A genetic animal model of differential sensitivity to methamphetamine reinforcement

Abstract

Sensitivity to reinforcement from methamphetamine (MA) likely influences risk for MA addiction, and genetic differences are one source of individual variation. Generation of two sets of selectively bred mouse lines for high and low MA drinking has shown that genetic factors influence MA intake, and pronounced differences in sensitivity to rewarding and aversive effects of MA play a significant role. Further validation of these lines as a unique genetic model relevant to MA addiction was obtained using operant methods to study MA reinforcement. High and low MA drinking line mice were used to test the hypotheses that: 1) oral and intracerebroventricular (ICV) MA serve as behavioral reinforcers, and 2) MA exhibits greater reinforcing efficacy in high than low MA drinking mice. Operant responses resulted in access to an MA or non-MA drinking tube or intracranial delivery of MA. Behavioral activation consequent to orally consumed MA was determined. MA available for consumption maintained higher levels of reinforced instrumental responding in high than low MA drinking line mice, and MA intake in the oral operant procedure was greater in high than low MA drinking line mice. Behavioral activation was associated with amount of MA consumed during operant sessions. High line mice delivered more MA via ICV infusion than did low line mice across a range of doses. Thus, genetic risk factors play a critical role in the reinforcing efficacy of MA and the oral self-administration procedure is suitable for delineating genetic contributions to MA reinforcement.

Long-term effects of exposure to methamphetamine in adolescent rats

“…This difference suggests that mAMPH pre-treated rats accrued an enhanced sensitivity to the rewarding effects of the drug upon adolescent exposure, similar to what has been found with other substances (Anker et al, 2011; Doremus et al, 2003). These findings are also consistent with other reports of increased sensitivity to the rewarding and reinforcing effects of mAMPH in a genetic mouse model of heightened oral self-administration (Shabani et al, 2011; 2012a). Such increased sensitivity is believed to result in an amplified resistance to drug extinction and increased drug-seeking behavior (Kitamura et al, 2006; Rogers et al, 2008), though this remains untested in the present study.…”

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

“…Considerable attention has been given to positive rewarding effects associated with MA addiction (Beckmann et al, 2010;Horton et al, 2011;Kamens et al, 2005;Mahler et al, 2013;Meyer et al, 2011;Mizoguchi et al, 2004;Shabani et al, 2011Shabani et al, , 2012aWheeler et al, 2009), whereas aversive effects that could limit intake have been given less consideration (Harrod et al, 2010;Pringle et al, 2008;Shabani et al, 2011Shabani et al, , 2012bWheeler et al, 2009). Greater Figure 3 (a) Methamphetamine (MA) consumption differs by Taar1 genotype.…”

“…Finally, MAHDR mice show little sensitivity to aversive effects of MA in conditioned place and conditioned taste aversion (CTA) assays, whereas MALDR mice exhibit high sensitivity. The geneticallydetermined, robust sensitivity to aversive effects in MALDR mice likely limits their MA intake (Shabani et al, 2011(Shabani et al, , 2012aWheeler et al, 2009).…”

Effect of the environmental enrichment on the severity of psychological dependence and voluntary methamphetamine consumption in methamphetamine withdrawn rats

“…The daily consumption of METH measured based on mg/kg/18 h. Preference ratios (ml METH solution consumed/total ml consumed from both bottles) and also, the average of water consumption were evaluated during a 4-day period. The oral METH at relatively low doses causes arousing and rewarding effects in the rats and humans [8,31].…”