Dopamine receptor

Dopamine

Dopamine receptors are a class of metabotropic 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 have key roles in many processes, including the control of motivation, learning, and fine motor movement, 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 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, D_1-2 receptor subtypes are found at 10-100 times the levels of the D_2-5 subtypes.^[3]

D₁-like family (excitatory)

Activation of D₁-like family receptors is coupled to the G protein G_αs, which subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP). Increased cAMP in neurons is typically excitatory and can induce an action potential by modulating the activity of ion channels.

• D₁ (DRD1)

• D₅ (DRD5)

D₂-like family (inhibitory)

D₂-like activation is coupled to the G protein G_αi, which directly inhibits the formation of cAMP by inhibiting the enzyme adenylate cyclase.^[4]

• D₂ (DRD2). There is a short version of D₂ (D₂Sh) and a long version of D₂ (D₂Lh):
  • The D₂Sh are pre-synaptic situated, having modulatory functions (called autoreceptor, they regulate the neurotransmission by feed-back mechanisms, i.e., synthesis, storage and release of dopamine into the synaptic cleft).
  • The D₂Lh may have the classic function of a post-synaptic receptor, i.e., keep going on the neurotransmission (excitatory or inhibitory) once blocked by a receptor antagonist or stimulated by the endogenous neurotransmitter itself or a synthetic full or partial agonist.

• D₃ (DRD3) Maximum expression of dopamine D₃ receptors is noted in the islands of Calleja and nucleus accumbens.^[5]

• D₄ (DRD4). The D₄ receptor has the following variants D_4.2, D_4.3a, D_4.3b, D_4.4a, D_4.4b, D_4.4c, D_4.4d, D_4.4e, D_4.5a, D_4.5b, D_4.6a, D_4.6b, D_4.7a, D_4.7b, D_4.7c, D_4.7d, D_4.8, D_4.10. These variants differ in a variable number tandem repeat domain present within the coding sequence of exon 3. Some of these alleles are associated with greater incidence of certain diseases. For example, the D_4.7 alleles have an established association with attention-deficit hyperactivity disorder.

Role of dopamine receptors in the central nervous system

Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory.^[6]. 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 vasorelaxive effects of dopamine in the blood.^[7] In rats, D₁-like receptors are present on the smooth muscle of the blood vessels in most major organs.^[8]

D₄ receptors have been identified in the atria of rat and human hearts.^[9] 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.^[8] In rats, D₁-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D₂-like receptors are present on the renal tubules, glomeruli, postganglionic sympathetic nerve terminals, and zona glomerulosa cells of the renal cortex.^[8] 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,^[10] Tourette's syndrome,^[11] Parkinson's disease,^[12] schizophrenia,^[11] neuroleptic malignant syndrome^[13] Attention-deficit hyperactivity disorder (ADHD),^[14] and drug and alcohol dependence.^[11][15]

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 D_4.7 variant of D₄ has been consistently shown to be more frequent in ADHD patients.^[16] 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.^[16]

The D_4.7 allele has suppressed gene expression compared to other variants.^[17]

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,^[18] increased D₁^[15] and D₂^[18] receptor signaling mediates the "rewarding" stimulus of drug intake.^[18] 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

Main article: Dopamine hypothesis of 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.^[19] This can occur in animal models and humans with defective dopamine receptor activity, particularly D₁.^[8]

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 (cause less average activity) or upregulate (cause greater activity) 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 tardive dyskinesia (fine muscles, like the face, twitch involuntarily), or just plain dyskinesia (same but only temporary).

Haloperidol, and some other antipsychotics, have been shown to increase the activity of the D2 receptor. ^[20] Haloperidol induced activity up to 98% higher than baseline in as many as two weeks, but yielded significant dyskinesia side effects. Another study ^[21] showed in a living subject, dopamine 2 receptors had increased approximately 90% after neuroleptic treatment.

There are differing reports of abused stimulants, and up/down regulation. According to one study ^[22] cocaine, heroin, amphetamine, alcohol, and nicotine cause decreases in dopamine 2 receptor quantity. A similar association has been linked to food addiction ^[23], with a low availability of dopamine receptors present in people with greater food intake. A recent news article ^[24] summarized a U.S. DOE Brookhaven National Laborotory study showing that increasing dopamine receptors with genetic therapy decreased cocaine consumption up to 75%, but only lasting for six days.

A contrasting study of cocaine^[25] shows that cocaine upregulates D3 receptors in the nucleus accumbens, possibily contributing to drug seeking behavior.

See also

• Category:Dopamine agonists
• Category:Dopamine antagonists

External links

• "Dopamine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)

References