Role of 5-HT1B receptors in the sensitization to amphetamine in mice

The present study was designed to determine how 5-HT1B receptor ligands affected the development or the expression phase of sensitization to the amphetamine-induced locomotor response in mice. Mice were treated repeatedly (for 5 days) with amphetamine (2.5 mg/kg) in combination with either vehicle, N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1.2,4-oxadiazol-3yl)-[1, 1'-biphenyl]-4-carboxamide hydrochloride (SB 216641; an antagonist of 5-HT1B receptors), 3-(1,2.5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253, an agonist of 5-HT1B receptors), or SB 216641 + CP 94,253; afterwards, on day 10, they received a challenge dose of amphetamine (2.5 mg/kg). In another experiment, mice were given either vehicle or amphetamine (2.5 mg/kg) for 5 days, and were then challenged with amphetamine (2.5 mg/kg) in combination with vehicle, SB 216641, or CP 94.253 on day 10. Locomotor hyperactivity induced by acute administration of amphetamine(day 1) was dose-dependently inhibited by SB 216641 and enhanced by CP 94,253, but not affected by a combination of SB 216641 + CP 94,253. The 5-HT1B receptor ligands affected similarly the behavioral response to the challenge dose of amphetamine on day 10 (ca. 55-110% more potent than the response to its first administration) when they were combined with the psychostimulant during the development phase (days 1-5) of sensitization. On the other hand, neither SB 216641 nor CP 94,253 administered together with the challenge dose of amphetamine (day 10) affected its behavioral hyperactivity effect in mice treated repeatedly (days 1-5) with the psychostimulant alone. Our results suggest that 5-HT1B receptors may play a permissive role in the development, but not expression, of behavioral sensitization, as well as in the acute locomotor response to amphetamine in mice. (C) 2001 Elsevier Science B.V. All rights reserved.