Abstract
RationaleCytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats.MethodsTo investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release.ResultsCYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization.ConclusionsCYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.
Highlights
CanadaMethamphetamine (MAMP) is a highly addictive psychostimulant and neurotoxin
Stereotypy response sensitized across seven daily MAMP injections, and stereotypy sensitization was enhanced by propranolol pretreatment, as compared to vehicle pretreatment, both in the presence and absence of microdialysis conducted during the first and last sessions
Brain MAMP and AMP concentrations following MAMP injection on day 1 correlated with striatal dopamine and serotonin release, which correlated with the slope of stereotypy time across daily MAMP sessions, as well as with stereotypy response on day 7
Summary
MAMP use can lead to dependence and addiction, characterized by craving and high rates of relapse (Brecht and Herbeck 2014; Lopez et al 2015). In animals, repeated MAMP administration induces behavioral sensitization and altered neurotransmission, for example, enhanced dopamine and serotonin release (Ago et al 2006; Kazahaya et al 1989). Behavioral sensitization has been used to model components of addiction, for example, drug craving and relapse (Robinson and Berridge 1993; Steketee and Kalivas 2011), as well as to model MAMP-induced psychosis and psychotic disorders (Akiyama et al 1994; Schmidt and Beninger 2006). Identifying factors that influence behavioral sensitization in other species may provide insight into individual differences in susceptibility to chronic effects of MAMP in humans
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