title: GABA(A) receptors mediate the attenuating effects of a 5-HT(3) receptor antagonist on methamphetamine-induced behavioral sensitization in mice.
abstract: We previously showed that 5-HT(3) receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. Here, we examined whether the dopaminergic or the GABAergic systems are involved in the attenuating effects of the 5-HT(3) receptor antagonist MDL72222 on MAP-induced locomotor sensitization. Quantitative autoradiography of D1 ([(3)H]SCH23390), D2 ([(3)H]raclopride) receptor, and GABA(A) receptor benzodiazepine ([(3)H]flunitrazepam) binding was carried out in the brains of mice treated with chronic MAP and pretreatment with MDL72222. No significant differences were found in D(1) and D(2) binding between the two groups, suggesting that the attenuating effects of MDL72222 on MAP-induced locomotor sensitization is not medicated by D1 and D2 receptors. Postsynaptic dopamine (DA) receptor supersensitivity was measured by challenge with apomorphine, a dopamine D(1) and D(2) receptor agonist, after repeated MAP treatment or pretreatment with MDL72222 before MAP. Apomorphine induced an enhanced locomotor activity in both chronic MAP-treated mice and mice pretreated with MDL 72222, with no significant differences between the two groups. The binding of [(3)H]flunitrazepam was significantly decreased in the motor and cingulate cortex, caudate putamen, and nucleus accumbens of mice in the repeated MAP treatment group compared with the control group, and this effect was reversed by pretreatment with MDL72222. This suggested that GABA(A) benzodiazepine binding sites are involved in the attenuating effects of a 5-HT(3) receptor antagonist on MAP-induced locomotor sensitization.
authors: Division of Biochemical Sciences, Faculty of Health and Medical Sciences, University of Surrey, Surrey, United Kingdom.
authors: Ji-Hoon
authors: JH
authors: Yoo
authors: Ha-Kyung
authors: HK
authors: Lee
authors: Hyoung-Chun
authors: HC
authors: Kim
authors: Seok-Yong
authors: SY
authors: Lee
authors: Choon-Gon
authors: CG
authors: Jang
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy / Q000209:etiology*; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001931:Brain Mapping; D018491:Dopamine Agonists / Q000494:pharmacology; D004347:Drug Interactions; D005445:Flunitrazepam / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D020891:Raclopride / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014316:Tritium / Q000378:metabolism; D014326:Tropanes / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; C534628:SCH 23390; D012702:Serotonin Antagonists; D014326:Tropanes; D014316:Tritium; D020891:Raclopride; D008694:Methamphetamine; D005445:Flunitrazepam; D001058:Apomorphine; C042253:bemesetron