Role of the ERK pathway in psychostimulant-induced locomotor sensitization

A dose of SL327 (30 mg/kg) that reduced the number of activated ERK-positive neurons by 62 to 89% in various brain areas, had virtually no effect on the spontaneous locomotor activity or the acute hyperlocomotion induced by cocaine or D-amphetamine. Pre-treatment with SL327 (30 mg/kg) prior to each drug administration prevented the locomotor sensitization induced by repeated injections of D-amphetamine or cocaine. The SL327 pre-treatment abolished also conditioned locomotor response of mice placed in the context previously paired with cocaine or D-amphetamine. In contrast, SL327 did not alter the expression of sensitized response to D-amphetamine or cocaine.Altogether these results show that ERK has a minor contribution to the acute locomotor effects of psychostimulants or to the expression of sensitized responses, whereas it is crucial for the acquisition of locomotor sensitization and psychostimulant-conditioned locomotor response. This study supports the important role of the ERK pathway in long-lasting behavioral alterations induced by drugs of abuse.Behavioral sensitization corresponds to a progressive enhancement of locomotor responses following repeated exposure to cocaine or D-amphetamine (D-amph) [1]. When established, sensitization is long-lasting since it is observed after re-exposure to the drug several weeks or even one year later [2]. Sensitization is thought to underlie important aspects of vulnerability to drug addiction and relapse [2,3]. In rodents sensitization was shown to enhance predisposition to psychostimulant self-administration [4] and to facilitate the reinstatement by drugs of extinguished self-administration [5,6]. Behavioral sensitization is strengthened by association of psychostimulant injections with contextual cues and context-dependent sensitization involves different behavioral and neurobiological mechanisms from context-independent sensitization [7,8].Processes underlying induction and expression of behavioral sensitization invol