A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of
drug which blocks
dopamine receptors
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
by
receptor antagonism. Most
antipsychotics are dopamine antagonists, and as such they have found use in treating
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
,
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, and
stimulant psychosis.
Several other
dopamine antagonists are
antiemetics
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be ...
used in the treatment of
nausea and
vomiting.
Receptor pharmacology
Dopamine receptors are all
G protein–coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, and are divided into two classes based on which G-protein they are coupled to.
The D
1-like class of dopamine receptors is coupled to Gα
s/olf and stimulates
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
production, whereas the D
2-like class is coupled to Gα
i/o and thus inhibits adenylate cyclase production.
D1-like receptors: D1 and D5
D1-like receptor
The D1-like receptors are a subfamily of dopamine receptors that bind the endogenous neurotransmitter dopamine. The D1-like subfamily consists of two G protein–coupled receptors that are coupled to Gs and mediate excitatory neurotransmission
...
s – D
1 and D
5 are always found post-synaptically. The genes coding these receptors lack introns, so there are no splice variants.
D1 receptors
*
D1 receptors are found mainly on neurons in the
nucleus accumbens as well as
substantia nigra,
striatum,
amygdala,
frontal cortex and
olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
and retina
* Also found (in lower levels) in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
,
cerebellum and
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
* Peripherally, these receptors have been found in the renal artery, mesenteric artery, and splenic artery where activation leads to vasodilation.
In addition, D
1 receptors have been found in the kidney
D5 receptors
* Low levels of
D5 receptors have been found in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46 ...
and
cingulate cortex; as well as memory areas such as
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
,
dentate gyrus
The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute t ...
and
entorhinal cortex.
* In addition, D
5 receptors have been found in the kidney
D2-like receptors: D2, D3 and D4
D2-like receptors unlike the D
1-like class, these receptors are found pre and post-synaptically. The genes that code these receptors have introns, leading to many alternately spliced variants.
D2 receptors
*
D2 receptors are found in the striatum, substantia nigra, ventral tegmental area, hypothalamus, cortex, septum, amygdala, hippocampus, and olfactory tubercle.
* These receptors have also been found in the retina and pituitary gland.
* Peripherally, these receptors have been found in the renal, mesenteric, and splenic arteries as well as on the adrenal cortex and medulla and within the kidney.
D3 receptors
*
D3 receptors are highly expressed on neurons in islands of Calleja and nucleus accumbens shell and lowly expressed in areas such as the substantia nigra pars compacta, hippocampus, septal area, and ventral tegmental area.
* Additional studies have found these receptors peripherally in the kidney
D4 receptors
*
D4 receptors are found in amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, the thalamus, the retina and the kidney
Implications in disease
The dopaminergic system has been implicated in a variety of disorders. Parkinson's disease results from loss of dopaminergic neurons in the striatum.
Furthermore, most effective antipsychotics block D
2 receptors, suggesting a role for dopamine in schizophrenia.
Additional studies hypothesize dopamine dysregulation is involved in Huntington's disease, ADHD, Tourette's syndrome, major depression, manic depression, addiction, hypertension and kidney dysfunction.
Dopamine receptor antagonists are used for some diseases such as
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
,
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
,
nausea and
vomiting.
*
Melatonin suppresses dopamine activity as part of normal
circadian rhythm functions, although pathological imbalances have been implicated in
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
Side effects
They may include one or more of the following and last indefinitely even after cessation of the
dopamine antagonist, especially after long-term or high-dosage use:
*
Cardiovascular disease
*
Extrapyramidal symptoms
Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...
(EPS) associated with typical antipsychotics:
** Early stage – occurs at onset of treatment or following increased dose, patients recover when dose is decreased
*** Acute
dystonias
– muscle spasms and sustained abnormal postures and onset occurs within a few days; can be treated with anticholinergics
**** risk factors include age, gender and family history
***
Akathisia
Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back a ...
- pacing and restlessness and onset occurs within the first few months; can be treated with
beta blockers
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
and
benzodiazepines
***
Parkinsonism due to effects on the nigrostriatal pathway
- includes tremors, bradykinesia and muscle rigidity
**** risk factors include age and gender
** Late stage – occurs after prolonged (months-years) treatment, symptoms persist even after dose is decreased
***
Tardive dyskinesia
Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...
- includes involuntary and repetitive facial movements
**** risk factors include age, race and gender
** It is hypothesized that these effects are due to chronic blockade of the D
2 receptor
*
Hyperprolactinaemia
Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Reference ranges for common blood tests, Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum ...
due to blockade of the D
2 receptors in the anterior pituitary leading to increased prolactin release
*
Increased appetite
Polyphagia or hyperphagia is an abnormally strong, incessant sensation of hunger or desire to eat often leading to overeating. In contrast to an increase in appetite following exercise, polyphagia does not subside after eating and often leads to ...
including increased craving and binge eating that lead to weight gain
* Increased risk for
insulin resistance
*
Sexual dysfunction
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...
* Metabolic changes with increased risk of
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
and
diabetes mellitus type 2
*
Sedation
*
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fa ...
is a medical emergency caused by a decrease in
dopaminergic activity, resulting in a central D
2 receptor blockade.
Examples
First-generation antipsychotics (typical)
First generation antipsychotics are used to treat schizophrenia and are often accompanied by extrapyramidal side effects.
They inhibit dopaminergic neurotransmission in the brain by blocking about 72% of the D2 dopamine receptors.
They can also block noradrenergic, cholinergic, and histaminergic activity.
*
Benperidol binds D
2 and some
serotonin receptors.
It is absorbed very easily and has a high
first pass effect.
*
Chlorpromazine
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar di ...
binds D
3 with the highest affinity, but also binds D
1, D
2, D
4 and D
5
*
Clopenthixol
Clopenthixol (Sordinol), also known as clopentixol, is a typical antipsychotic drug of the thioxanthene class. It was introduced by Lundbeck in 1961.
Clopenthixol is a mixture of '' cis'' and ''trans'' isomers. Zuclopenthixol, the pure ''cis' ...
*
Droperidol is used as an antipsychotic and antiemetic.
*
Haloperidol
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...
binds D
2, D
3 and D
4 with the highest affinity, but also binds D
1 and D
5. Haloperidol also has a risk for
QTc prolongation.
*
Fluphenazine
Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-pote ...
binds D
2 and D
3 with the highest affinity but D
1 and D
5 as well
*
Flupentixol
Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. It was introduced in 1965 by Lundbeck. In addition to single drug pre ...
binds D
1, D
2, D
3, and D
5 and is also used as an antidepressant.
*
Fluspirilene
Fluspirilene (Redeptin, Imap, R6218) is a diphenylbutylpiperidine typical antipsychotic drug, used for the treatment of schizophrenia. It is administered intramuscularly. It was discovered at Janssen Pharmaceutica in 1963.C. Janssen, NV Res. Lab ...
*
Penfluridol
Penfluridol (Semap, Micefal, Longoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic. It was discovered at Janssen Pharmaceutica in 1968. Related to other diphenylbutylpiperidine antipsychotics, pimozide and flus ...
*
Perazine
*
Perphenazine
Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades.
Perphenazine is roughly ten times as pote ...
*
Pimozide
Pimozide (sold under the brand name Orap) is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis ...
binds D
2 and D
3 with high affinity, also binds D
4 receptors
*
Spiperone
Spiperone (Spiroperidol; brand name: Spiropitan ( JP)) is a typical antipsychotic and research chemical belonging to the butyrophenone chemical class. It is licensed for clinical use in Japan as a treatment for schizophrenia. Additionally, spip ...
binds D
2, D
3 and D
4 with high affinity; can also bind D
1
*
Sulpiride
Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic (although some texts have referred to it as a typical antipsychotic) medication of the benzamide class which is used mainly in the treatment of psychosis ...
binds D
2 and D
3 and is also used as an antidepressant.
*
Thioridazine
Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwid ...
binds D
2, D
3 and D
4 with high affinity; can also bind D
1 and D
5 at higher concentrations
Thioridazine has the highest associated risk of
QTc prolongation among neuroleptics.
Second-generation antipsychotics (atypical)
These drugs are not only dopamine antagonists at the receptor specified, but also act on
serotonin receptor 5HT
2A. (Citation inappropriate) These drugs have less extrapyramidal side effects and are less likely to affect prolactin levels when compared to typical antipsychotics.
*
Amisulpride
Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold un ...
binds D
2 and D
3 and is used as an antipsychotic, antidepressant and also treats bipolar disorder.
It treats both the positive and negative symptoms of schizophrenia.
*
Asenapine
Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder.
It was chemically derived via altering the chemical structure of the ...
binds D
2, D
3 and D
4 and is used to treat bipolar disorder and schizophrenia. Its side effects include weight gain but there is lower risk for orthostatic hypotension, hyperprolactinemia
*
Aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
binds D
2 as a partial agonist but antagonizes D
3. In addition, aripiprazole treats schizophrenia, bipolar disorder (mania), depression,
and tic disorders
*
Clozapine
Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...
binds D
1 and D
4 with the highest affinity but still binds D
2 and D
3.
Clozapine is unique because it is only prescribed when treatment with at least two other antipsychotics has failed due to its very harsh side effects.
It also requires weekly white blood cell counts to monitor potential
neutropenia.
*
Loxapine
Loxapine, sold under the brand names Loxitane and Adasuve (''inhalation'' only) among others, is an antipsychotic medication used primarily in the treatment of schizophrenia. The medicine is a member of the dibenzoxazepine class and structural ...
binds D
2, D
3 and D
4 with high affinity; can also bind D
1. Loxapine is often used to treat agitated and violent patients with neuropsychiatric disorders such as bipolar disorder and schizophrenia.
*
Nemonapride binds D
3, D
4 and D
5.
*
Olanzapine
Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is t ...
binds all receptors
and is used to treat the positive and negative symptoms of schizophrenia as well as bipolar disorder and depression.
It has been associated with significant weight gain.
*
Quetiapine
Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its ...
binds D
1, D
2 and D
3 and can bind D
4 at high concentrations.
It is used to treat the positive symptoms of schizophrenia,
bipolar disorder and depression.
Of the second generation antipsychotics, quetiapine may produce fewer parkinsonian side effects.
*
Paliperidone binds D
2, D
3 and D
4 with high affinity; can also bind D
1 and D
5.
*
Remoxipride binds D
2 receptors with relatively low affinity.
*
Risperidone
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions ...
binds D
2, D
3 and D
4 receptors.
Risperidone not only treats the positive and negative symptoms of schizophrenia
but also treats bipolar disorder.
*
Tiapride blocks D
2 and D
3 and is used as an antipsychotic.
It is also often used to treat dyskinesias, psychomotor agitations, tics, Huntington's chorea and alcohol dependence.
*
Ziprasidone blocks the D
2 receptor and is used to treat schizophrenia, depression and bipolar disorder.
There is controversy on whether Ziprasidone treats negative symptoms and it has well documented gastrointestinal side effects.
Ziprasidone can also cause
QTc prolongation.
Dopamine antagonists used to treat nausea and vomiting
*
Domperidone is a peripherally selective dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent and galactagogue.
*
Bromopride binds enteric D
2 receptors and also treats
gastroparesis
Gastroparesis (gastro- from Ancient Greek γαστήρ – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis"), also called delayed gastric emptying, is a medical disorder consisting of weak muscular contractions (peristalsis) ...
.
*
Metoclopramide
Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesoph ...
also treats gastroparesis
Antagonists used only in research settings
*
Eticlopride binds D
2 and D
3 with high affinity but also binds D4
*
Nafadotride binds D
2 and D
3
*
Raclopride binds D
2 and D
3 and can be radiolabeled and used in PET imaging to identify disease progression in Huntington's Disease
References
External links
*
{{Drugs for functional gastrointestinal disorders