Bradley Wetzell

An assessment of MDPV-induced place preference in adult Sprague-Dawley rats

OBJECTIVE Most drugs of abuse have both aversive and rewarding effects, and the use and abuse potential of such drugs is thought to be a function of a balance of these affective properties. Characterizing these effects and their relative balance may provide insight into abuse vulnerability. One drug that has received recent attention is methylenedioxypyrovalerone (MDPV), a monoamine transport inhibitor similar to, but significantly more potent than, cocaine. MDPV is self-administered and has been shown to produce aversive and rewarding effects in adult rats. The present study extended this characterization of the affective properties of MDPV by examining its ability to support place conditioning at a range of doses known to produce taste avoidance. METHODS Male Sprague-Dawley rats were injected with MDPV (1, 1.8 or 3.2mg/kg) or saline and placed on the non-preferred side of a place conditioning apparatus for 30 min. On the next day, they were given an injection of saline and placed on the preferred side. This was repeated three times for a total of four conditioning cycles, and side preference was assessed on a final test. RESULTS All doses of MDPV produced significant increases in time spent in the drug-paired chamber, an effect not seen in vehicle-treated animals. CONCLUSIONS That the same doses of MDPV induced both taste avoidance and place preference allows assessments of how other factors might impact these effects and how they may, in turn, contribute to its abuse liability.

Adolescent nicotine exposure fails to impact cocaine reward, aversion and self-administration in adult male rats.

The present experiments examined the effects of adolescent nicotine pre-exposure on the rewarding and aversive effects of cocaine and on cocaine self-administration in adult male rats. In Experiment 1, adolescent Sprague-Dawley rats (postnatal days 28-43) were given once daily injections of nicotine (0.6mg/kg) or vehicle and then tested for the aversive and rewarding effects of cocaine in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure in adulthood. In Experiment 2, adolescent Sprague-Dawley rats were pre-exposed to nicotine then tested for cocaine self-administration (0.25 or 0.75mg/kg), progressive ratio (PR) responding, extinction and cue-induced reinstatement in adulthood. In Experiment 1, rats showed significant dose-dependent cocaine-induced taste avoidance with cocaine-injected subjects consuming less saccharin over trials, but no effect of nicotine pre-exposure. For place preferences, cocaine induced significant place preferences with cocaine injected subjects spending significantly more time on the cocaine-paired side, but again there was no effect of nicotine history. All rats in Experiment 2 showed clear, dose-dependent responding during cocaine acquisition, PR testing, extinction and reinstatement with no effect of nicotine pre-exposure. These studies demonstrate that adolescent nicotine pre-exposure does not have an impact on cocaines affective properties or its self-administration at least with the specific parametric conditions under which these effects were tested.

Measures of the aversive effects of drugs: A comparison of conditioned taste and place aversions

The present experiments directly compared the ability of the conditioned taste and place aversion designs (CTA and CPA, respectively) to measure the aversive effects of lithium chloride (LiCl) in male Sprague-Dawley rats. In the CTA assessment (Experiment 1), rats were given one of two novel tastes paired with LiCl (0, 0.18, 0.32, 0.56 or 1mEq/kg) and the alternate novel taste paired with vehicle the next day. This was repeated three times, followed by a final two-bottle test. In the CPA assessment (Experiment 2), rats were given LiCl at the same doses and placed on one side of an unbiased two-chambered apparatus, followed by vehicle injection and placement on the opposite side on alternating days. This was repeated three times followed by free access to both sides in an assessment of relative preference. LiCl induced robust, dose-dependent taste aversions with rats receiving 0.32mEq/kg or greater consuming a smaller percentage of the drug-paired taste than that of controls. LiCl did not induce place aversions at any dose with LiCl- and vehicle-treated subjects displaying comparable preferences for the drug-paired side. The basis for the differences of the two designs in indexing LiCls aversive effects was discussed.

Age differences in (±) 3,4‐methylenedioxymethamphetamine (MDMA)‐induced conditioned taste aversions and monoaminergic levels

Preclinical work indicates that adolescent rats appear more sensitive to the rewarding effects and less sensitive to the aversive effects of abused drugs. The present investigation utilized the conditioned taste aversion (CTA) design to measure the relative aversive effects of (±)3,4-methylenedioxymethamphetamine (MDMA; 0, 1.0, 1.8, or 3.2 mg/kg) in adolescent and adult Sprague-Dawley rats. After behavioral testing was complete, monoamine and associated metabolite levels in discrete brain regions were quantified using high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD) to determine if adolescent animals displayed a different neurochemical profile than did adult animals after being exposed to subcutaneous low doses of MDMA. Adolescent rats displayed less robust MDMA-induced taste aversions than adults during acquisition and on a final two-bottle aversion test. MDMA at these doses had no consistent effect on monoamine levels in either age group, although levels did vary with age. The relative insensitivity of adolescents to MDMAs aversive effects may engender an increased vulnerability to MDMA abuse in this specific population.

The effects of cannabidiol (CBD) on Δ⁹-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats.

Despite widespread cannabis use in humans, few rodent models exist demonstrating significant &Dgr;9-tetrahydrocannabinol (THC) self-administration, possibly due to THC’s co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse.

Adolescent exposure to methylphenidate has no effect on the aversive properties of cocaine in adulthood

Methylphenidate is the most widely prescribed pharmacotherapeutic treatment of AD/HD in children and teens and has actions that are also involved in drug reward and reinforcement. Its clinical use has often raised concerns over the possibility that it could potentiate the risk for later drug-related problems. Animals exposed to methylphenidate during adolescence exhibit attenuated cocaine-induced conditioned place preference, but tend to self-administer cocaine more quickly than controls. A drugs abuse potential, as reflected by self-administration, is thought to be the product of a balance between its rewarding and aversive properties, thus the present research assessed the effects of adolescent exposure to methylphenidate on conditioned taste aversions induced by cocaine in adulthood in 132 male Sprague Dawley rats. Although cocaine induced robust dose-dependent taste aversions in accordance with previous research, there were no effects of adolescent exposure to methylphenidate in spite of evidence that it was behaviorally active. The present results indicate that changes in adult cocaine self-administration are not likely mediated by changes in the aversive response. The possibility that such changes are a function of reductions in reward threshold is discussed.

Prepubertal Fischer 344 rats display stronger morphine-induced taste avoidance than prepubertal Lewis rats

The present report asked if the previously reported differences in morphine-induced conditioned taste avoidance between adult F344 and LEW rats (F344 > LEW) are also evident in prepubescence (early adolescence). To assess this possibility, adult (Experiment 1) and prepubertal (Experiment 2) F344 and LEW rats were assessed for their ability to acquire morphine-induced taste avoidance (0, 3.2, 10, or 18 mg/kg) in a modified taste avoidance procedure. In each experiment, rats of both strains were given repeated pairings of saccharin and morphine followed by a final two-bottle avoidance test. Adult and prepubertal F344 subjects displayed a more rapid acquisition of the avoidance response as well as stronger suppression of consumption than their LEW counterparts. These data suggest the strains differ in their sensitivity to the aversive effects of morphine and that this differential sensitivity is evident early in development and is developmentally stable. The basis for these strain differences in morphine-induced avoidance was discussed.