DIFFERENTIAL-EFFECTS OF DIRECT AND INDIRECT DOPAMINE AGONISTS ON THE INDUCTION OF GNAWING IN C57BL 6J MICE/

The ability of indirect dopamine agonists to induce gnawing in male C5 7Bl/6J mice was compared to that of direct dopamine agonists acting at dopamine D-1 or D-2 receptor subtypes. Holes left by the mice on the corrugations of packing cardboard were used as an objective index of g nawing. Indirect dopamine agonists, including dopamine releasers such as fencamfamine, (+)-amphetamine and amfenolic acid and dopamine uptak e inhibitors such as cocaine, GBR 12909 phenyl)methoxy]ethyl]-4-[3-phe nylpropyl]piperazine diHCl} and nomifensine produced dose-dependent in creases in gnawing. None of the direct agonists (e.g., apomorphine, qu inpirole or SKF 82958 lyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ]) increased gnawing. Although these compounds varied in potency and e fficacy, 18 structurally diverse compounds induced gnawing in 100% of the mice tested. Four weak indirect agonists (3,4-methylenedioxymetham phetamine, amantadine, 2-phenylethylamine and benztropine) failed to i nduce gnawing. The lack of efficacy of postsynaptic dopamine agonists was not changed by various combinations of postsynaptic agonists (e.g. , dopamine D-1 and D-2 agonists in combination). Nonetheless, the dopa minergic nature of the gnawing response was confirmed in experiments i n which a host of compounds with primary actions at nondopaminergic si tes did not induce gnawing; compounds included nicotine, caffeine, diz ocilpine, lidocaine, fluoxetine and nisoxetine. In addition, both the dopamine D-1 antagonist SCH 23390 hyl-1-phenyl-2,3,4,5-tetrahydro-1H-3 -benzazepine], the D-2 antagonist eticlopride and the dopamine D-1/D-2 antagonist flupenthixol produced dose-dependent blockade of gnawing i nduced by either cocaine or methylphenidate, All of the antagonists bl ocked gnawing at doses below those producing decreases in spontaneous locomotor activity, with eticlopride showing the greatest selectivity in blocking gnawing over locomotor suppression (7- to 14-fold). Given the general contrast between the effects of direct and indirect dopami ne agonists, the present procedure could serve as a rapid in vivo meth od of distinguishing direct- from indirect-acting dopamine agonists.