GABA(A) receptors mediate the attenuating effects of a 5-HT(3) receptor antagonist on methamphetamine-induced behavioral sensitization in mice.
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.
Yoo
Ji-Hoon
JH
Division of Biochemical Sciences, Faculty of Health and Medical Sciences, University of Surrey, Surrey, United Kingdom.
Lee
Ha-Kyung
HK
Kim
Hyoung-Chun
HC
Lee
Seok-Yong
SY
Jang
Choon-Gon
CG
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
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