Dopamine receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

Dopamine receptors are implicated in many neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders.[1] Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.

Dopamine receptor subtypes

There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 receptors are members of the D2-like family. There is also some evidence that suggests the existence of possible D6 and D7 dopamine receptors, but such receptors have not been conclusively identified.[2]

At a global level, D1 receptors have widespread expression throughout the brain. Furthermore, D1-2 receptor subtypes are found at 10-100 times the levels of the D3-5 subtypes.[3]

D1-like family

Activation of D1-like family receptors is coupled to the G protein G, which subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).

  • D1 is encoded by the DRD1).
  • D5 is encoded by the DRD5).

D2-like family

Activation of D2-like family receptors is coupled to the G protein G, which directly inhibits the formation of cAMP by inhibiting the enzyme adenylyl cyclase.[4]

  • D2 is encoded by the DRD2), of which there are two forms: D2Sh (short) and D2Lh (long):
    • The D2Sh form is pre-synaptically situated, having modulatory functions (viz., autoreceptors, which regulate neurotransmission by feed-back mechanisms, affecting synthesis, storage, and release of dopamine into the synaptic cleft).[5]
    • The D2Lh form may function as a classical post-synaptic receptor, i.e., transmit information (in either an excitatory or an inhibitory fashion) unless blocked by a receptor antagonist or a synthetic partial agonist.[5]
  • D3 is encoded by the
  • D4 is encoded by the

Role of dopamine receptors in the central nervous system

Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory.[11] Although dopamine receptors are widely distributed in the brain, different areas have different receptor types densities, presumably reflecting different functional roles.

Non-CNS dopamine receptors

Cardio-pulmonary system

In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood.[12] In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs.[13]

D4 receptors have been identified in the atria of rat and human hearts.[14] Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.[2]

Renal system

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density.[13] In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the glomeruli, zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionic sympathetic nerve terminals.[13] Dopamine signaling affects diuresis and natriuresis.[2]

Dopamine receptors in disease

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia,[15] Tourette's syndrome,[16] Parkinson's disease,[17] schizophrenia,[16] neuroleptic malignant syndrome,[18] attention-deficit hyperactivity disorder (ADHD),[19] and drug and alcohol dependence.[16][20]

Attention-deficit hyperactivity disorder

Dopamine receptors have been recognized as important components in the etiology of ADHD for many years. Drugs used to treat ADHD, including methylphenidate and amphetamine, have significant effects on dopamine signaling in the brain. Studies of gene association have implicated several genes within dopamine signaling pathways; in particular, the D4.7 variant of D4 has been consistently shown to be more frequent in ADHD patients.[21] ADHD patients with the 4.7 allele also tend to have better cognitive performance and long-term outcomes compared to ADHD patients without the 4.7 allele, suggesting that the allele is associated with a more benign form of ADHD.[21]

The D4.7 allele has suppressed gene expression compared to other variants.[22]

Recreational drug use and abuse

Dopamine is the primary neurotransmitter involved in the reward pathways in the brain. Thus, drugs that increase dopamine signaling may produce euphoric effects. Many recreational drugs, such as cocaine and amphetamines, alter the functionality of the dopamine transporter (DAT), the protein responsible for removing dopamine from the neural synapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling. When this occurs, particularly in the nucleus accumbens,[23] increased D1[20] and D2[23] receptor signaling mediates the "rewarding" stimulus of drug intake.[23] Reward pathway signaling can affect other regions of the brain as well, inducing long-term changes in regions such as the nucleus accumbens and frontal cortex; these changes can strengthen drug craving and alter cognitive pathways, with drug abuse potentially creating drug addiction and drug dependence.

Schizophrenia

While there is evidence that the dopamine system is involved in schizophrenia, the theory that hyperactive dopaminergic signal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, induce dramatic changes in dopamine signaling; large doses and prolonged usage can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D2 receptors.

Genetic hypertension

Dopamine receptor mutations can cause genetic hypertension in humans.[24] This can occur in animal models and humans with defective dopamine receptor activity, particularly D1.[13]

Dopamine regulation

Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels (via stimulants or antipsychotics mainly) can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors. With stimulants, downregulation is typically associated with loss of interest in pleasureable activities, shortened attention span, and drug seeking behavior. With antipsychotics, associated upregulation can cause temporary dyskinesia, or tardive dyskinesia (fine muscles e.g. facial muscles, twitch involuntarily).

Haloperidol, and some other antipsychotics, have been shown to increase the binding capacity of the D2 receptor when used over long periods of time (i.e. increasing the number of such receptors).[25] Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.

There are differing reports of abused stimulants, and up/down regulation. According to one study,[26] cocaine, heroin, amphetamine, alcohol, and nicotine cause decreases in D2 receptor quantity. A similar association has been linked to food addiction, with a low availability of dopamine receptors present in people with greater food intake.[27][28] A recent news article[29] summarized a U.S. DOE Brookhaven National Laborotory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days.

A contrasting study of cocaine[30] shows that cocaine upregulates D3 receptors in the nucleus accumbens, possibly contributing to drug seeking behavior.

Working memory training has been associated with dopamine D1 receptor downregulation, which is believed to have an important role in working memory tasks.[31]

See also

External links

  • Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)
  • Scholarpedia article on Dopamine anatomy

References

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