title: Electrophysiological effects of putative autoreceptor-selective dopamine agonists on A10 dopamine neurons.
abstract: The dopamine (DA) hypothesis of schizophrenia proposes hyperactivity of the mesocorticolimbic DA system, originating within the A10 DA cells of the ventral tegmental area (VTA), as a pathophysiological mechanism. Thus, reduction of activity in this system, including that produced by putative "autoreceptor-selective" DA agonists, may be of clinical utility. The present studies compared the ability of eight D2 DA receptor agonists to inhibit the firing of rat A10 DA neurons after i.v. administration. Both N-n-propyl-N-phenylethyl-p(3-hydorxyphenyl)ethylamine hydrochloride (RU 24213) and 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]- azepine dihydrochloride (B-HT 920) were potent, high-efficacy agonists which completely inhibited the firing of A10 DA cells. The putative autoreceptor-selective DA agonists 3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-(1)-butyl)-indole hydrochloride (EMD 23,448) and (+)-3-(3-hydroxy-phenyl)-N-n-propylpiperidine [(+)-3-PPP] were considerably weaker than RU 24213 and B-HT 920, but also exhibited "full" efficacy (i.e., they completely suppressed cell firing). The putative autoreceptor agonist preclamol [(-)-3-PPP] and its trans-fused congener (-)-HW 165 were weak partial agonists that failed to completely inhibit A10 DA cells. The new putative autoreceptor agonist N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,3]dimethylopropa namide (SDZ 208-911) was also a weak partial agonist that exhibited partial antagonist effects (reversed inhibition produced by the D2 agonist quinpirole), whereas its structural analog N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2-dimethylopropa namide (SDZ 208-912) was nearly inactive as an agonist, but was an effective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Neuroscience, University of Health Sciences, Chicago Medical School, Illinois.
authors.forename: J M
authors.initials: JM
authors.lastname: Ackerman
authors.forename: P A
authors.initials: PA
authors.lastname: Johansen
authors.forename: D
authors.initials: D
authors.lastname: Clark
authors.forename: F J
authors.initials: FJ
authors.lastname: White
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004594:Electrophysiology; D004873:Ergolines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010616:Phenanthrenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001381:Azepines; D015259:Dopamine Agents; D004873:Ergolines; D007211:Indoles; D010616:Phenanthrenes; C062737:N-(2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide; C059362:N-(2-chloro-6-methylergoline-8-yl)-2,2-dimethylpropanamide; C037307:3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-1)-butyl)indole; C024763:talipexole; C046064:HW 165; D004298:Dopamine