Dopamine receptor

Dopamine

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. 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

The existence of multiple types of receptors for dopamine was first proposed in 1976. 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.

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_3-5 subtypes.

D₁-like family

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

• D₁ is encoded by the Dopamine receptor D₁ gene (DRD1).
• D₅ is encoded by the Dopamine receptor D₅ gene (DRD5).

D₂-like family

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

• D₂ is encoded by the Dopamine receptor D₂ gene (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 via feedback mechanisms. It affects synthesis, storage, and release of dopamine into the synaptic cleft).
  • 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.
• D₃ is encoded by the Dopamine receptor D₃ gene (DRD3). Maximum expression of dopamine D₃ receptors is noted in the islands of Calleja and nucleus accumbens.
• D₄ is encoded by the Dopamine receptor D₄ gene (DRD4). The D₄ receptor gene displays polymorphisms that differ in a variable number tandem repeat present within the coding sequence of exon 3. Some of these alleles are associated with greater incidence of certain disorders. For example, the D_4.7 alleles have an established association with attention-deficit hyperactivity disorder.

Receptor heteromers

Dopamine receptors have been shown to heterodimerize with a number of other G protein-coupled receptors. The resulting dopamine receptor heterodimers include:

• D₁–adenosine A₁
• D₁–D₂ dopamine receptor heteromer
• D₁–D₃ dopamine receptor heteromer
• D₂–D₄ dopamine receptor heteromer
• D₂–adenosine A_2A
• D₂–ghrelin receptor
• D_2sh–TAAR1 (an autoreceptor heterodimer)
• D₄–adrenoceptor α_1B
• D₄–adrenoceptor β₁

Role of dopamine receptors in the central nervous system

Further information: Neurotransmitter § Brain neurotransmitter systems

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

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. In rats, D₁-like receptors are present on the smooth muscle of the blood vessels in most major organs.

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

Renal system

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density. 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. Dopamine signaling affects diuresis and natriuresis.

Dopamine receptors in disease

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

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 neuronal dopamine signaling. 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. 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.

The D_4.7 allele has suppressed gene expression compared to other variants.

Addictive drugs

Main article: ΔFosB

Dopamine is the primary neurotransmitter involved in the reward pathway in the brain. Thus, drugs that increase dopamine signaling may produce euphoric effects. Many recreational drugs, such as cocaine and substituted amphetamines, inhibit 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, increased D₁ and decreased D₂ receptor signaling mediates the "rewarding" stimulus of drug intake.

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, indirectly increase dopamine signaling; large doses and prolonged use 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. This can occur in animal models and humans with defective dopamine receptor activity, particularly D₁.

Dopamine regulation

See also: Yerkes–Dodson law

Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors. With stimulants, downregulation of DRD1 is typically associated with loss of interest in pleasureable activities, shortened attention span, and drug seeking behavior. With antipsychotics, associated D2-like receptor 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). Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.

Addictive stimuli have variable effects on dopamine receptors, depending on the particular stimulus. According to one study, 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. A recent news article summarized a U.S. DOE Brookhaven National Laboratory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days. Cocaine upregulates D₃ receptors in the nucleus accumbens, possibly contributing to drug seeking behavior.

Certain stimulants will enhance cognition in the general population (e.g., direct or indirect mesocortical DRD1 agonists as a class), but only when used at low (therapeutic) concentrations. Relatively high doses of dopaminergic stimulants will result in cognitive deficits.

Summary of addiction-related plasticity

Form of neural or behavioral plasticity	Type of reinforcer						Sources
	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment
ΔFosB expression in nucleus accumbens D1-type MSNs	↑	↑	↑	↑	↑	↑
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated
Psychostimulant self-administration	↑	↑	↓		↓	↓
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑
Reinstatement of drug-seeking behavior	↑	↑			↓	↓
Neurochemical plasticity
CREB phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2
Altered striatal opioid signaling	↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change
Changes in striatal opioid peptides	↑dynorphin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑
Dendritic spine density in the nucleus accumbens	↓	↑		↑

See also

• D2 short (presynaptic)
• Category:Dopamine agonists
• Category:Dopamine antagonists

External links

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