Characterization of the discriminative stimulus effect of quinpirole: Further evidence for functional interaction...

Dysfunction of the central dopamine D₂-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D₂-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D₂-receptor-containing MSN (D₂-MSN) may be synchronized with the activity of dopamine D₁-receptor-containing MSN (D₁-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D₂-receptor agonist quinpirole to further investigate the "D_1/D₂-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D₂-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A_2A-receptor antagonist istradefylline, both of which may act on D₂-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D₁-receptor antagonist SCH23390 and the GABA_B-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D₂-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D₁-receptors and agonistic modulation of GABA_B-receptors may share the discriminative stimulus effect via the activation of central dopamine D₂-receptors.