Dopaminergic activation

This inference is consistent with known characteristics of dopamine-induced PI signaling and D 5 receptor expression among the brain regions. For instance, as indicated in past and the present results, both receptor expression and agonist-induced signaling are relatively higher in the hippocampus than in the striatum, with intermediate effects in the prefrontal cortex Undie and Friedman, Other consistent observations are those indicating that the D 5 receptor can couple to G q -like G proteins in various cell lines or in renal brush-border membranes Sidhu and Niznik, , that the receptor directly modulates calcium currents and burst firing in the subthalamic nucleus Baufreton et al.

The present findings, therefore, could provide new insights toward understanding those agonistic D 1 -like effects that have hitherto defied explanation on the basis of adenylyl cyclase coupling. Our current results are also supported by previous experiments involving the expression of a D 1 -like receptor encoded by striatal mRNA in Xenopus laevis oocytes. Mahan et al. Moreover, using size fractionation techniques, it was shown that mRNA encoding the striatal PI-linked D 1 -like receptor was between 2.

Moreover, there was general agreement between the in vitro and in vivo drug effects. Although baseline accumulations of inositol phosphate or CDP-diacylglycerol were lower in the mutant hippocampal slices compared with the wild-type tissue, no such differences were observed in the striatum or frontal cortex, and no hippocampal differences were evident in the in vivo assay.

Furthermore, factoring out the basal accumulation for each phenotype did not change the outcome of the analyses of drug effects, thus indicating that the difference in drug effects among the phenotypes outweighed any baseline differences. Although pharmacological agents that sufficiently discriminate among the subtypes of D 1 -like receptors are still lacking, there are, nevertheless, distinguishable anatomical, biochemical, and molecular characteristics within the D 1 -like receptor subfamily.

For instance, the D 5 receptor is widely but discretely distributed in the brain, with a pattern that differs substantially from the distribution of D 1 receptors Meador-Woodruff et al. Within the striatum, the D 5 receptor is expressed predominantly in cholinergic interneurons, whereas D 1 receptors predominate in GABAergic neurons Rivera et al. Unlike the D 1 receptor, D 5 receptors do not form functional complexes with A 1 adenosine receptors Le Crom et al. These observations indicate significant structural differences between the receptor subtypes, and this is consistent with the recent observation of differential physicochemical susceptibility of G s -coupled versus G q -coupled D 1 -like sites to reducing agents or plasma membrane perturbations Panchalingam and Undie, Thus, although there may be substantial pharmacological overlap within the D 1 -like family, the two subtype members are sufficiently differentiated in structure, anatomical distribution, and function to warrant their differential coupling to downstream signaling cascades.

Nevertheless, future studies on the D 5 receptor should address whether such coupling ultimately involves receptor hetero-oligomerization, functional selectivity, or multiple G protein interactions—phenomena that could explain a receptor's ability to induce unique or multiple signaling responses.

With regard to neurobiological function, evidence suggests that the D 5 receptor is probably the D 1 -like receptor subtype that mediates a range of dopamine's effects, including the regulation of peripheral blood pressure Hollon et al.

At the behavioral level, congenic D 5 receptor mutant mice show marked reductions in grooming, a characteristic D 1 -like dopaminergic response that is nevertheless not cyclase-mediated O'Sullivan et al. Hence, the D 5 receptor probably regulates a defined subset of physiological dopaminergic responses, as was believed previously for the dopamine-linked PI signaling response Undie et al. Our present observations, therefore, offer potential new clues toward clarifying the downstream intracellular pathways that define the neurochemical and behavioral phenotype of the D 5 dopamine receptor.

National Center for Biotechnology Information , U. Molecular Pharmacology. Mol Pharmacol. Published online Dec 1. Asha Sahu , Kimberly R. Tyeryar , Habiba O. Vongtau , David R. Sibley , and Ashiwel S. Author information Article notes Copyright and License information Disclaimer.

Address correspondence to: Dr. Ashiwel S. E-mail: ude. Received Oct 23; Accepted Dec 1. Copyright U. Government work not protected by U. This article has been cited by other articles in PMC. Abstract Dopamine activates phospholipase C in discrete regions of the mammalian brain, and this action is believed to be mediated through a D 1 -like receptor. Materials and Methods Animals.

Open in a separate window. Discussion Dopaminergic stimulation of PI signaling has long been known to be mediated through a D 1 -like receptor mechanism Felder et al. Acknowledgments We thank David Cabrera for technical assistance. J Neurosci 23 Synapse 37 Annu Rev Pharmacol Toxicol 33 Biochem J J Pharmacol Exp Ther Mol Pharmacol 51 Biochem Pharmacol 49 Pharmacol Ther 99 Finally, drug-induced postsynaptic alterations in structural, messenger, and transcription proteins offer an exciting focus for future medication targets.

In addition to the previously discussed prospective medications, dopaminergic agents presently being assessed include vanoxerine, , a long-acting, noncompetitive inhibitor of the presynaptic DAT, and disulfiram, which inhibits dopamine-B-hydroxylase. Other receptor systems directly synapse upon dopaminergic neurons and offer excellent possibilities for pharmacologic intervention. As noted early in the review, most drugs of abuse have high affinity binding with G protein-mediated or ion channel receptors that activate dopaminergic release.

Pharmacologic manipulations of these receptor systems have proven of some utility in drug treatment, and several new approaches are in development. Naltrexone, for example, appears to decrease alcohol craving , by blocking the mu-opioid receptors that suppress GABAergic neurons.

These neurons, in turn, tonically inhibit VTA dopaminergic neurons. Opioid antagonists seem to have little effect, however, on the craving for other substances, including heroin. Baclofen, a GABA B receptor agonist that inhibits dopamine release, reduces stimulant self-administration in preclinical studies and has shown early promise in reducing cocaine use in human studies. This compound has demonstrated efficacy in both alcohol- and cocaine-dependent subjects.

Glucocorticoid antagonists or agonists may prove useful by altering the permissive effects of mesolimbic DA release, particularly during periods of stress. Metyrapone, which blocks the synthesis of cortisol, is currently being assessed for cocaine addiction in phase I clinical trials, although suppression of HPA-axis activity by ketoconazole has not been effective in decreasing cocaine use.

Preclinical studies have demonstrated an inhibitory effect of cholinergic agonists on cocaine self-administration. Experience with other chronic medical and psychiatric disorders, such as depression, epilepsy, hypertension, and schizophrenia, suggest that a cocktail of pharmacologic interventions will be required for the successful treatment of many addicted individuals.

Preparation of this manuscript was supported by National Institute on Drug Abuse grant no. National Center for Biotechnology Information , U. Harv Rev Psychiatry. Author manuscript; available in PMC Jul Bryon Adinoff , MD. Find articles by Bryon Adinoff. Author information Copyright and License information Disclaimer.

Lancaster Road, Dallas, TX Email: ude. Copyright notice. See other articles in PMC that cite the published article. Abstract Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state.

Keywords: amygdala, cocaine, cues, dopamine, impulsive behavior, nucleus accumbens, substance-related disorders, ventral tegmental area. Open in a separate window. Brain Areas Involved in Addiction Amygdala: Amygdalar activity is related to memory consolidation for emotionally arousing events.

Priming: The Nucleus Accumbens and Dopamine Preclinical studies of priming confirm clinical observations—that a single drug administration is the most potent stimulus to renew drug use. The Obsessive Drive for Drugs: The Striato-Thalamo-Orbitofrontal Circuit The pathway involved in the compulsive drive for substances is the striato-thalamo-orbitofrontal circuit.

Stress-Induced Relapse: The Limbic-Hypothalamic-Pituitary-Adrenal Axis Stress is a common precipitant of relapse in addicted patients, and intermittent stress is a powerful inducer for the reinstatement of substance use in animal models. References 1. Clarification and standardization of substance abuse terminology.

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Anterior cingulate cortex and response conflict: effects of frequency, inhibition and errors. Although dopamine has been shown to be a key determinant during reward learning, the role of dopaminergic neurotransmission for amplifying reward-related memories during sleep remains unclear.

In this study, we scrutinize the idea that dopamine is needed for the preferential consolidation of rewarded information. We impaired dopaminergic neurotransmission, thereby aiming to wipe out preferential sleep-dependent consolidation of high- over low-rewarded memories during sleep. Following a double-blind, balanced, crossover design, 17 young healthy men received the dopamine d2-like receptor blocker sulpiride mg or placebo, after learning a motivated learning task.