Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine

Abstract

Methamphetamine (MA) and cocaine induce behavioral effects primarily through modulation of dopamine neurotransmission. However, the genetic regulation of sensitivity to these two drugs may be similar or disparate. Using selective breeding, lines of mice were produced with extreme sensitivity (high MA activation; HMACT) and insensitivity (low MA activation; LMACT) to the locomotor stimulant effects of acute MA treatment. Studies were performed to determine whether there is pleiotropic genetic influence on sensitivity to the locomotor stimulant effect of MA and to other MA-and cocaine-related behaviors. The HMACT line exhibited more locomotor stimulation in response to several doses of MA and cocaine, compared to the LMACT line. Both lines exhibited locomotor sensitization to 2 mg/kg of MA and 10 mg/kg of cocaine; the magnitude of sensitization was similar in the two lines. However, the lines differed in the magnitude of sensitization to a 1 mg/kg dose of MA, a dose that did not produce a ceiling effect that may confound interpretation of studies using higher doses. The LMACT line consumed more MA and cocaine in a two-bottle choice drinking paradigm; the lines consumed similar amounts of saccharin and quinine, although the HMACT line exhibited slightly elevated preference for a low concentration of saccharin. These results suggest that some genes that influence sensitivity to the acute locomotor stimulant effect of MA have a pleiotropic influence on the magnitude of behavioral sensitization to MA and sensitivity to the stimulant effects of cocaine. Further, extreme sensitivity to MA may protect against MA and cocaine self-administration.

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly

“…Although MA-preference/taking can relate to sensitivity to the drug’s psychomotor-activating effects (16,30,31), within the large sample of B6 mice tested, group differences in spontaneous or MA-induced locomotor activity were not detected (Suppl. Table S1).…”

A role for neuronal nicotinic acetylcholine receptors in ethanol-induced stimulation, but not cocaine- or methamphetamine-induced stimulation

“…An independent set of selected lines has been bred for high (HMACT) or low (LMACT) sensitivity to an acute injection of MA. Similar to the FAST and SLOW mouse lines, the HMACT line was more stimulated by EtOH and COC compared to the LMACT line (Kamens et al 2005(Kamens et al , 2006. Furthermore, lines of mice selectively bred for sensitivity to COC's stimulatory effects also differed in response to amphetamine, such that the lines that were more stimulated by COC were more stimulated by amphetamine (Marley et al 1998).…”

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.…”