GAMMA-AMINOBUTYRIC ACID(A) AGONISTS DIFFERENTIALLY AUGMENT GNAWING INDUCED BY INDIRECT-ACTING DOPAMINE AGONISTS IN C57BL 6J MICE/

Evidence from structure-activity, molecular biology, ligand binding an d behavioral studies has suggested potential differences in the pharma cological effects of indirect dopamine agonists. Striatal dopaminergic neurotransmission is under the regulatory control of GABAergic inputs . The ability of agonists of gamma-aminobutyric acid(A) (GABA(A)) rece ptors to enhance stereotyped gnawing was used as a method for dissocia ting the pharmacological effects of indirect-acting dopamine agonists. Gnawing on corrugated cardboard was studied in C57BL/6J mice. The GAB A(A) agonists, gaboxadol HCl (THIP) and muscimol, were not effective i n augmenting gnawing in the presence of the direct-acting dopamine ago nists, apomorphine, pergolide, RU 24213 or SKF 38393. In addition, THI P did not enhance the gnawing produced by cocaine, bupropion, GBR 1290 9 or WIN 35428. In contrast, THIP produced marked augmentation of the gnawing induced by methylphenidate, (+)-amphetamine, methamphetamine, amfonelic acid, indatraline, nomifensine, diclofensine, mazindol and G BR 12935. The qualitative differences in potentiation were not caused by differences in the maximal effect of the drugs alone, inadequate do se or routes of administration, or by differences in duration of actio n. Neither can the absence of potentiation be accounted for by unique effects of THIP; muscimol was only marginally effective in potentiatin g the effects of WIN 35428 and bupropion but completely inactive in au gmenting the effects of cocaine and GBR 12909. Muscimol was efficaciou s in augmenting the effects of the drugs for which THIP was active. Th ese results add to a small but growing literature that demonstrates di fferences in the in vitro and in vivo pharmacological effects of indir ect dopamine agonists. The methods used here may help in defining the molecular and neural substrates of these differential effects.