Nicotinic receptors differentially modulate the induction and expression of behavioral sensitization to methylphenidate in rats

Rationale: Nicotinic acetylcholine receptors (nAChRs) regulate sensitization to stimulant drugs such as d-amphetamine and cocaine. Objectives: The current study determined if nAChRs modulate the induction and/or expression of behavioral sensitization to high methylphenidate doses. Methods: In experiment 1, rats received saline or mecamylamine (3 mg/kg, sc), followed by saline or methylphenidate (5.6 or 10 mg/kg, sc) during 10 daily sessions; the effect of methylphenidate (1-17 mg/kg, sc) alone was determined 14 days later. In experiment 2, rats received saline or dihydro-β-erythroidine (DHβE; 3 mg/kg, sc), followed by saline or 5.6 mg/kg of methylphenidate. In experiment 3, rats received saline or methylphenidate (5.6 or 10 mg/kg, sc) alone for 10 days; the effect of acute mecamylamine (3 mg/kg, sc) on the response to methylphenidate (1-17 mg/kg, sc) was determined 14 days later. Locomotor activity, sniffing, rearing, grooming, and stereotypy ratings were dependent measures. Results: Methylphenidate produced dose-dependent increases in locomotor activity, sniffing, and stereotypy on day∈1 and these effects were enhanced on day∈10, indicative of sensitization. Mecamylamine attenuated methylphenidate-induced stereotypy only on day∈1, but reduced locomotor activity, sniffing, rearing, and stereotypy on day∈10 and during the methylphenidate challenge phase; similar results were obtained with DHβE. However, acute mecamylamine did not alter the effects of the methylphenidate challenge following the induction of sensitization to methylphenidate alone. Conclusions: Although nAChRs do not appear to regulate the expression of methylphenidate-induced behavioral sensitization, inhibition of high-affinity β2 subunit nAChRs attenuates the induction of behavioral sensitization to high doses of methylphenidate.