicity? Due to tolerance buildup of the dopamine blocker, my assumption is that it should result in dopamine upregulation when dopamine antagonist use is stopped.

As an example, in extremely high doses of methamphetamine, meth induces temporary schizophrenia (skin picking, crank bugs, paranoia, hallucinations, etc), and extremely similar, if not exact, effects to bipolar, which are the only two neurological diseases resulted from dopamine over-production and release. Over time, tolerance to meth builds up and it stops being effective, unless it is stopped for a period of time resulting in reverse-tolerance. Can this same dopamine downregulation effect be used in dopamine antagonists as dopamine upregulation, creating the same euphoric feeling resulted from meth use or bipolar hypomania if the dopamine antagonist is taken for a period of time then stopped?

The role of dopamine in sleep regulation

A group of Spanish researchers has discovered a new function of the neurotransmitter dopamine in controlling sleep regulation. Dopamine acts in the pineal gland, which is central to dictating the 'circadian rhythm' in humans--the series of biological processes that enables brain activity to adapt to the time of the day (that is, light and dark cycles). The researchers, from the CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), dependant on the Spanish Ministry of Economy and Competitiveness through the Carlos III Health Institute, and from the Faculty of Biology of the University of Barcelona, publish their findings 19 June in the open-access journal PLoS Biology.

All animals respond to cycles of light and dark with various patterns in sleeping, feeding, body temperature alterations, and other biological functions. The pineal gland translates the light signals received by the retina into a language understandable to the rest of the body, for example through the synthesis of the hormone melatonin, which is produced and released at night and which helps to regulate the body's metabolic activity during sleep.

Another hormone, norepinephrine, is involved in regulating this synthesis and release of melatonin in the pineal gland. The functions of norepinephrine are carried out via binding to its receptors in the membranes of cells. It was long believed that these norepinephrine receptors all acted independently of other proteins, but in the new study, researchers have discovered that this is not the case. In fact, the receptors collaborate with other dopamine receptors forming 'heteromers'.

When dopamine then interacts with its receptors, it inhibits the effects of norepinephrine--which means a decrease in the production and release of melatonin. Interestingly, the researchers found that these dopamine receptors only appear in the pineal gland towards the end of the night, as the dark period closes. Therefore, the researchers conclude, the formation of these heteromers is an effective mechanism to stop melatonin production when the day begins and to 'wake up' the brain.

"These results are interesting as they demonstrate a mechanism in which dopamine, normally increased at times of stimulation, can directly inhibit production and release of a molecule, melatonin, that induces drowsiness and prepares the body for sleep," explained Dr McCormick.

The discovery of this new function of dopamine could be extremely useful when designing new treatments to help mitigate circadian rhythm disturbances, such as those related to jet lag, those found among people who work at night, and in cases of sleep disorders in general which, according to the World Health Organisation, affect 40% of the world's population. Circadian rhythm disturbances can also produce alterations in body mass index, and can lead to behavioural disorders that affect 1 in 4 people at least once in their lifetime, in which melatonin levels are related.

Funding: This study was supported by grants from the Spanish Ministerio de Ciencia y Tecnología (SAF2010-18472, SAF2008-01462), funds from the Generalitat of Catalonia (2009SGR12), and NIDA intramural funds to SF. PJM is a Ramón y Cajal Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Citation: González S, Moreno-Delgado D, Moreno E, Pérez-Capote K, Franco R, et al. (2012) Circadian-Related Heteromerization of Adrenergic and Dopamine D4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland. PLoS Biol 10(6): e1001347. doi:10.1371/journal.pbio.1001347

Peter McCormick
University of Barcelona
Biochemistry and Molecular Biology
Avda. Diagonal 645
Tel: +34-934039280
[email protected]

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Porn, Addiction, and the Brain: 3 Misunderstandings Corrected by a Neurosurgeon

In recent years, neuroscience discoveries about the reward system and human sexuality have shed new light on both problematic and healthy sexual behavior. As can be expected with any new paradigm, however, some doubtful neuroscience claims have also appeared in the media. As a neurosurgeon and the author of several papers on problematic sexual behavior and the appetite/reward mechanisms of the brain, I sometimes help to correct these misunderstandings.

Here are a few examples that might be of interest to our readers.

ERROR #1 – “Dopamine does not underlie addiction”

Dopamine plays many benign roles in our physiology, such as facilitating movement and choices. However, all experts in the fields of addiction or neuroscience acknowledge the central role of dopamine in addiction.

In fact, addiction cannot develop without high, but brief, bursts of dopamine in response to an addictive substance or activity. As experts Volkow and Koob explained in a recent paper, these dopamine surges elicit reward signals at a cell receptor level, which then trigger so-called Pavlovian learning. The molecular mechanisms that facilitate this process appear similar for all forms of learning and memory. Repeated experiences of reward (for example, consuming porn) become associated with the stimuli in the consumer’s environment that precede them.

Interestingly, after repeated exposure to the same reward (in this example, porn), dopamine cells tend to fire more strongly in anticipation of consuming rather than in conjunction with actual consuming—although internet porn’s endless novelty means that using and anticipation are interwoven, in contrast with, say, a cocaine habit. As any addiction develops, cues and triggers, such as hearing a porn star’s name, time alone, or a mental state associated with past use (boredom, rejection, fatigue, etc.) can elicit conditioned, sudden surges of dopamine release. These surges then trigger cravings to use or even binge. Such conditioned responses may become deeply ingrained and can bring on strong cravings even long after someone quits using porn.

Watch these experts talk about porn’s effects on the consumer’s brain:

Although dopamine is sometimes thought of as a “pleasure molecule,” this is technically inaccurate. Dopamine drives seeking and searching for reward—the anticipation, the wanting. In some unfortunate people, this seeking deepens into the disorder known as addiction. The consumer’s desperate search for satiety (that eventually often proves fleeting or unattainable) progresses to the point of marked distress or significant impairment in personal, family, social, educational, occupational, or other important areas of functioning.

However, addiction is now being defined not solely by this behavioral definition. It is also increasingly defined as a form of disordered reward learning. As Kauer and Malenka said, “addiction represents a pathological but powerful form of learning and memory.” This is why the American Society of Addiction Medicine (ASAM) redefined addiction as including both substances and behaviors. ASAM’s position is a recognition of the brain’s central role in driving what Marc Lewis called a “rut, a line of footprints in the neural flesh, which harden and become indelible.” (Lewis, Memoirs of an Addicted Brain, 2011).

ERROR #2 – “At a brain level, sexual activity is no different from playing with puppies”

While playing with puppies might activate the reward system (unless you are a cat person), such activation doesn’t support the claim that all natural rewards are neurological equivalents. First, sexual arousal and orgasm induce far higher levels of dopamine and endogenous opioids than any other natural reward. Rat studies reveal that the dopamine levels occurring with sexual arousal equal those induced by the administration of morphine or nicotine.

Sexual arousal is also unique because it activates precisely the same reward system nerve cells as do addictive drugs. In contrast, there’s only a small percentage of nerve-cell activation overlap between addictive drugs and natural rewards such as food or water. Not surprisingly, researchers have also established that the natural reward of food does not cause the same persistent change in synaptic plasticity as sexual activity (Chen et al., 2008).

However, this is not to say that gustatory reward cannot become addictive or disruptive to individuals and precipitate public health concerns, or cause brain changes in reward circuits. Any physician knows that obesity is a tremendous health concern consuming billions in medical costs, and dopamine receptor depletion in the brain’s reward center returns to more normal density with weight loss after gastric banding surgery. Also, the DNA transcripts which produce reward system proteins important in the craving states that are evoked with salt depletion/repletion are identical to those produced with drug craving (Leidke et al., 2011, PNAS). A National Geographic article on this paper said drugs “hijack” these natural reward pathways, and this is true for all addiction, whether to poker, porn, or popcorn.

Addictive drugs not only hijack the precise nerve cells activated during sexual arousal, they co-opt the same learning mechanisms that evolved to make us desire sexual activity. Activation of the same nerve cells that make sexual arousal so compelling helps explain why meth, cocaine, and heroin can be so addictive. Also, both sex and drug use can induce transcription factor DeltaFosB, resulting in neuroplastic alterations that are nearly identical for both sexual conditioning and chronic use of drugs.

While far too complex to elucidate in detail, multiple temporary neurological and hormonal changes occur with an orgasm that do not occur with any other natural rewards. These include decreased brain androgen receptors, increased estrogen receptors, increased hypothalamic enkephalins, and increased prolactin. For example, ejaculation mimics the effects of chronic heroin administration on reward system nerve cells (the ventral tegmental area, or VTA). Specifically, ejaculation temporarily shrinks the same dopamine-producing nerve cells that shrink with chronic heroin use, leading to temporary down-regulation of dopamine in the reward center (nucleus accumbens).

A 2000 fMRI study compared brain activation using two different natural rewards, one of which was porn. Cocaine addicts and healthy controls viewed films of: 1) explicit sexual content, 2) outdoor nature scenes, and 3) individuals smoking crack cocaine. The results: cocaine addicts had nearly identical brain activation patterns when viewing porn and viewing cues related to their addiction. (Incidentally, both cocaine addicts and healthy controls had the same brain activation patterns for porn.) However, for both the addicts and controls, brain activation patterns when viewing nature scenes were completely different from the patterns when viewing for porn.

In short, there are multiple biological reasons we experience an orgasm differently from playing with puppies or viewing sunsets. Millions of adolescent boys and increasingly girls are not just watching puppies on the Internet, and MindGeek knows that to make billions in ad revenues you name a site “Pornhub,” not “PuppyHub!”

ERROR #3 – “The brain effects of today’s porn are no different than static porn of the past”

This claim implies that all porn is equally harmless. However, as the recent paper Park et al., 2016 points out, research demonstrates that video porn is significantly more sexually arousing than other forms of porn. (I know of no research on VR porn yet.) In addition, the ability to self-select material makes internet porn more arousing than pre-selected collections. Today’s porn consumer can also maintain or heighten sexual arousal by clicking to a novel scene, new video or fresh genre. Novel sexual visuals trigger greater arousal, faster ejaculation, and more semen and erection activity than familiar material.

Thus today’s digital porn, with its limitless novelty, potent delivery (hi-def video or virtual), and the ease with which the consumer can escalate to more extreme material, appears to constitute a “supranormal stimulus.” This phrase, coined by Nobel laureate Nikolaas Tinbergen, refers to an exaggerated imitation of a stimulus that a species has evolved to pursue due to its evolutionary salience, but which can evoke more of a neurochemical response (dopamine) than the stimulus it imitates.

Tinbergen originally found that birds, butterflies, and other animals could be duped into preferring artificial substitutes designed specifically to appear more attractive than the animal’s normal eggs and mates. Just as Tinbergen’s and Magnus’s ‘butterfly porn’ successfully competed for male attention at the expense of real females (Magnus, 1958 Tinbergen, 1951), so today’s porn is unique in its power to compete for consumers’ attention at the expense of real partners.

The Brain: The Primary Sex Organ

The three errors discussed above are typical of commentators anxious to ignore the brain’s central role in human volition, behavior, and emotion. One sexologist wrote, “There is brain science and neuroscience, but none of that applies to sexual science.” On the contrary, those educated in biology will increasingly understand the brain’s central role in every human activity. After all, both sexologists and neuroscientists alike should understand that the genitals take their marching orders from the brain, the primary sex organ.

About the author

Donald L. Hilton Jr, MD, FACS, FAANS is an adjunct associate professor of neurosurgery at the University of Texas Health Science Center at San Antonio, the director of the spine fellowship and the director of neurosurgical training at the Methodist Hospital rotation. He has authored numerous articles and speaks nationally and internationally on the neurobiology of porn consumption.

Dopamine Fasting Probably Doesn't Work, Try This Instead

A behavioral brain fad called “dopamine fasting” (#dopaminefasting) has been floating around the internet for the past year. The idea is that by restricting most of your pleasurable daily activities — from social media, to watching videos, gaming, talking, or even eating — you can “reset” your brain. The idea also plays into people’s simplistic beliefs about how the brain works.

Can you have conscious control over discrete dopamine levels in your brain? Let’s delve into the science behind one of your brain’s most important neurotransmitters, dopamine.

During a “dopamine fast,” you’re supposed to abstain from the kinds of things you normally enjoy doing, such as alcohol, sex, drugs, gaming, talking to others, going online and, in some extremes, pleasurable eating. The idea is to “reset” your neurochemical system by de-stimulating it.

If it sounds a bit out there, you’re not alone in your skepticism. It should also be of no surprise to learn that no scientists were involved in the creation of this fad. Instead, it was apparently created by a “life coach” named Richard in November 2018 on his YouTube channel.

The trend got an unfortunate boost of legitimacy from a psychologist earlier this year, according to this Vice article on the topic:

A viral article posted on LinkedIn by University of California San Francisco assistant clinical psychiatry professor and “executive psychologist” Cameron Sepah put dopamine fasting back on the radar in early August. The post linked the practice to Silicon Valley, dubbing it the “hot trend” akin to intermittent fasting.

“It’s unclear what the long-term implications of this overstimulation are on our brains, but in my private practice working with executive clients, I have observed that this interferes with our ability to sustain attention, regulate our emotions in non-avoidant ways, and enjoy simple tasks that seem boring by comparison,” Sepah wrote. “We may be getting too much of a good thing, especially when dopamine reinforces behaviors that are out of line with our values.” He also links dopamine release to addiction: “Even behaviors such as gaming or gambling can become problematic and addictive through the reinforcement that dopamine brings.” MEL spoke to Sepah, who admitted the term “dopamine fasting” was more about provoking a reaction than maintaining accuracy.

Indeed. It’s not clear a single day (or even two) of “activity fasting” from over-stimulation (what defines over-stimulation? who defines over-stimulation, the patient or some arbitrary metric?) would be of much use to most people.

To better understand how neurotransmitters work, I spoke with Prof. Kim Hellemans, a neuroscience researcher at Carleton University in Canada. Along with Prof. Jim Davies, she hosts an awesome podcast called Minding the Brain.

“For starters, it’s important to note that most neurotransmitters are synthesized from precursor amino acids that are obtained from our diet […] and certain food items contain these amino acids in varying abundance,” Prof. Hellemans said.

“However, these amino acids compete with other large, neutral amino acids to cross the blood brain barrier. Which is a fancy way of saying that you’d need to eat a lot of any particular food item to significantly increase (or decrease) the biosynthesis of a given neurotransmitter. ”

“Dopamine is involved in much more than pleasure… it’s involved in both [eating behaviors] and stress responses,” Prof. Hellemans noted. “It is a signal that seems to be released when the organism needs to ‘pay attention’ and learn about the signals in the environment that are motivationally relevant.”

For example, “here is a hamburger, [so I] must remember its sight/smell/taste of this so next time I am hungry, I can plan to eat this tasty food item.” Or, as another example, “here is a bear, [so I] must remember this environment so I can avoid it in the future.”

“Dopamine is also critically involved in movement,” said Hellemans, as we’ve seen that the “loss of dopamine-projecting fibers is implicated in Parkinson’s disease.”

Walter Piper, a neuroscience researcher at New York University, agrees with Prof. Hellemans that people can indeed exert some control over dopamine levels. “A person can exert limited control over their dopamine or norepinephrine levels. […] Exercise and many other elements of a healthy lifestyle can boost dopamine activity in sustainable ways,” he noted. In addition to eating, Hellemans also noted that significant changes in our gut microbiota can impact certain neurotransmitter levels.

“Think of the receptors as a signal receiver and changes in the dopamine as a detected signal,” Piper suggests.

“In a healthy dopamine system, receptors would be plentiful, and dopamine would exhibit a pattern: moderate levels at rest, heightened levels when confronted by a cue of motivational significance, and quick, strong pulses when an unexpected reward is obtained, or rapid declines when an expected reward is withheld.”

But the dopamine system is dynamic in nature, meaning that it’s always changing and adapting according to what our body needs. “It will respond to the levels of stimulation an individual is exposed to,” said Hellemans, “but neurotransmitters are synthesized on demand and stored in vesicles (basically, little packages) inside the cell, ready for release.”

“If the cells are firing, they are released, and more will be synthesized in preparation. If the cells are not firing, the dopamine will still be there, waiting to be released.” Trying to “dopamine fast,” in short, would not likely have much meaningful impact on dopamine levels.

But even if dopamine were something that you could exert discrete control over, how would you measure dopamine levels in your body?

Prof. Hellemans tells me that dopamine measurements in humans are extremely difficult. “You can measure indirectly via looking at metabolites (breakdown products of neurotransmitters) in the cerebrospinal fluid, but that is extremely invasive and is only an indirect and correlative measure.” Piper suggests specialized PET scans may one day help us do so, too.

But the fact is, there’s been no research yet conducted on humans measuring the impact of “dopamine fasting.” Our understanding of dopamine comes mostly from human animal models, according to Prof. Hellemans, and very few studies have looked at its use in humans. What research we do have suggests the dopamine system is far more complex than most people realize for better understanding addictive eating, sex, gambling, and drugs (Volkow, Wise & Baler, 2017).

In people struggling with an addiction, Piper notes, “the turbulence of dopamine swings related to addiction effectively drowns out signals from other realms of life.” To retrain an addicted person’s dopamine system takes time — usually many months of staying away from the addicted drug or stimuli — but it can be done.

In people who don’t struggle with an addiction, how much would a day’s worth of fasting or staying away from stimuli actually result in meaningful change in the brain’s dopamine motive system? It’s unlikely to provide much of a benefit.

Antagonists important in ANS

this section, we will discuss antagonists that are important in the autonomic
nervous system.

Muscarinic Antagonists

The muscarinic receptor antagonists bind to acetylcholine receptors and prevent their activation. As acetylcholine is the main neurotransmitter of the parasympathetic system, these antagonists can successfully block the entire parasympathetic activation.

are three types of muscarinic receptors

  1. M1 receptors, excitatory receptors present in brain
  2. M2 receptors, inhibitory receptors present in heart
  3. M3 receptors, excitatory receptors present inn smooth muscles, glands, eyes, etc.

these receptors are G-protein coupled receptors. M1 and M3 are Gq-coupled
while M2 are Gi-coupled receptors.

the muscarinic antagonists are non-specific in nature and block all types of

antagonists find a number of uses. These include the following

  • Management of AChE inhibitors overdose
  • Ophthalmology (dilation of pupil)
  • Asthma and COPD
  • Motion sickness
  • Overreactive bladder
  • Anti-spasmodic
  • Antidiarrheal


drugs in this category include atropine, benztropine, ipratropium, scopolamine,

Nicotinic Receptor Antagonists

antagonists block the activation of nicotinic receptors present in ganglia and
skeletal muscle. Thus, they are further classified into two types

Ganglionic blockers

These antagonists block the nicotinic receptors present in ganglia. Thus, they are able to block sympathetic as well as parasympathetic firing. It is because the ganglia of both these system have nicotinic receptors.

They reduce the predominant autonomic tone. In the case of arterioles, venules and sweat glands, they block the sympathetic tone while in other organs, they block the parasympathetic tone.

important ganglionic blockers include hexamethonium and mecamylamine.

Neuromuscular blocking drugs

They block the nicotinic receptors present at neuromuscular junction. They are used as skeletal muscle relaxants. These include tubocurarine, atracurium, etc.

Alpha Receptor Antagonists

drugs block the activation of alpha receptors.

are further classified depending on the type of alpha receptors they block.

Alpha-1 blockers

block the alpha-1 receptors present in arteries, venules, eyes, bladder, etc.
these include prazosin, tamsulosin, etc.

  • Hypertension
  • Urinary retention
  • Dilation of eye
  • Cardiovascular disorders

Alpha-2 blockers

block the alpha-2 receptors present in the presynaptic nerve terminal. These
include drugs like methyl-dopa and clonidine.

are used in hypertension, especially for the management of hypertension in

Beta Receptor Antagonists

block the beta-2 receptors. They are of two types

  1. Cardiocelective, they block only beta-1 receptors present in the heart.
  2. Non-cardioselective, they are non-selective block both beta-1 and beta 2 receptors.

drugs include esmolol, atenolol, propranolol, etc.

are used in angina, myocardial infarction, cardiac failure, asthma etc.


An antagonist is a drug or ligand that tends to stop or impede a biological reaction. They produce effects opposite to that of the agonist.

are of different types depending on their mechanism of action.

  • Physical antagonists
  • Chemical antagonists
  • Physiological antagonists
  • Pharmacological antagonists
  • Allosteric antagonists

inverse agonist is a special type of antagonist that decreases the intrinsic
activity of a receptor.

find important applications in the CNS as well as the ANS.

important CNS antagonists include dopamine antagonists and serotonin

important ANS antagonists include muscarinic antagonists, nicotinic
antagonists, alpha-blockers and beta-blockers.

Author information


The Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Minh-Thanh T. Nguyen, Shruti Vemaraju, Gowri Nayak, Yoshinobu Odaka, Nuria Alonzo, Uyen Tran, Brian A. Upton & Richard A. Lang

Center for Chronobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Minh-Thanh T. Nguyen, Shruti Vemaraju, Gowri Nayak, Yoshinobu Odaka, Brian A. Upton & Richard A. Lang

Department of Ophthalmology, University of Washington Medical School, Seattle, WA, USA

Ethan D. Buhr & Russell N. Van Gelder

Clinical Engineering, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Pathology, University of Washington Medical School, Seattle, WA, USA

Martin Darvas & Russell N. Van Gelder

Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic

Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Rashmi S. Hegde & Richard A. Lang

Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA

Pharmacology, Emory University School of Medicine, Atlanta, GA, USA

Biological Structure, University of Washington Medical School, Seattle, WA, USA

Department of Ophthalmology, University of Cincinnati, College of Medicine, Cincinnati, OH, USA

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M.-T.T.N., S.V., G.N., Y.O., E.D.B., B.A.U., N.A., S.R. and U.T. performed the experimental analysis. M.B. designed and built the required lighting systems. M.D. and Z.K. provided essential tools. M.-T.T.N., S.V., G.N., Y.O., E.D.B., S.R., R.S.H., P.M.I. and R.N.V.G. designed the experiments and provided coordinating leadership within the collaborative group. M.-T.T.N., S.V., G.N., E.D.B., P.M.I., R.N.V.G. and R.A.L. wrote the paper. R.A.L. designed the experimental analysis and provided overall project leadership.

Corresponding author

Why can certain dopamine receptors upregulate in an irreversible manner?

Dopamine is a neurotransmitter important for movement, motivation, concentration and cognition.

It has been long known that antipsychotics can induce Tardive Dyskinesia (TD) through upregulation of dopamine receptors. TD is mainly characterized by involuntarily muscle contractions (dopamine hypersensitivity in the substantia niagra), but also with sleep problems and effects on cognition (dopamine hypersensitivity in other areas of the brain).

TD is, in most cases, a permanent illness which cannot be treated at all. From this reason, it seems that the dopamine receptors upregulated by the antipsychotic medication the patient has taken are permanently upregulated. The sensitivity to dopamine seems to permanently increase with every dose of a dopamine antagonist.

Why is it permanent? Caffeine is an adenosine receptor antagonist, and it upregulates adenosine receptors as a result. But this is not permanent. The adenosine system is completely normalized after a few months of abstaining from Caffeine (or a few weeks, depending on how much it was upregulated).

Opioid antagonists upregulate opioid receptors and thus increase sensitivity to endorphins, but this is not permanent as well. It's a temporary change.

Dopamine antagonists seem to upregulate dopamine receptors PERMANENTLY. Why are most of the dopamine receptors upregulated by dopamine antagonists never downregulate?

TLDR: Dopamine antagonists cause a permanent upregulation of certain dopamine receptors, which do not downregulate even after years of abstaining. Why can dopamine sensitivity permanently increase, while other systems cannot be permanently sensitized?


The hypothesis that dopamine signalling is altered in schizophrenia is supported by animal studies, post-mortem research, and the clinical effects of drugs that either block or accentuate dopaminergic neurotransmission. In addition, over the past 25 years, substantial evidence has accumulated from PET studies that there is increased dopamine synthesis and release capacity in schizophrenia, that is greatest within the dorsal striatum.

Genetic findings do not provide strong support for the idea that dopaminergic dysregulation is a primary abnormality. Rather, it appears that the dopaminergic dysfunction is more likely to develop downstream of abnormalities in other systems, including the glutamatergic system. It also appears that environmental factors may play a significant role in the development of dopaminergic dysregulation. Dopamine antagonists remain the mainstay for pharmacological treatment of schizophrenia, but there is increasing evidence that these are not effective for all patients.

Evidence for glutamate playing a role in the pathophysiology of schizophrenia initially came from the psychotomimetic effects of NMDA antagonists. While preclinical and post-mortem findings are consistent with this hypothesis, there is limited support from imaging studies. However, in contrast to dopamine, recent genetic findings do provide support for the view that glutamatergic abnormalities may play a major role in schizophrenia pathophysiology. However, progress is hampered by the challenges involved in precisely characterizing the system in vivo, and, while a wide range of glutamate modulating agents have been investigated, none have clear clinical efficacy.

Despite the limitations described, as regards both treatment efficacy and direct evidence for dysfunction, the dopamine and glutamate hypotheses of schizophrenia remain influential and relevant. This is not least because, as recent data demonstrate, they possess the flexibility to accommodate new findings, and to provide ongoing potential avenues for the development of novel treatments.

New model explains role of dopamine in immune regulation

Dopamine is a neurotransmitter that is associated with emotions, movement, and the brain's pleasure and reward system. In the current issue of Advances in Neuroimmune Biology, investigators provide a broad overview of the direct and indirect role of dopamine in modulating the immune system and discuss how recent research has opened up new possibilities for treating diseases such as Parkinson's and Alzheimer's disease, schizophrenia, multiple sclerosis or even the autoimmune disorders.

Dopamine can be synthesized not only in neurons, but also in immune cells which orchestrate the body's response to infection or malignancy. "Data strongly supports the theory that an autocrine/paracrine regulatory loop exists in lymphocytes, where dopamine produced and released by the cells then acts on its own receptors, and can have an influence on its own function," explains lead investigator György M. Nagy, PhD, DSc, of the Department of Human Morphology, Cellular and Molecular Neuroendocrine Research Laboratory, Hungarian Academy of Sciences, and Semmelweis University, Budapest, Hungary.

Elements of dopamine signaling and metabolites can also serve as a communication interface between the central nervous system and immune system, and that communication can work in both directions. Lymphocytes that can pass the blood brain barrier can be "educated" by locally secreted neurotransmitters, including dopamine. Then they transmit brain-driven messages to other cells of the immune system via direct or indirect pathways.

Permanent dysfunctions of either the central (CNS) or the peripheral (immune) dopaminergic system are frequently associated with immune malfunctions. Current dopamine replacement or receptor blocking therapies are based on the supposed action of these drugs at the target site, and they often only relieve disease symptoms. The mainstream in design of new therapies is to find drugs having more-and-more specific action and minimal or no potential side effects, however, there is always a risk/benefits consideration in the drug development processes. These approaches may need to be revisited with the concepts of neuroimmunomodulatory influence, and focus on the cross-talk between the immune and nervous systems," Dr. Nagy says.

Various immune mechanisms may contribute to the pathogenesis of neurological disorders. The pharmacological design of targeted drug delivery systems could carry a desired compound right to the sites of cellular pathologies, Dr. Nagy observes. "Well designed clinical trials are needed for the critical evaluation of the new theories in human therapy, either by the use of available drugs with extended immunomodulatory functions, or newly designed compounds, or the combination of both. Evaluation of clinical efficacy and data on safety of patients should provide an answer to these questions," he concludes.

In a commentary accompanying the article, Istvan Berczi and Toshihiko Katafuchi, Editors-in-Chief of Advances in Neuroimmune Biology, ask why a central nervous system mediator such as dopamine would be produced locally, when dopamine made centrally could be deployed when necessary. "We suggest that the function of paracrine/autocrine (P/A) circuits is to maintain tissue viability in emergency situations, when no other regulators are available. Local P/A circuits are the key to healing and recovery," they say.

Dr. Berczi and Prof. Katafuchi note that the science of cryobiology, which deals with the medical application of hypothermia and freezing and tissue culture techniques, which grow cells and tissues in vitro from animals and man, owe their existence to P/A circuits to preserve tissue viability and reactivity beyond clinical death or under proper culture conditions. "Clearly, P/A circuits hold the possibility of resurrection after clinical death," they conclude.

Dopamine linked to a personality trait and happiness

Researchers have long suspected that the chemistry of the brain largely influences personality and emotions. Now, a Cornell clinical psychologist has shown for the first time how the neurotransmitter dopamine affects one type of happiness, a personality trait and short-term, working memory.

"One personality trait in humans is how sensitive and responsive we are to incentives and rewards," said Richard Depue, professor of human development and family studies and director of the Laboratory of Neurobiology of Personality and Emotion at Cornell. Depue is an expert in the neurobiology of personality, emotion and temperament with particular expertise in the neurotransmitters dopamine, serotonin and norepinephrine. "Some of us are motivated by signals of incentive-reward and pursue goals, and others are not."

A major reason for the difference, he argues, is related to different levels of or responsiveness to dopamine, one of the chemical substances that transmits nerve impulses through the brain.

From a series of experiments with humans and based on what was already known from animal studies, Depue has concluded that dopamine is strongly related to the trait some researchers call extraversion, but Depue and his colleagues prefer to refer to it as "positive emotionality."

"This is the first time it has been shown in humans that a central nervous system neurotransmitter is associated strongly with an emotional trait in humans," Depue said.

The higher the level of dopamine, or the more responsive the brain is to dopamine, the more likely a person is to be sensitive to incentives and rewards. "When our dopamine system is activated, we are more positive, excited and eager to go after goals or rewards, such as food, sex, money, education or professional achievements," Depue said.

To examine this relationship, Depue first measured this trait in volunteers using personality tests. He then used Ritalin, an amphetamine widely prescribed for attention deficit disorder, to activate the dopamine system. How much the dopamine system is activated can be assessed by levels of a hormone (prolactin) in the blood and by changes in the rate of spontaneous eye blinks, which previous studies have shown to be significant.

Depue found that how reactive someone is to dopamine highly correlates with high scores on positive emotionality. People who responded easily to the drug and showed an increase in spontaneous eye blinks had a more active dopamine system in general and, Depue suspects, feel happier than others in response to incentives.

"We have strong evidence that the feelings of being elated and excited because you are moving toward achieving an important goal are biochemically based, though they can be modified by experience," Depue said.

He published his findings on dopamine's relationship to personality in the Journal of Personality and Social Psychology (1994, Vol. 67), on neurobiological factors in personality and depression in the European Journal of Personality(1995, Vol. 9) and on the neurochemistry of the incentive reward behaviors and how these behaviors are related to a universal personality trait in a forthcoming issue of Behavioral and Brain Science. In addition, he published the neurobiological implications for personality, emotion and personality disorder in the new book, Major Theories of Personality Disorder, edited by Jon Clarkin and Cornell Professor Mark Lenzenweger (Guilford Press, 1996).

By better understanding the role of dopamine in humans and how temperament types and personality traits can be driven biochemically, we can glean insight into personality and psychological disorders, Depue suggests. "There is now overwhelming evidence that 50 to 70 percent of individual variation in personality trait scores, for example, is related to genetic influence," he said.

He also points out that some research suggests that low levels of serotonin, which can result in irritability and volatile emotions, also may make people more responsive to dopamine. These people, therefore, may be more susceptible to drugs that activate the dopamine system, such as cocaine, alcohol, amphetamine and, to a lesser extent, opiates and nicotine. One theory is that different dopamine receptors in the brain may be related to different types of abuse and that people who have particularly low dopamine functioning may be more susceptible to depression and Parkinson's disease.

In related research, Depue has shown that dopamine is strongly related to how well the prefrontal cortex holds information. "To hold in short-term memory a spatial map of the environment, for example, you must have the dopamine system activated without it, you can't do this type of cognitive functioning," Depue concludes from his research in this area.

Depue now is measuring the emotional responses of volunteers to emotional film clips before and after their dopamine systems have been stimulated or with the use of a placebo.

Depue's work is supported, in part, with grants from the National Institute of Mental Health.