Male and female C57BL/6 mice display drug-induced aversion and reward in the combined conditioned taste avoidance/conditioned place preference procedure.

BACKGROUND: Drugs of abuse have rewarding and aversive effects that, in balance, impact abuse potential. Although such effects are generally examined in independent assays (e.g., CPP and CTA, respectively), a number of studies have examined these effects concurrently in rats in a combined CTA/CPP design. The present study assessed if similar effects can be produced in mice which would allow for determining how each is affected by subject and experiential factors relevant to drug use and abuse and the relationship between these affective properties. METHODS: Male and female C57BL/6 mice were exposed to a novel saccharin solution, injected (IP) with saline or 5.6, 10 or 18 mg/kg of the synthetic cathinone, methylone, and placed on one side of the place conditioning apparatus. The following day, they were injected with saline, given access to water and placed on the other side of the apparatus. After four conditioning cycles, saccharin avoidance and place preferences were assessed in a final two-bottle CTA test and a CPP Post-Test, respectively. RESULTS: In the combined CTA/CPP design, mice acquired a significant dose-dependent CTA (p = 0.003) and a significant CPP (p = 0.002). These effects were independent of sex (all ps > 0.05). Further, there was no significant relationship between the degree of taste avoidance and place preference (p > 0.05). CONCLUSIONS: Similar to rats, mice displayed significant CTA and CPP in the combined design. It will be important to extend this design in mice to other drugs and to examine the impact of different subject and experiential factors on these effects to facilitate predictions of abuse liability.

Pre-conception exposure to THC fails to impact nicotine reward in adult offspring.

Exposure to environmental stimuli in one generation can produce altered behavioral and neurobiological phenotypes in descendants. Recent work has shown that parental exposure to cannabinoids alters the rewarding properties of other abused drugs in the subsequent generation. However, whether preconception Δ9-tetrahydrocannabinol (THC) administration modifies the affective properties of nicotine in offspring is unknown. To address this question, male and female rats (F0) received THC (0 or 1.5 mg/kg) throughout the adolescent window and were bred on PND 65. In Experiment 1, adult F1-THC and F1-Veh progeny (males and females) underwent nicotine locomotor sensitization procedures during which nicotine (0 or 0.4 mg/kg) was administered every other day for five exposures, and locomotor activity was recorded on each exposure followed by a final nicotine challenge. There was no cross-generational effect of THC on nicotine locomotor sensitization, although acute exposure to nicotine produced greater activity in females relative to males independent of THC history. In Experiment 2, adult F1-THC and F1-Veh progeny (males and females) were implanted with jugular catheters and trained to self-administer nicotine (0.03 mg/kg/infusion). Following acquisition, all subjects were allowed to self-administer nicotine on a number of reinforcement schedules, e.g., FR2, FR5 and PR, followed by dose response and extinction procedures. Across all indices, F1-THC and F1-Veh subjects displayed similar IVSA of nicotine with no sex differences. The fact that there was no evidence of cross-generational effects of THC on nicotine suggests that such effects are drug-specific.

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 cocaine's affective properties or its self-administration at least with the specific parametric conditions under which these effects were tested.

3,4-Methylenedioxypyrovalerone (MDPV)-induced conditioned taste avoidance in the F344/N and LEW rat strains.

The inbred Fischer (F344) and Lewis (LEW) rats, while originally developed as animal models for cancer and tissue transplantation research, have since been used to study genetic differences in a variety of physiological and behavioral endpoints. In this context, LEW rats show greater sensitivity to the aversive effects of cocaine as compared to F344 rats in a conditioned taste avoidance procedure. Like cocaine, 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") acts as a dopamine transport blocker and possesses aversive properties, making it a good candidate for assessing whether the aforementioned strain differences with cocaine would generalize to drugs with similar biochemical action. Accordingly, male F344 and LEW rats were exposed to a novel saccharin solution followed by injections of one of four doses of MDPV in a taste avoidance procedure. Over the four saccharin/MDPV pairings during conditioning, core body temperatures were also assessed. Similar to previous research, MDPV induced robust dose-dependent taste avoidance, although no effect of strain was observed. MDPV also produced hyperthermia that was independent of strain and unrelated to the conditioned taste avoidance. These findings argue for a complex influence of multiple (and likely interacting) monoaminergic systems mediating MDPV-induced taste avoidance in the two strains and suggest different mechanisms of avoidance learning for cocaine and MDPV.

Exposure to nicotine during periadolescence or early adulthood alters aversive and physiological effects induced by ethanol.

The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4mg/kg, IP) from postnatal days 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0g/kg) and the hypothermic effects of alcohol (1.0g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8g/kg) and hypothermic (1.8g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine may alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed.

The impact of early environmental rearing condition on the discriminative stimulus effects and Fos expression induced by cocaine in adult male and female rats.

RATIONALE: A number of environmental manipulations, including maternal separation (MS), have been shown to alter behavioral responses to drugs of abuse. OBJECTIVES: This study assessed if MS affected the stimulus and Fos-inducing effects of cocaine. MATERIALS AND METHODS: In experiment 1, male and female Sprague-Dawley rats were exposed to brief maternal separations (BMS), long maternal separations (LMS), or animal facility rearing (AFR) and then trained as adults to discriminate cocaine (10 mg/kg, intraperitoneally) from saline. Following training, generalization tests to novel doses of cocaine and other dopaminergic compounds were performed. Assessments of variations in training dose pretreatment times were also made. In experiment 2, male and female rats exposed to MS conditions were administered cocaine or saline for 14 days, and Fos expression in the mesolimbic system was measured. RESULTS: In males, BMS retarded the acquisition of the cocaine discrimination. Generalization to novel doses of cocaine did not differ among rearing conditions, but the training dose cue lasted longer in LMS. Distinct generalization and ED(50) profiles were found between male rearing conditions for all dopamine compounds. While BMS females had higher cocaine ED(50) estimates, no other differences were found in females. LMS males and females, as well as AFR females, had significant increases in Fos expression after cocaine in a region-specific manner. No differences were found with other rearing groups. CONCLUSION: Early environmental variables altered the stimulus effects (in a sex-dependent manner) as well as the neuronal responsiveness to cocaine, which may be mediated by the dopamine system.

Adolescent exposure to nicotine alters the aversive effects of cocaine in adult rats.

Nicotine is one of the most commonly used drugs in adolescence and has been shown to alter the rewarding effects of cocaine when administered in adulthood. Although the abuse potential of a drug has been suggested to be a balance between its rewarding and aversive effects, the long-term effects of nicotine on the aversive properties of other drugs had not been studied. To that end, in the present study rats exposed to nicotine (0.4 mg/kg) during adolescence (postnatal days 35-44) were tested for the acquisition and extinction of a cocaine-induced conditioned taste aversion (10, 18 or 32 mg/kg) in adulthood. Conditioning consisted of four saccharin-drug pairings followed by six extinction trials. Although cocaine-induced aversions at all doses, no effect of nicotine preexposure was seen during acquisition. During extinction, the nicotine-preexposed groups conditioned with 10 and 18 mg/kg cocaine displayed a decreased rate of extinction compared to their respective controls. These results suggest that while adolescent nicotine exposure does not appear to directly alter the aversive properties of cocaine it may affect other processes related to the response to drugs given in adulthood.

The effects of nicotine on ethanol-induced conditioned taste aversions in Long-Evans rats.

RATIONALE: Overall drug acceptability is thought to be a function of the balance between its rewarding and aversive effects, the latter of which is reportedly affected by polydrug use. OBJECTIVES: Given that nicotine and alcohol are commonly co-used, the present experiments sought to assess nicotine's impact on ethanol's aversive effects within a conditioned taste aversion design. MATERIALS AND METHODS: Experiment 1 examined various doses of nicotine (0, 0.4, 0.8, 1.2 mg/kg) to determine a behaviorally active dose, and experiment 2 examined various doses of ethanol (0, 0.5, 1.0, 1.5 g/kg) to determine a dose that produced intermediate aversions. Experiment 3 then examined the aversive effects of nicotine (0.8 mg/kg) and ethanol (1.0 g/kg) alone and in combination. Additionally, nicotine's effects on blood alcohol concentrations (BAC) and ethanol-induced hypothermia were examined. RESULTS: Nicotine and ethanol combined produced aversions significantly greater than those produced by either drug alone or the summed aversive effects of the individual compounds. These effects were unrelated to changes in BAC, but nicotine and ethanol combined produced a prolonged hypothermic effect which may contribute to the increased aversions induced by the combination. CONCLUSIONS: These data demonstrate that nicotine may interact with ethanol, increasing ethanol's aversive effects. Although the rewarding effects of concurrently administered nicotine and ethanol were not assessed, these data do indicate that the reported high incidence of nicotine and ethanol co-use is unlikely due to reductions in the aversiveness of ethanol with concurrently administered nicotine. It is more likely attributable to nicotine-related changes in ethanol's rewarding effects.

An assessment of sex differences in nicotine-induced conditioned taste aversions.

Sex differences in taste aversion learning have been reported for a number of different compounds. It is unknown, however, to what degree, if any, such differences exist when nicotine is the aversion-inducing agent. To address this issue, in the present experiment male and female rats were given limited access to saccharin followed by an intraperitoneal (i.p.) injection of either vehicle or nicotine (0.4, 0.8 or 1.2 mg/kg). Although nicotine induced significant taste aversions in both males and females, the aversions were generally weak at all doses tested. There were no sex differences in the acquisition or strength of the aversions induced by nicotine. The vulnerability to drug abuse has been suggested to be a function of the balance of the rewarding and aversive effects of a drug. Given the relatively weak aversions induced in both sexes and the absence of differences between males and females, it is unlikely that the reported sex difference in the self-administration of nicotine is a function of differences in nicotine's aversive effects. The reported difference in the self-administration of nicotine by males and females is more likely a function of differences in the sensitivity to the rewarding effects of the drug.

Strain differences in the acquisition of nicotine-induced conditioned taste aversion.

Lewis (LEW) and Fischer (F344) rat strains differ on a variety of physiological and behavioral endpoints, including reactivity to drugs of abuse. Although they differ in drug reactivity, such assessments are generally limited to morphine and cocaine. To determine if these differences generalize to other drugs, the present study examined these strains for their reactivity to the affective properties of nicotine, specifically their sensitivity to nicotine in the conditioned taste aversion preparation. For four or five conditioning cycles given every other day, rats from both strains were allowed access to saccharin and injected with nicotine (0.1, 0.4, 0.8 mg/kg) or vehicle. On intervening days, all rats were given access to water and injected with vehicle. Under this one-bottle training and testing procedure, neither strain displayed aversions at the lowest dose of nicotine (0.1 mg/kg). Aversions were evident for both strains at 0.4 and 0.8 mg/kg, although the F344 rats acquired the aversions at 0.4 mg/kg faster and displayed a significantly greater aversion at 0.8 mg/kg than subjects from the LEW strain. For both strains, aversions were evident at all doses (and in a dose-dependent manner) when subjects were given access to saccharin and water in a two-bottle test. There were, however, no strain differences on this test. Differences between the two strains in their acquisition of nicotine-induced taste aversions were discussed in the context of aversion assessments with other compounds as well as in relation to differences in the self-administration of nicotine in the two strains.

Morphine- and cocaine-induced c-Fos levels in Lewis and Fischer rat strains.

Lewis (LEW) and Fischer 344 (F344) rat strains have been reported to differ in their sensitivity to the rewarding and aversive effects of both cocaine and morphine. Specifically, LEW rats self-administer morphine and cocaine to a greater extent than F344 rats, while LEW (compared to F344) rats are more sensitive to the aversive effects of cocaine but less sensitive to the aversive effects of morphine. Consistent with assessments of the rewarding effects of morphine and cocaine in these two strains, LEW rats have lower basal, and generally higher drug-induced, activity in brain regions associated with reward. Although the brain areas that mediate the aversive effects of drugs are becoming better defined, no studies have compared the activation of these areas by aversion-inducing drugs in the LEW and F344 strains. As such, the relationship between the ability of drugs to activate these aversion-associated brain areas and to induce a conditioned taste aversion (CTA) in these strains is unknown. To explore this relationship, LEW and F344 rats were injected with saline or doses of morphine or cocaine (32 mg/kg for both drugs) that have been shown to generate differential taste aversion learning in these strains. All animals were subsequently tested for c-Fos expression in areas of the brain associated with aversion learning (the lateral and medial parabrachial nucleus, intermediate and caudal nucleus tractus solitarius and area postrema), reward (the shell of the nucleus accumbens) and locomotion (the core of the nucleus accumbens and the caudate putamen). The present results indicated that patterns of morphine- and cocaine-induced c-Fos within CTA-associated, but not reward- or locomotor-associated, brain regions paralleled the differential behavioral sensitivities of LEW and F344 rats to these drugs within CTA learning. Analyses with other drugs that do and do not induce aversions differentially would further assess the role of these brain areas in aversion learning, in general, and in strain-dependent differences, in particular.