Locomotor inhibition, yawning and vacuous chewing induced by a novel dopamine D2 post-synaptic receptor agonist

The N-n-propyl analog of dihydrexidine ((+/-)-trans-10, 11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine) is a dopamine receptor agonist with high affinity for dopamine D2 and D3 receptors (K0.5 = 26 and 5 nM, respectively). Members of the hexahydrobenzo[a]phenanthridine structural class are atypical because they display high intrinsic activity at post-synaptic dopamine D2 receptors, but low intrinsic activity at dopamine D2 autoreceptors. The present study examined the effects of (+/-)-N-n-propyl-dihydrexidine on unconditioned behaviors in rats. The most striking results observed were large, dose-dependent decreases in locomotor activity (e.g., locomotor inhibition), and increases in vacuous chewing; yawning was also increased at the highest dose of (+/-)-N-n-propyl-dihydrexidine. The locomotor inhibition and yawning induced by (+/-)-N-n-propyl-dihydrexidine were blocked by pre-treatment with (-)-remoxipride (S(-)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)-methyl)-2, 6-dimethoxybenzamide), a dopamine D2 receptor antagonist, but not by the dopamine D1 receptor antagonist (+)-SCH23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine). Vacuous chewing was decreased by both (-)-remoxipride and (+)-SCH23390. These data support the hypothesis that a subpopulation of post-synaptic dopamine D2 receptors has a critical role in decreases in locomotor activity and induction of vacuous chewing and yawning.