Behavioral genetic contributions to the study of addiction-related amphetamine effects

Abstract

Amphetamines, including methamphetamine, pose a significant cost to society due to significant numbers of amphetamine-abusing individuals who suffer major health-related consequences. In addition, methamphetamine use is associated with heightened rates of violent and property-related crimes. The current paper reviews the existing literature addressing genetic differences in mice that impact behavioral responses thought to be relevant to the abuse of amphetamine and amphetaminelike drugs. Summarized are studies that used inbred strains, selected lines, single gene knockouts and transgenics, and quantitative trait locus (QTL) mapping populations. Acute sensitivity, neuroadaptive responses, rewarding and conditioned effects are among those reviewed. Some gene mapping work has been accomplished, and although no amphetamine-related complex trait genes have been definitively identified, translational work leading from results in the mouse to studies performed in humans is beginning to emerge. The majority of genetic investigations has utilized single-gene knockout mice and has concentrated on dopamine-and glutamate-related genes. Genes that code for cell support and signaling molecules are also well-represented. There is a large behavioral genetic literature on responsiveness to amphetamines, but a considerably smaller literature focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and behavioral toxicity. Also missing are genetic investigations into the effects of amphetamines on social behaviors. This information might help to identify at-risk individuals and in the future to develop treatments that take advantage of individualized genetic information.

Methamphetamine-induced locomotor changes are dependent on age, dose and genotype

“…As there are many dosing regimens available in the literature we needed to select one that would be best suited for our study conditions (Imam et al, 2001a, Phillips et al, 2008, Zhu et al, 2006a). A pilot strain survey was conducted using a single 2 mg/kg METH dose to assess whether different OFA behavioral profiles would be elicited across 5 inbred strains (results not shown).…”

“…A continuum of effects ranging from neurotoxicity to acute hyperactivity and behavioral sensitization have been observed. These regimens have spanned from single large doses of 40 mg/kg METH (Imam et al, 2001a) and 4 × 5 mg/kg METH every 2 hours (Zhu et al, 2006a), to acute low doses ranging between 1 and 5 mg/kg METH (Phillips et al, 2008. The use of a 7.5 mg/kg METH challenge 8 days after a single session of 4 × 10 mg/kg METH every 2 hours produced a significant decrease in spontaneous activity, an increase in stereotypic behavior, and a significant decline in the concentration of DA in the caudate nucleus and the nucleus accumbens of rats (Wallace et al, 1999).…”

“…This response profile was again observed during the repeated dosing regimen of 2 mg/kg, administered 5 times at 3 day intervals. Quantitative trait locus mapping and targeted gene mutation studies have begun to identify and characterize genes that confer genetic variation to METH responses in the mouse (Bryant et al, 2009; Grisel et al, 1997; Phillips et al, 2008; Uhl et al, 2008). Effects of age were observed in a study in which rats aged 1, 6 and 12 months were exposed to four different METH doses ranging from 5 to 40 mg/kg.…”

Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids

“…Variation in sensitivity to the locomotor stimulant effect of amphetamines and opioids is heritable (Belknap et al, 1998;Phillips et al, 2008;Gill and Boyle, 2008;Oliverio et al, 1975;Philip et al, 2010). Because epidemiological studies indicate that sensitivity to drug liking in humans can predict an individual's susceptibility to drug abuse (Haertzen et al, 1983;Schuckit, 2009), drug sensitivity and abuse are hypothesized to share a genetic basis.…”

Genome-Wide Association Studies and the Problem of Relatedness Among Advanced Intercross Lines and Other Highly Recombinant Populations

“…We used an AIL to study sensitivity to methamphetamine, which is a genetically complex trait that may be useful for identifying genetic factors influencing the subjectively euphoric response to stimulant drugs and susceptibility to drug abuse (Palmer et al 2005;Phillips et al 2008;Bryant et al 2009). For example, a prior study suggested that the gene Casein Kinase 1 Epsilon (Csnk1e) might influence sensitivity to the acute locomotor response to methamphetamine in mice (Palmer et al 2005).…”