Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice

Abstract

Previous studies have reported intravenous cocaine selfadministration behavior in several strains of mice with the exception of BALB/cByJ, a strain considered a mouse model of high emotional reactivity. The present experiments further investigated acquisition of self-administration in BALB/cByJ mice using a low dose and a habituation session. Following evidence of an initial drug-seeking behavior, we observed a progressive decline of intravenous self-administration. Pretreatment with diazepam (0.5 mg/ kg, IP), reinstated cocaine-maintained responding. To test the hypothesis that injections directly into a rewardrelevant brain region might support consistent cocaineseeking behavior, BALB/cByJ mice implanted in the nucleus accumbens (NAc) or the caudate-putamen nucleus (CPu) were trained to discriminate between the arm enabling a microinjection of cocaine (30 pmol/50 nl or 150 pmol/50 nl) The reinforcing effect of cocaine has long been demonstrated in several species including humans, (Pickens and Thompson 1968;Woods and Schuster 1968;Deneau et al. 1969;Goldberg 1973;Fischman and Schuster 1982). However, in studies using monkeys as well as rats, not all individual subjects exhibit acquisition of self-administration, and data from subjects that fail to acquire selfadministration are usually excluded (Davis and Smith 1987). Consistent with these observations, many humans experiencing psychostimulant drugs do not develop compulsive drug-seeking behavior (Siegel 1984;O'Brien et al. 1986). Recently, an increasing number of studies have investigated the biological basis of the vulnerability to drug abuse in outbred rats. From this work, it is possible to define a vulnerability profile based on a number of behavioral, neurochemical, and endocrinological features (Hooks et al. 1991;Piazza and Le Moal 1996). Importantly, traits associated with a vulnerable phenotype in rats, such as novelty-induced activity, can be compared to psychological dimensions measured in humans, such as novelty-seeking behavior (see Bardo et al. 1996). It is of special interest to note here that novelty- Cocaine Self-Administration in BALB/cByJ Mice 301 seeking and drug-seeking behaviors co-vary in humans as well as laboratory animals (Bardo et al. 1996). These behaviors are also expressed differentially in inbred strains of mice making these mice a potentially important model for further examining the relationship between behavioral traits, their underlying biological basis, and drug-seeking behavior (Crabbe et al. 1994).Of particular interest in this context is the difficulty of demonstrating intravenous cocaine self-administration in BALB/cByJ mice (Deroche et al. 1997;Roberts et al. 1997;Yu et al. 1997), using doses known to maintain self-administration in C57BL/6 or several other strains (Carney et al. 1991;Grahame et al. 1995;Deroche et al. 1997;Rocha et al. 1998). This observation cannot be accounted for by pharmacokinetic differences (Ruth et al. 1988), capacity to learn operant tasks (Cazala 1976;Deroche et al. 1997;Heyser et al. 199...

Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats

“…This gradual extinction/suppression of cocaine self-administration was reversed by diazepam pretreatment, and the results were interpreted by the authors to support the hypothesis that cocaine has anxiogenic effects. The results of the present experiment concur with this hypothesis, and combine with those of David et al (2001) to suggest that individuals with high trait levels of anxiety are more sensitive to cocaine's aversive effects.…”

“…David et al (2001) successfully trained these mice to nose-poke for low doses of i.v. (0.2 mg kg −1 infusion −1 ) or intraaccumbens (10 ng) cocaine infusions, but the mice gradually extinguished responding, and exhibited retreat behaviors reminiscent of those reported by Ettenberg and Geist (1991).…”

High anxiety is a predisposing endophenotype for loss of control over cocaine, but not heroin, self-administration in rats

“…Data are expressed as the mean ± SEM of the time taken to complete the first active (a and c) or inactive (b and d) lever press for each SA session cocaine in rats (Ettenberg et al 1999) may only be evident in those individuals characterized as LA on the EPM (Rogerio and Takahashi 1992). It has also been suggested that these effects could limit the rewarding properties of the drug (David et al 2001), with the implication being that the relative insensitivity of HA rats to cocaine-associated anxiogenesis could render them more vulnerable to escalation of drug intake. In the present study, however, there were no differences between HA and LA rats with respect to latencies to the first active lever press of each SA session, which has been taken to be an index of sensitivity to the anxiogenic properties of cocaine experienced in previous sessions (Maier et al 2008).…”

Norepinephrine Signaling Through β-Adrenergic Receptors is Critical for Expression of Cocaine-Induced Anxiety

“…anxiety, paranoia, nausea, hypertension). In addition to its well-documented rewarding and locomotor activating effects in rodents, cocaine also induces anxiety-like behavior that can be reversed by administration of typical anxiolytic drugs, such as diazepam (1)(2)(3)(4)(5)(6)(7). Whereas cocaine-induced reward has been studied extensively, less is known about the processes underlying the negative behavioral states associated with acute administration of the drug.…”