Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice

Abstract

Introduction Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice. Methods We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus. We also used gas chromatographic methods to measure brain tissue levels of EtOH and the d and l isomers of MPH and the metabolite, ethylphenidate (EPH). Results In discrimination, EtOH (1g/kg) produced a significant leftward shift in the MPH generalization curve (1-2mg/kg) for MPH-trained mice, but no effects of MPH (0.625-1.25mg/kg) on EtOH discrimination in EtOH-trained mice (0-2.5g/kg) were observed. In CPP, the MPH (1.25mg/kg) and EtOH (1.75g/kg) combination significantly increased time on the drug paired side compared to vehicle (30.7%), but this was similar to MPH (28.8%) and EtOH (33.6%). Footslip errors measured in a parallel rod apparatus indicated that the drug combination was very ataxic, with footslips increasing 29.5% compared to EtOH. Finally, brain EtOH concentrations were not altered by 1.75g/kg EtOH combined with 1.25mg/kg MPH. However, EtOH significantly increased d-MPH and l-EPH without changing l-MPH brain concentrations. Conclusions The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain d-MPH concentrations. These studies are consistent with observations in humans of increased interoceptive awareness of the drug combination and provide new clinical perspectives regarding enhanced ataxic effects of this drug combination.

Ethylphenidate: availability, patterns of use, and acute effects of this novel psychoactive substance

“…Twenty-four papers were not specifically included: 20 related to methylphenidate rather than ethylphenidate, 3 described ethylphenidate's use as an internal standard for measuring methylphenidate, and a further paper related to analytical identification of ethylphenidate [6,7,9,10,[12][13][14][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66].…”

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

“…To enable crossspecies comparisons, we used the same dose ranges used in previous SSRTT studies in rats (Bari et al, 2009;Eagle et al, 2007). These doses ranges have been shown to be effective in other behavioral tasks in mice (Davis and Gould, 2007;Griffin et al, 2013) and lead to systematic changes in monoamine release in mouse mPFC assessed using microdialysis (Koda et al, 2010). Furthermore, the chosen dose range of methylphenidate gives rise in the mouse to approximate plasma levels obtained following therapeutic dosing in patients (Balcioglu et al, 2009).…”

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice

“…Concern regarding prescription drug abuse in general, and MPH in particular, has prompted the continued study of MPH in humans and rodents under a variety of situations and conditions [ e.g. (Bell et al , 2011; Brookshire and Jones, 2012; Griffin et al , 2012a; Hammerness et al , 2012; Jones and Dafny, 2013; Patrick et al , 2007)]. Moreover, recent reports indicate that despite behavioral effects similar to psychostimulants such as cocaine, MPH has distinct effects on monoaminergic transmission, which appear to be unique among the variety of drugs that target the dopamine transporter (Calipari et al , 2012; Ferris et al , 2012).…”

“…Direct evidence that MPH produces a discriminative stimulus comes from several drug discrimination studies in humans (Duke et al , 2011; Lile et al , 2006; Stoops et al , 2005b), rats (Overton and Shen, 1988; Perkins et al , 1991) and mice (Griffin et al , 2012a; McGovern et al , 2011). A number of reports also describe the ability of MPH to at least partially substitute for other psychostimulants such as cocaine (Bondareva et al , 2002; Li et al , 2006; Rush et al , 2002; Schweri et al , 2002), amphetamine (Bondareva et al , 2002; Czoty et al , 2004) and methamphetamine (Desai et al , 2010; Sevak et al , 2009).…”

“…Interestingly, although low doses of MPH (<5mg/kg) do not overtly increase locomotion (Griffin et al , 2010; 2012a; Williard et al , 2007), low doses can support the development of place preference (Griffin et al , 2012a) and reduce ethanol consumption (Griffin et al , 2010). Additionally, these low doses interact pharmacologically with ethanol to augment locomotion and discrimination (Griffin et al , 2010; 2012a).…”