Partial and full dopamine D1 agonists produce comparable increases in ventral pallidal neuronal activity: contribution of endogenous dopamine.
Systemic administration of the partial DA D1 agonist SKF38393 often increases the firing rate of neurons in the VP of rats. This study extended this finding by comparing responses to (+/-)SKF38393 with those produced by two D1 agonists that have greater intrinsic efficacy, (+/-)SKF82958 and (+/-)DHX. The role of endogenous DA in D1 agonist-induced effects also was examined. Extracellular recordings of single VP neurons were obtained in chloral hydrate-anesthetized male rats, to which equimolar doses of SKF38393, SKF82958 or DHX were administered i.v. Each of the agonists increased firing rate in about 45% of the neurons tested. Moreover, each agonist produced the same maximal increase in activity (161% to 178% of spontaneous rate). Acute decreases in synaptic DA, produced by either GBL or combined treatment with reserpine and AMPT, potentiated the maximal increase in activity evoked by SKF38393 or SKF82958. These DA-depleting treatments did not alter the percentage of neurons that displayed this response to D1 agonist challenge. Low doses of the selective D1 antagonists SCH23390 or SCH39166 generally attenuated the agonist-induced changes in firing rate, supporting the conclusion that D1 receptors were activated by SKF38393, SKF82958 and DHX. Thus, these three D1 agonists, which produce different maximal increases in striatal adenylyl cyclase activity, had comparable efficacy to increase VP neuronal activity. A reduction in endogenous DA enhanced the D1 agonist-induced effects, possibly through a reduction in inhibitory influences on VP neurons that are mediated by other DA receptor subtypes.
Heidenreich
B A
BA
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
Mailman
R B
RB
Nichols
D E
DE
Napier
T C
TC
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D005917:Globus Pallidus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000494:pharmacology; D019805:alpha-Methyltyrosine
D001552:Benzazepines; D018491:Dopamine Agonists; D008781:Methyltyrosines; D017447:Receptors, Dopamine D1; D019805:alpha-Methyltyrosine; C071262:SK&F 82958; D012110:Reserpine; D015107:4-Butyrolactone; D004298:Dopamine