The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice

Abstract

The concomitant use of alcohol (EtOH) and the psychotherapeutic agent dl-methylphenidate (MPH) has risen as a consequence of an increase in ADHD diagnoses within the drinking age population. It was recently found that the combination of MPH and EtOH increases the self-report of pleasurable feelings relative to MPH alone. This finding raises concerns regarding the combined abuse liability for these two widely used drugs. The present behavioral study reports on the development of an adult male C57BL/6J (B6) mouse model to further characterize this MPH-EtOH interaction. We examined the effects of MPH on EtOH consumption in a limited access paradigm and EtOH stimulation of locomotor activity. B6 mice consumed about 2 g/kg EtOH daily and MPH dose-dependently reduced drinking. The most effective dose of MPH was 1.25 mg/kg, which produced a 41% decrease in drinking and had no effect on locomotor activity. However, when the 1.25 mg/kg dose of MPH was combined with a stimulatory dose of ethanol (1.75 g/kg) by intraperitoneal injection, there was a significantly enhanced stimulation of locomotor activity. The drug combination increased activity compared to the vehicle or MPH injections by 45% and increased the activity relative to EtOH alone by an additional 25%. The results of the EtOH and MPH interactions observed with the mouse model appear to be behaviorally relevant and suggest several converging mechanisms that may underlie MPH-EtOH interactions.

Comparative Ethanol-Induced Potentiation of Stimulatory Responses to Dexmethylphenidate Versus Methylphenidate

“…In animal models we have previously reported that (1) a sub-stimulatory dose of dl-MPH potentiates a stimulatory dose of ethanol, 14 (2) a depressive dose of ethanol strongly potentiates a stimulatory dose of dl-MPH 15 and (3) combining dl-MPH with ethanol potentiates ataxia. 16 Integrating these preclinical investigations with the present human behavioral time course studies using pure d-MPH-ethanol support an underlying neuropharmacological component to this drug combination synergism.…”

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

“…3 mg/kg or less) in behavioral pharmacology experiments is driven by clinical significance. Relatively low doses of MPH are used therapeutically in humans to treat ADHD (Kuczenski and Segal, 2005) and can significantly interact with ethanol in humans (Patrick et al , 2007) and in rodent models (Griffin et al , 2010, 2012a). Further, evidence indicates that low doses of MPH not only affect behavior but also increase extracellular levels of dopamine and norepinephrine in rodents in a regionally specific manner (Balcioglu et al , 2009; Berridge et al , 2006; Koda et al , 2010; Kuczenski and Segal, 1997, 2001).…”

“…Locomotor activity was assessed using a Digiscan Animal Activity Monitor system, model RXYZCM(8) TAO (Accuscan Instruments, Columbus, OH) that has been described in several publications (Griffin et al , 2012a; Griffin and Middaugh, 2006; Griffin et al , 2012b; Griffin et al , 2010)…”

“…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).…”

“…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). Work from other laboratories indicates that MPH (<5 mg/kg) produces significant changes in monoamine concentrations (Balcioglu et al , 2009; Berridge et al , 2006; Koda et al , 2010; Kuczenski and Segal, 1997).…”