Vol. 284, Issue 1, 116-124, 1998

-Aminobutyric Acid_A Agonists Differentially Augment Gnawing Induced by Indirect-Acting Dopamine Agonists in C57BL/6J Mice¹

Ezio Tirelli², Beth Geter-Douglass and Jeffrey M. Witkin

Drug Development Group, Preclinical Pharmacology Laboratory, Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland

Evidence from structure-activity, molecular biology, ligand binding and behavioral studies has suggested potential differences in the pharmacological effects of indirect dopamine agonists. Striatal dopaminergic neurotransmission is under the regulatory control of GABAergic inputs. The ability of agonists of -aminobutyric acid_A (GABA_A) receptors to enhance stereotyped gnawing was used as a method for dissociating the pharmacological effects of indirect-acting dopamine agonists. Gnawing on corrugated cardboard was studied in C57BL/6J mice. The GABA_A agonists, gaboxadol HCl (THIP) and muscimol, were not effective in augmenting gnawing in the presence of the direct-acting dopamine agonists, apomorphine, pergolide, RU 24213 or SKF 38393. In addition, THIP did not enhance the gnawing produced by cocaine, bupropion, GBR 12909 or WIN 35428. In contrast, THIP produced marked augmentation of the gnawing induced by methylphenidate, (+)-amphetamine, methamphetamine, amfonelic acid, indatraline, nomifensine, diclofensine, mazindol and GBR 12935. The qualitative differences in potentiation were not caused by differences in the maximal effect of the drugs alone, inadequate dose or routes of administration, or by differences in duration of action. Neither can the absence of potentiation be accounted for by unique effects of THIP; muscimol was only marginally effective in potentiating the effects of WIN 35428 and bupropion but completely inactive in augmenting the effects of cocaine and GBR 12909. Muscimol was efficacious in augmenting the effects of the drugs for which THIP was active. These results add to a small but growing literature that demonstrates differences in the in vitro and in vivo pharmacological effects of indirect dopamine agonists. The methods used here may help in defining the molecular and neural substrates of these differential effects.