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.
Smith
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Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill 27599-7250, USA.
Nichols
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Mailman
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Lawler
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D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000494:pharmacology; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D003198:Computer Simulation; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019329:Idazoxan / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008409:Mastication / Q000187:drug effects*; D010617:Phenanthridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D012015:Reference Standards; D017330:Remoxipride / Q000008:administration & dosage / Q000494:pharmacology; D013237:Stereoisomerism; D015000:Yawning / Q000187:drug effects*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D010617:Phenanthridines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017330:Remoxipride; C061532:dihydrexidine; D001058:Apomorphine; D019329:Idazoxan