Modulation of A10 dopamine neurons by gamma-aminobutyric acid agonists.
Microinjection of the gamma-aminobutyric acidA agonist, muscimol, into the A10 region of the rat produced a dose-dependent increase in motor activity. This effect was antagonized by intra-A10 administration of the gamma-aminobutyric acidA antagonist, bicuculline, and by peripheral administration of haloperidol, and was associated with an increase in extracellular levels of dopamine metabolites in the nucleus accumbens. Although microinjection of the gamma-aminobutyric acidB agonist, baclofen, into the A10 region did not alter motor activity, it abolished the capacity of intra-A10 injection of mu opioid agonist, Tyr-D-Ala-Gly-MePhe-Gly(ol), or muscimol to increase motor activity. Baclofen also prevented the motor stimulant response to peripheral injection of cocaine or amphetamine, but was ineffective in blocking caffeine-induced behavioral activity. Pretreatment with baclofen prevented the capacity of a mu opioid agonist to elevate dopamine metabolite levels in the nucleus accumbens and prefrontal cortex in postmortem tissue. Baclofen also prevented the elevation of extracellular dopamine content in the nucleus accumbens produced by injection of a mu opioid agonist into the A10 region, as measured in the conscious rat with in vivo dialysis. Finally, when dopamine metabolite levels were elevated in the prefrontal cortex by mild footshock, it was shown that pretreatment with baclofen in the A10 region abolished this response. These data support electrophysiological studies suggesting that activation of gamma-aminobutyric acidB receptors on dopamine perikarya inhibits dopaminergic activity, while activation of gamma-aminobutyric acidA receptors results in an indirect disinhibition of dopaminergic function.
Kalivas
P W
PW
Department of Veterinary Comparative Anatomy, Washington State University, Pullman.
Duffy
P
P
Eberhardt
H
H
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D001679:Biogenic Amines / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects*; D009118:Muscimol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects
D001679:Biogenic Amines; D011954:Receptors, Dopamine; D011963:Receptors, GABA-A; D009118:Muscimol; D001418:Baclofen; D004298:Dopamine; D001640:Bicuculline