Behavioral pharmacology of dopamine D2 and D3 receptor agonists and antagonists in rats.

摘要

Dopamine D2-like receptors are involved in the regulation of a variety of behaviors, and have proven to be important pharmacologic targets for the treatment of diseases such as Parkinson's disease, schizophrenia, restless leg syndrome, and depression, however, the receptor(s) responsible for the therapeutic and behavioral effects have yet to be elucidated. Identification of behaviors specifically mediated by the D2 and/or D3 receptors would not only provide insight into the receptor(s) mediating these therapeutic and behavioral effects, but it would also aid in the evaluation of novel D2-like agonists and antagonists. These studies were primarily aimed at the pharmacologic evaluation of the hypothesis that the induction of yawning by D2-like agonists is mediated by a specific activation of the D3 receptor, while the inhibition of yawning observed at higher doses is mediated by a concomitant activation of the D2 receptor.;Convergent evidence from the effects of D2-like agonists alone, and in combination with a series of D2-like antagonists support this general hypothesis. All D3-preferring agonists elicited dose-dependent yawning behavior resulting in a characteristic inverted U-shaped dose-response curve. These functions were differentially modulated by D3- and D2-preferring antagonists, with D3-preferring antagonists producing selective rightward shifts of the ascending limb, and D2-preferring antagonists producing selective shifts of the descending limb. The selectivity of these effects was confirmed by a comparison of the relative potencies of D2- and D3-preferring agonists to induce yawning and hypothermia (a well validated D2-mediated effect), as well as the relative potencies of D2- and D3-preferring antagonists to inhibit the induction of yawning and hypothermia by D2-like agonists. Similar comparisons of the effects of D2-like agonists and antagonists on the induction of yawning and penile erection not only provided further support for the differential roles of the D3 and D 2 receptors in the regulation of yawning, but suggest that D2-like agonist-induced yawning and penile erection are similarly mediated by the D3 (induction) and D2 (inhibition) receptors in rats. These studies not only provide strong pharmacologic evidence for a specific D3-mediated behavior, but have also allowed for the identification of other D3-mediated behaviors and determinations of in vivo D2/D3 selectivity.