Effects of intraperitoneal administration of apomorphine and the isomers of 3-(1-propyl-3-piperidinyl)phenol on the firing activity of substantia nigra dopamine neurons: comparison of agonist efficacies and development of acute tolerance.
The effects of intraperitoneal administration of apomorphine, (+)-3-PPP, and (-)-3-PPP on slow-(less than 4 spikes/sec) and fast-(greater than 4 spikes/sec) firing dopaminergic neurons in the substantia nigra zona compacta of rats anesthetized with chloral hydrate were assessed. All compounds completely inhibited slow-firing dopaminergic neurons. When a dose-response was determined by administering each dose in a single bolus injection, apomorphine and (+)-3-PPP produced dose-related inhibitions of fast-firing dopaminergic neurons, with the largest dose of each compound completely inhibiting nearly all cells tested. In contrast, (-)-3-PPP only partially inhibited (50%) fast-firing dopaminergic neurons. Thus, on fast-firing neurons, (-)-3-PPP had the profile of a partial agonist, while apomorphine and (+)-3-PPP demonstrated greater efficacy than (-)-3-PPP. Pretreatment while doses of apomorphine, (+)-3-PPP, or (-)-3-PPP that partially inhibited the activity of dopaminergic neurons antagonized the complete inhibitory effects of a dose of apomorphine that normally produced complete inhibition of neuronal firing. In addition, pretreatment with doses of (+)-3-PPP that partially inhibited the activity of cells antagonized the complete inhibitory effects of a dose of (+)-3-PPP that, normally produced complete inhibition of neuronal firing. From the antagonism studies alone, it was not clear if tachyphylaxis or partial agonist activity accounted for the observed antagonisms. However, since apomorphine and (+)-3-PPP completely inhibited the activity of fast-firing DA neurons, it is proposed that they antagonize by inducing a dose- and time-dependent tachyphylaxis. In contrast, (-)-3-PPP is proposed to antagonize by virtue of its partial agonist activity.
Meltzer
L T
LT
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Christoffersen
C L
CL
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004361:Drug Tolerance; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects*
D010880:Piperidines; D011954:Receptors, Dopamine; C026539:preclamol; D001058:Apomorphine