Effects of a selectively bred novelty-seeking phenotype on the motivation to take cocaine in male and female rats

Abstract

BackgroundGender and enhanced novelty reactivity can predispose certain individuals to drug abuse. Previous research in male and female rats selectively bred for high or low locomotor reactivity to novelty found that bred High Responders (bHRs) acquire cocaine self-administration more rapidly than bred Low Responders (bLRs) and that bHR females in particular self-administered more cocaine than the other groups. The experiments presented here aimed to determine whether an individual's sex and behavioral phenotype interact to affect motivation to take cocaine.MethodsWe examined motivation for taking cocaine in two experiments using a range of doses on a progressive ratio (PR) schedule of responding in bHR or bLR males and females. Additionally, we included a measure of continuing to respond in the absence of reinforcement, a feature of addiction that has been recently incorporated into tests of animal models on the basis of the criteria for substance use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Statistical analyses were performed using PASW Statistics 18.0 software. Data were analyzed using repeated-measures analysis of variance followed by a Bonferroni correction post hoc test when applicable.ResultsWe found sex differences as well as effects of novelty reactivity on the motivation to self-administer cocaine. Specifically, females demonstrated higher breaking points on the PR schedule compared with males, regardless of phenotype, and bHR males and females exhibited higher motivation than bLR animals at a number of the doses studied.ConclusionsAn individual's sex continues to be a predisposing factor with respect to drug abuse liability and can be compounded by additional individual differences such as reactivity to novelty.

Sex Differences in Animal Models: Focus on Addiction

“…Female rats will work harder for cocaine during the estrous phase of the cycle than during other phases of the cycle. Estradiol enhances motivation in ovariectomized rats, and females work harder than males for cocaine at moderate doses (Roberts et al, 1989;Becker and Hu, 2008;Cummings et al, 2011). In other studies, estradiol treatment increases the initial binge period and enhances cocaine self-administration .…”

High novelty-seeking rats are resilient to negative physiological effects of the early life stress

“…We believe that the bLR rat represents a useful new rodent model of co-morbid anxiety- and depression given their naturally high levels of anxiety- and depressive-like behavior (Kabbaj et al, 2000, White et al, 2007, Flagel et al, 2010, Clinton et al, 2011a, Perez et al, 2009, Clinton et al, 2008, Stedenfeld et al, 2011, Garcia-Fuster et al, 2012), diminished aggression (Kerman et al, 2011) and sexual motivation (McCullumsmith et al, 2007), and reduced responsivity to reward (Kabbaj, 2004, Piazza et al, 1989, Flagel et al, 2011, Davis et al, 2008, Garcia-Fuster et al, 2010, Cummings et al, 2011). The present study together with our earlier work (Clinton et al, 2008, Stedenfeld et al, 2011) also demonstrates bLRs’ high vulnerability to chronic stress whereas bHRs are fairly resilient.…”

“…Rats bred for high response to novelty (bred High Responders, bHRs) exhibit increased aggression (Kerman et al, 2011), impulsivity (Flagel et al, 2010), and proclivity to addictive behavior (Cummings et al, 2011, Davis et al, 2008, Flagel et al, 2010) compared to low novelty reactive rats (bred Low Responders, bLRs), which show high levels of anxiety- and depressive-like behavior (Stedenfeld et al, 2011, Stead et al, 2006, Perez et al, 2009, Clinton et al, 2011b, Clinton et al, 2008). The distinct bHR/bLR phenotypes are likely driven by several factors, including distinct ontogeny of hippocampal circuits (Clinton et al, 2011b), HPA axis reactivity (Clinton et al, 2008, Kerman et al, 2012), and the Fibroblast Growth Factor (FGF) system (Perez et al, 2009, Turner et al, 2011).…”

Individual Differences and Social Influences on the Neurobehavioral Pharmacology of Abused Drugs

“…Selective breeding, recombinant inbred lines, knock-out, knockin, and gene silencing techniques are powerful tools for examining genetic heritability of individual differences in drug use. For example, selectively bred and recombinant inbred rats have been used to demonstrate that individual differences in response to novelty or preference for novelty are associated with individual differences in stimulant self-administration (Meyer et al, 2010;Cummings et al, 2011). Genetic influences also play a role in social behaviors, as illustrated by work showing the influence of serotonin (5-HT) transporter 258 polymorphisms on social intrusion in nonhuman primates (Schwandt et al, 2010).…”

“…Although individual differences have been reported for maintenance across various unit doses in cocaine self-administration (Piazza et al, 2000), they are most influential for acquisition at low unit doses (0.25 mg/kg per infusion; Mantsch et al, 2001), suggesting that HR/LR differences may be most closely associated with sensitivity to drug reinforcement. The HR/LR difference probably is due, at least in part, to genetic factors because inbred lines possessing the HR and LR phenotypes also display differences in the psychostimulant and reinforcing effects of stimulants (Gingras and Cools, 1997;Davis et al, 2008;Turner et al, 2008;Cummings et al, 2011).…”