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 C57Bl/6J mice was compared to that of direct dopamine agonists acting at dopamine D1 or D2 receptor subtypes. Holes left by the mice on the corrugations of packing cardboard were used as an objective index of gnawing. Indirect dopamine agonists, including dopamine releasers such as fencamfamine, (+)-amphetamine and amfenolic acid and dopamine uptake inhibitors such as cocaine, GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine diHCl) and nomifensine produced dose-dependent increases in gnawing. None of the direct agonists (e.g., apomorphine, quinpirole or SKF 82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine]) increased gnawing. Although these compounds varied in potency and efficacy, 18 structurally diverse compounds induced gnawing in 100% of the mice tested. Four weak indirect agonists (3,4-methyl-enedioxymethamphetamine, amantadine, 2-phenylethylamine and benztropine) failed to induce gnawing. The lack of efficacy of postsynaptic dopamine agonists was not changed by various combinations of postsynaptic agonists (e.g., dopamine D1 and D2 agonists in combination). Nonetheless, the dopaminergic nature of the gnawing response was confirmed in experiments in which a host of compounds with primary actions at nondopaminergic sites did not induce gnawing; compounds included nicotine, caffeine, dizocilpine, lidocaine, fluoxetine and nisoxetine. In addition, both the dopamine D1 antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine], the D2 antagonist eticlopride and the dopamine D1/D2 antagonist flupenthixol produced dose-dependent blockade of gnawing induced by either cocaine or methylphenidate.(ABSTRACT TRUNCATED AT 250 WORDS)
Tirelli
E
E
Psychobiology Section, National Institute on Drug Abuse Addiction Research Center, Baltimore, Maryland, USA.
Witkin
J M
JM
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects*
D018491:Dopamine Agonists; D016202:N-Methylaspartate; D001058:Apomorphine; D004298:Dopamine