Controversial Feelings about Dopamine Receptors

Dopamine (DA) is a neurotransmitter involved in the control of several crucial cerebral and peripheral functions. It plays a role in modulating autonomic and peripheral functions, controls the cardiovascular and renal functions. These actions are mediated through the interaction of DA with specific DA receptors, which are a class of metabotropic G-protein coupled receptors. Five subtypes of DA receptors are well characterized and known to be involved in Parkinson’s disease, schizophrenia, attention-deficit hyperactivity disorder (ADHD), addiction, as well as hypertension, thus serving as common neurologic drug targets. Alomone Labs offers related antibodies, directed towards the DA receptors. These valuable research tools can progress research regarding the involvement of these receptors in various normal and pathological states.

Introduction

Dopamine receptors are a class of metabotropic seven transmembrane domain G-protein coupled receptors (GPCRs), and are prominent in the vertebrate central nervous system (CNS) as well as the peripheral nervous system (PNS). The neurotransmitter dopamine (DA), a precursor of noradrenaline and adrenaline, is one of the main endogenous catecholamine ligand for DA receptors. Dopamine is a neuromodulator that is synthesized in neural and non-neural tissues and alters the responses of target neurons to other neurotransmitters in a manner that depends on the functional state of these neurons. Although dopamine neurons are few in the brain, they play an important role in regulating several aspects of basic brain function, including cognition, memory, learning, motivation, pleasure, and fine motor control, as well as modulation of neuroendocrine signaling².

There are at least five subtypes of dopamine receptors, D₁, D₂, D₃, D₄, and D₅, based on their sequence homology, pharmacology and functional properties. Recent findings point to the possible existance of D₆ and D₇ receptors, although their role has not been identified yet¹. The affinity of dopamine to its receptors is in the nanomolar range. At higher concentrations, α and β-adrenergic and serotonin receptors are also occupied⁴. Although dopamine receptors are widely distributed in the brain, different areas have different receptor type densities, presumably reflecting different functional roles. Several neuropsychiatric disorders are derived from abnormal dopamine receptor signaling and dopaminergic nerve dysfunction. Dopamine receptors are also widespread in non-CNS areas, containing the cardio-pulmonary system and the renal system.

Traditionally, DA receptors are divided into two families according to the stimulation or inhibition they may produce at the adenyl cyclase (AC) enzyme level.

D₁-like family: Two types of D₁-like receptors have been described: the D_1A (D₁ in humans) and the D_1B (D₅ in humans). Activation of the D₁-like family is coupled to the G-protein Gs, which subsequently activates AC, increasing the intracellular concentration of cAMP.

D₂-like family: Five types of D₂-like receptors have been described: D_2Short(S) and D_2Long(L) isoforms, D₃ and D₄ receptors. Activation of the D₂-like family is coupled to the G-protein G_i, which directly inhibits the formation of cAMP by inhibiting the AC enzyme.

Distribution of Dopamine Receptors

Dopamine Receptors in the CNS

The D₁ dopamine receptors have the most widespread distribution and overall highest density in the brain than the other dopamine receptors. Few studies have examined the distribution of the D₅ dopamine receptor in human brain. This receptor has a more restricted distribution than that of the D₁ receptor. The distribution of D₂ receptors in the brain is very similar to that of the D₁ dopamine receptor whereas that of D₃ receptor is much more restricted. The distribution of the D₄ dopamine receptor is unlike the other D₂-like dopamine receptors and resembles more to the D₁-like dopamine receptor distribution. It is mostly expressed in cortical and other extrastriatal brain regions, with very low expression levels in striatal regions³.

Dopamine Receptor Localization in the Kidney

Both D₁-like and D₂-like dopamine receptors have been detected in the renal system^1,7. Activation of D₁-like receptors results in vasodilation, hypotention, increase in renal flow, diuresis, natriuresis and renin release. The modulation mechanism includes the Na⁺/H⁺ exchanger inhibition by the paracrine effect of DA on the proximal tube, resulting from D₁-like dopamine receptor activation. Although both classes of dopamine receptors are expressed in the kidneys, the natriuretic effect of dopamine is primarily mediated by D₁-like receptors, mostly by D₁ receptor. During Na⁺ loading, D₂-like receptors may also contribute to the natriuresis, mostly by the D₃ dopamine receptor⁴.

Dopamine Receptors in the Cardio-Pulmonary System

in vivo administration or in vitro application of dopamine or dopamine receptor agonists induces vasodilation that causes hypotension. The D₁-like receptors, which seem to be mostly involved in this mechanism, are located within vascular smooth muscle. Their stimulation causes vasorelaxation and reduction of vascular resistance. D₂-like dopamine receptors are mainly prejunctional and are involved in the inhibition of neurogenic (sympathetic) vasoconstriction⁸.

Dopamine Receptor Function in Normal and Diseased States

Dopamine Receptors in Memory

Spatial working memory operates optimally within a limited range of dopamine transmission and D₁ dopamine receptor signaling in the prefrontal cortex. Insufficiency in prefrontal dopamine, as in aging, and excessive transmission, as in acute stress, lead to impairments in working memory, that can be ameliorated by D₁ receptor agonist and antagonist treatment, respectively. Both in vivo and in vitro studies have demonstrated a role for dopamine in promoting the excitability of prefrontal pyramidal cells and facilitating their N-methyl-D-aspartate (NMDA) inputs. Evidence indicates that there is a fine balance between the synergistic mechanisms of D₁ receptor modulation in working memory. There is experimental evidence from both animal and human studies that prefrontal dopamine transmission operates within a limited working range for efficient cortical function and the cognitive processes it subserves¹⁰.

Dopamine Receptors in Neuropsychiatric Disorders, ADHD and Addiction

Dopamine transmission within cortical and subcortical structures is involved critically in the processing of emotionally relevant sensory information. Emerging evidence from clinical, genetic, behavioral and electrophysiological investigations demonstrate a role for the D₄ dopamine receptor subtype as a crucial modulator of emotional memory expression, as well as neuropathological syndromes both at the level of the single neuron, and at the neuronal system⁶. The theory that excess dopamine transmission underlies neuropsychiatric disorders such as schizophrenia has several key supporting components. Most research surrounding the dopamine theory of schizophrenia has concentrated on the D₂ receptor. Whereas there is no genetic linkage between D₄ and schizophrenia, there is increasing evidence to support an important role specifically for the D₄ dopamine receptor subtype in various neuropsychiatric disorders including ADHD where considerable evidence now links dysregulated expression and signaling of the receptor to the pathophysiology⁶.

Despite the complexity of addiction in terms of underlying psychological variables and neuropathological correlates, an important feature common to addictive behaviors involves disturbances in emotional processing, learning and memory processes and impulsive behaviors. Perturbations in dopamine transmission are well established factors related to both the rewarding and dependence producing properties of most drugs of abuse. Increasing evidence points to a role for the D₄ receptor as an underlying factor related to addiction. A growing body of research using reductionist models of emotional learning and memory are demonstrating a role for D₄ dopamine receptor-mediated transmission in specific neural circuits important for emotional processing and neuroplasticity⁶.

Parkinson’s Disease

Disappearance of nigrostriatal neurons and hence a dramatic decrease in the dopamine content of specific regions in the brain results in Parkinson’s disease³. In addition, combined D₂ and D₃ receptor mutations aggravate Parkinsonian symptoms⁵. Functional alterations in dopaminergic neurotransmission occur in the striatum and extrastriatal brain regions as a consequence of the dopaminergic neuron degeneration and chronic L-DOPA or dopamine agonist treatment. These changes, together with the continued degeneration of dopaminergic neurons, are believed to underlie the gradual failure in the effectiveness of treatment and development of motor and psychiatric side effects.

In Parkinson’s disease, the dopaminergic innervation of the striatum degenerates and consequently presynaptic D₂ dopamine receptors are lost. As a result, there is an increase in the numbers of D₂ dopamine receptors on the remaining dopaminergic neuron terminals, or increased synthesis within striatopallidal neurons or cholinergic interneurons. In addition, it was found that the neuronal distribution of striatal D₂ dopamine receptors is different in treated Parkinson’s disease versus untreated controls³.

Dopamine receptors present on dopaminergic neurons in areas other than striatum are also affected by the neurodegeneration which occurs in Parkinson’s disease. In Parkinson’s disease cases, studies found a significant reduction of D₁ dopamine receptors in the red nucleus, an area involved in motor coordination that receives afferent fibers from the cerebellum, motor cortex and striatum, which is linked to the substantia nigra. D₂ dopamine receptors were unchanged in the both parts of the substantia nigra and other specific regions in the brain, but were increased in the CA3 region of the hippocampus and deep layers of the occipital cortex. D₃ dopamine receptor was unchanged in both segments of the globus pallidus in Parkinson’s disease cases³. Data from animal models of the disorder indicate that alterations in dopamine receptor expression levels are not solely responsible for dyskinesia, or the other motor side effects of treatment. However, the extrastriatal changes (cortical and hippocampal) may play a role in the cognitive and psychiatric symptoms of Parkinson’s disease and side effects of treatment.

Dopamine Receptors and Blood Pressure

Dopamine is also known as an important regulator of blood pressure. Thus, impairment of dopamine receptor function and/or dopamine production outside the CNS increases blood pressure and produces hypertension. Its actions on renal hemodynamics, epithelial transport and humoral agents, place it in a central homeostatic position for regulating extracellular fluid volume and blood pressure. Dopamine also modulates fluid and Na⁺ intake via the CNS and gastrointestinal tract, and by regulating cardiovascular centers that control the functions of the heart, arteries and veins⁴. Abnormalities in dopamine production and receptor function accompany a high percentage of human essential hypertension and several forms of rodent genetic hypertension. All five dopamine receptor subtypes participate in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors (D₂ and D₅) influence the central and/or peripheral nervous systems; others influence epithelial transport and regulate the secretion and receptors of several humoral agents (D₁, D₃ and D₄receptors, which interact with the renin-angiotensin system). Modifications of the usual actions of the receptor can produce blood pressure changes⁴.

In addition, there is a tight correlation between obesity and hypertension. Indeed, a decrease in the expression of D₂ dopamine receptors in the brain of obese individuals was reported⁹. Also, defects in D^1A can lead to arterial hypertension (AHT) development1. As D₁ and D₂ receptors have synergic effects on diuresis and natriuresis, defects in any of them does not exclude the possibility of joint alterations both at the renal level as well as in the development of obesity.

Other findings suggest the possible role for dopamine and its receptors in the pulmonary endothelium-dependent vasorelaxation activity. The heterogeneous distribution and density of dopamine receptor subtypes along the human pulmonary arterial tree may be related to the different functional roles of dopamine at various levels of the pulmonary circulation. The dopamine-induced vasodilatory responses in pulmonary arteries are to a larger extent endothelium-dependent and are thought to be mediated mostly through D₁-like dopamine receptors in human⁸.

Receptor immunoreactivity is the best tool to distinguish the receptor subtype as the availability of highly selective ligands is limited. Alomone Labs offers highly specific antibodies directed against all five dopamine receptors: Anti-D₁ Dopamine Receptor (#ADR-001), Anti-D₂ Dopamine Receptor (extracellular) (#ADR-002), Anti-D₃ Dopamine Receptor (extracellular) (#ADR-003), Anti-D₄ Dopamine Receptor (#ADR-004) and Anti-D₅ Dopamine Receptor (extracellular) (#ADR-005) antibodies. These antibodies enable the detection of these receptors using either western blot or immunohistochemistry applications.

References

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