G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia

Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Active solely during waking, they maintain wakefulness and attention. Three of the four known histamine receptors and binding to glutamate NMDA receptors serve multiple functions in the brain, particularly control of excitability and plasticity. H1 and H2 receptor-mediated actions are mostly excitatory; H3 receptors act as inhibitory auto- and heteroreceptors. Mutual interactions with other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, learning, and memory in health and disease.

Histamine in the Nervous System

The physiology of brain histamine.

The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission. The parallels between the DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants.

https://science.sciencemag.org/content/sci/283/5400/397.full.pdf

Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.

d-Amphetamine is markedly more potent an inhibitor of catecholamine uptake by norepinephrine neurons in the brain than is 1-amphetamine, whereas the two isomers are equally active in inhibiting catecholamine uptake by the dopamine neurons of the corpus striatum. In behavioral studies, d-amphetamine is ten times as potent as 1-amphetamine in enhancing locomotor activity, while it is only twice as potent in eliciting a compulsive gnawing syndrome. This suggests that the locomotor stimulation induced by amphetamine involves central norepinephrine, while dopamine neurons play an important role in the induced compulsive gnawing behavior. Assessment of differential actions of d- and 1-amphetamine may be an efficient method to differentiate behaviors involving norepinephrine or dopamine in the brain.

https://science.sciencemag.org/content/sci/168/3938/1487.full.pdf

Amphetamine: Differentiation by d and l Isomers of Behavior Involving Brain Norepinephrine or Dopamine

Differential effects of D- and L-amphetamine on behavior and on catecholamine disposition in dopamine and norepinephrine containing neurons of rat brain

By comparing biochemical and behavioral actions of d- and l- isomers of amphetamine, the authors show that locomotor hyperactivity, an animal model for the central stimulant effects of amphetamine, is mediated by brain norepinephrine. By contrast, stereotyped, compulsive gnawing behavior in rats, which resembles symptoms of amphetamine psychosis, appears to be regulated by brain dopamine. Since haloperidol, a potent blocker of dopamine receptors, is uniquely efficacious in treating Gilles de la Tourette's disease, the authors suggest that hyperactivity of dopamine systems in the brain may be a factor in the pathophysiology of this condition.

The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs.

Histamine content of rat brain was lowered quickly by inhibitors of histidine decarboxylase, suggesting that a portion of brain histamine turns over rapidly. Restraint and exposure to cold also reduced brain histamine levels and markedly augmented its formation in the hypothalamus.

http://science.sciencemag.org/content/sci/172/3987/1037.full.pdf

Kenneth M. Taylor

Papers

Amphetamine: Differentiation by d and l Isomers of Behavior Involving Brain Norepinephrine or Dopamine

Differential effects of D- and L-amphetamine on behavior and on catecholamine disposition in dopamine and norepinephrine containing neurons of rat brain

The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs.

Brain histamine: rapid apparent turnover altered by restraint and cold stress.

Regional localization of histamine and histidine in the brain of the Rhesus monkey