Quantitative Trait Locus Analysis Identifies Rat Genomic Regions Related to Amphetamine-Induced Locomotion and Gαi3 Levels in Nucleus Accumbens

Abstract

Identification of the genetic factors that underlie stimulant responsiveness in animal models has significant implications for better understanding and treating stimulant addiction in humans. F 2 progeny derived from parental rat strains F344/NHsd and LEW/NHsd, which differ in responses to drugs of abuse, were used in quantitative trait locus (QTL) analyses to identify genomic regions associated with amphetamine-induced locomotion (AIL) and G-protein levels in the nucleus accumbens (NAc). The most robust QTLs were observed on chromosome 3 (maximal log ratio statistic score (LRS max ) ¼ 21.3) for AIL and on chromosome 2 (LRS max ¼ 22.0) for Ga i3 . A 'suggestive' QTL (LRS max ¼ 12.5) was observed for AIL in a region of chromosome 2 that overlaps with the Ga i3 QTL. Noveltyinduced locomotion (NIL) showed different QTL patterns from AIL, with the most robust QTL on chromosome 13 (LRS max ¼ 12.2). Specific unique and overlapping genomic regions influence AIL, NIL, and inhibitory G-protein levels in the NAc. These findings suggest that common genetic mechanisms influence certain biochemical and behavioral aspects of stimulant responsiveness.

A genetic animal model of differential sensitivity to methamphetamine reinforcement

“…Fewer (but some) have utilized unbiased gene mapping approaches (e.g., Bryant et al, 2009; Potenza et al, 2008) or have focused on traits with greater face validity for human addiction, such as drug self-administration (Meyer et al, 2010). The relative paucity of these types of studies is understandable, because methods used for measuring amphetamine self-administration in animals have typically involved indwelling intravenous (IV) catheters and extensive training (Roberts et al, 2007), and complex trait mapping typically requires large scale studies involving many individuals.…”

Lewis rats have greater response impulsivity than Fischer rats

“…Third, only male rats were studied. Although this is a common practice in studies of Fischer and Lewis rats (Potenza et al, 2004, 2008), future research examining impulsivity in female Fischer and Lewis rats and sex differences would be valuable, particularly given the sex differences in impulsivity, motivations and addictive behaviors that are observed in people (Chapple & Johnson, 2007; Cross, Copping, & Campbell, 2011; Stoltenberg, Batien, & Birgenheir, 2008). …”

“…Lewis rats have a higher intake of and preference for drugs including cocaine, morphine, ethanol, and nicotine (Horan, Smith, Gardner, Lepore, & Ashby, 1997; Kosten & Ambrosio, 2002; Suzuki, George, & Meisch, 1988; Suzuki, Otani, Koike, & Misawa, 1988). They also demonstrate the differences from Fischer rats in stress measures (including corticosterone levels), drug responsiveness (including amphetamine-induced locomotion) and brain function (including ventral striatal differences), and these differences have been linked to specific genetic locations between the different strains (Potenza et al, 2004; Potenza et al, 2008). Lewis and Fischer rats differ with respect to dopamine (DA) neurotransmission, with Lewis rats having higher levels of DA release in response to stimulants (Camp, Browman, & Robinson, 1994; Strecker, Eberle, & Ashby, 1995), as well as lower levels of DA receptors and DA transporters (Flores, Wood, Barbeau, Quirion, & Srivastava, 1998) than Fischer rats.…”