Assessment of aversive effects of methylone in male and female Sprague-Dawley rats: Conditioned taste avoidance, body temperature and activity/stereotypies.

Methylone's rewarding effects have been well characterized; however, little is known about its aversive effects and how such effects may be impacted by sex. In this context, the present study investigated the aversive effects of methylone (vehicle, 5.6, 10 or 18 mg/kg, IP) in 35 male and 31 female Sprague-Dawley rats assessed by conditioned taste avoidance and changes in body temperature and activity/stereotypies. Methylone induced significant taste avoidance, changes in temperature and increased activity and stereotypies in both males and females. Similar to work with other synthetic cathinones, methylone has aversive effects as indexed by significant taste avoidance and changes in temperature and activity (two characteristics of methylone overdose in humans). The only endpoint for which there were significant sex differences was in general activity with males displaying a faster onset and females displaying a longer duration. Although sex was not a factor with taste avoidance and temperature, separate analyses for males and females revealed different patterns, e.g., males displayed a more rapid acquisition of taste avoidance and females displayed changes in temperature at lower doses. Males displayed a faster onset and females displayed a longer duration of activity (consistent with the analyses considering sex as a factor), while time- and dose-dependent stereotypies did not show consistent pattern differences. Although sex differences were relatively limited when sex was specifically assessed as a factor (or only evident when sex comparisons were made in the patterns of effects), sex as a biological variable in the study of drugs should be made to determine if differences exist and, if evident, the basis for these differences.

An assessment of concurrent cannabidiol and Δ9-tetrahydrocannabinol administration in place aversion and taste avoidance conditioning.

Rising interest in medical marijuana has prompted research into its phytocannabinoid constituents, particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Coadministration of CBD with THC has been shown to modulate a number of THC's effects, including its negative stimulus properties (e.g., anxiety, paranoia, psychosis) in a clinical setting. The present series of experiments extended these analyses by examining the ability of CBD to impact the aversive effects of THC as assessed in a combined taste and place conditioning procedure. In Experiment 1, male and female Wistar rats were given access to a novel saccharin solution, injected with a vehicle solution CBD (0.075, 0.75 mg/kg), THC (0.75 mg/kg) or several combinations of CBD and THC (1:10 or 1:1 dose ratio), and then placed in a distinct chamber of a place conditioning apparatus. When THC was administered alone, it induced significant place aversions and taste avoidance. At both dose ratios, CBD failed to modulate either effect. There were no sex differences in either assay or at any ratio. A follow-up experiment (Experiment 2) employed identical dose ratios, but a higher dose of THC (7.5 mg/kg) and corresponding CBD doses (0.75, 7.5 mg/kg). Similar to the initial assessment, CBD had no effect on THC-induced place or taste conditioning at either dose ratio. These results may reflect the specific phytocannabinoid dose ratios examined or species differences in cannabinoid action. The current findings further suggest that altering CBD content in medicinal cannabis will likely have minimal effects in terms of tolerability. (PsycINFO Database Record

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.

Assessment of the aversive effects of peripheral mu opioid receptor agonism in Fischer 344 and Lewis rats.

The Fischer 344 (F344) and Lewis (LEW) inbred rat strains differ on a host of biochemical, neuroanatomical, immunological and behavioral endpoints. One behavioral difference of interest is their differential reactivity to the aversive effects of morphine as indexed by the conditioned taste aversion preparation (aversions acquired by F344 rats are significantly greater than those acquired by the LEW strain). This differential effect appears to be specific to opioids that work primarily on the mu opioid receptor. Given that morphine works systemically, it is unknown whether these differential effects in F344 and LEW animals are centrally or peripherally mediated. To address this issue, the present study investigated the ability of the peripherally acting mu preferring opioid agonist loperamide to induce differential taste aversions in F344 and LEW animals. Both F344 and LEW animals acquired dose-dependent taste aversions to the loperamide-associated solution with no difference between them. Additionally, control animals initially injected with vehicle during aversion training with loperamide and subsequently conditioned with morphine displayed the typical aversive profile to morphine (F344>LEW). Although the basis for the present data is unknown, their relation to morphine-induced taste aversions and the role of the interaction of stimulus effects of drugs that produce differential abuse liability were discussed.

Discriminative stimulus properties of naloxone in Long-Evans rats: assessment with the conditioned taste aversion baseline of drug discrimination learning.

RATIONALE: The characterization of the discriminative stimulus properties of naloxone has focused primarily on its actions at the mu opioid receptor, although naloxone also displays an affinity for delta and kappa receptor subtypes. OBJECTIVES: The present study extends this characterization of the naloxone cue by investigating if relatively specific antagonists for the mu (naltrexone: 0.10-0.56 mg/kg), delta (naltrindole: 1-18 mg/kg), and kappa (MR2266: 1.8-10 mg/kg) opioid receptor subtypes will substitute for naloxone in animals trained to discriminate naloxone from its vehicle. The temporal nature of the naloxone cue was examined by varying pretreatment time points (15, 30, 45, 60 min). Finally, various doses of naltrexone methobromide (1-18 mg/kg) were assessed to determine peripheral mediation of the cue. MATERIALS AND METHODS: Female Long-Evans rats (N = 30) received an injection of naloxone (1 mg/kg; i.p.) 15 min prior to a pairing of saccharin (20-min access) and the emetic LiCl (1.8 mEq; i.p.; n = 16, group NL) or vehicle (n = 14, group NW); on other days, they were injected with saline prior to saccharin alone. Substitution tests with compounds with various receptor affinities and selective CNS and PNS actions were then assessed. RESULTS: Only naloxone and naltrexone produced dose-dependent decreases in saccharin consumption. Naloxone administered at 15 and 30 min before saccharin produced decreases in consumption similar to that displayed on training days. Naltrexone methobromide substituted only at the highest dose tested (18 mg/kg). CONCLUSIONS: Naloxone's stimulus effects appear to be mediated centrally via activity at the mu opioid receptor.

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.

Assessment of the aversive and rewarding effects of alcohol in Fischer and Lewis rats.

RATIONALE: Application of the Fischer-Lewis genetic model of drug abuse to the study of alcohol's motivational properties has been limited. OBJECTIVES: To assess the aversive and rewarding effects of ethanol in Fischer and Lewis rats. MATERIALS AND METHODS: Fischer and Lewis rats underwent a four-trial combined conditioned taste aversion/conditioned place preference procedure (CTA/CPP; 0, 1, 1.25, or 1.5 g/kg IP ethanol). Others received 0, 1, or 1.5 g/kg followed by tail blood sampling at 15-, 60- and 180-min post-injection. In additional groups, hypothermia to 0, 1.5, and 3 g/kg was assessed before and 30- and 60-min post-injection. RESULTS: All alcohol-treated groups except low-dose Lewis acquired CTA after one trial. Fischer rats developed stronger CTAs than Lewis at 1.25 and 1.5 g/kg. Ethanol-induced reward in taste or place conditioning was not evident in either strain. Lewis animals showed overall higher peak blood alcohol concentrations, but hypothermia did not vary by strain. CONCLUSION: Compared to Fischer, Lewis rats are less sensitive to alcohol's aversive effects as assessed in the CTA paradigm. The behavioral differences observed are not due to hypothermia, but pharmacokinetic differences may contribute. These data underscore the importance of genetic factors and the aversive effects of initial drug exposures in modeling vulnerability to abuse. In addition to its application with other drugs, the Fischer-Lewis model may be useful for investigating the biobehavioral bases of alcohol abuse.

Assessment of monoamine transporter inhibition in the mediation of cocaine-induced conditioned taste aversion.

Although the mechanisms of cocaine reward have been well characterized, the pharmacological basis of cocaine's aversive effects is less understood. Using the conditioned taste aversion (CTA) preparation, the present study examined the role of monoamine uptake inhibition in cocaine's aversive effects by comparing cocaine to three reuptake inhibitors with relative specificity for the transporters of dopamine (DAT; GBR 12909), norepinephrine (NET; desipramine) and serotonin (SERT; clomipramine). Specifically, 104 male Sprague-Dawley rats were given 20-min access to a novel saccharin solution followed immediately by a subcutaneous injection of cocaine, GBR 12909, desipramine, clomipramine (each at 18, 32 or 50 mg/kg; 12 groups) or drug vehicle (equivolume to the highest cocaine dose). Over trials, cocaine and desipramine each dose-dependently suppressed saccharin consumption and did so in an equivalent manner when matched by dose. However, both GBR 12909 and clomipramine conditioned weaker aversions than cocaine at the two lowest doses (18 and 32 mg/kg). At the highest dose (50 mg/kg), GBR 12909 produced equivalent suppression of saccharin consumption to cocaine while clomipramine's conditioned suppression remained relatively weak at this dose. These results suggest that cocaine's adrenergic actions resulting from NET inhibition may play a more significant role in the mediation of its aversive effects than its actions at DAT and SERT.

Assessment of the contributions of Na+ channel inhibition and general peripheral action in cocaine-induced conditioned taste aversion.

While the rewarding properties of cocaine appear to be mediated by its blockade of central monoamine uptake, the mechanisms and sites of action for cocaine's aversive effects have yet to be determined. Using the conditioned taste aversion (CTA) preparation, the present study examined the role of Na(+) channel blockade in cocaine's aversive effects by comparing cocaine to the local anesthetic procaine at three doses (18, 32 and 50 mg/kg). Furthermore, the role of cocaine's peripheral actions in its aversive effects was examined by comparing cocaine to the quaternary analog cocaine methiodide (equimolar to the three doses of cocaine) in establishing CTAs. Procaine and cocaine methiodide each dose-dependently suppressed saccharin consumption, indicating that the aversive effects of cocaine are, in part, mediated by its inhibition of Na(+) channels and via its activity in the PNS. However, the fact that the aversions induced by procaine and cocaine methiodide were weaker than those induced by cocaine at each dose tested suggests other factors are involved in its aversive effects. Possible reasons for the weaker aversions induced by procaine and cocaine methiodide relative to cocaine were discussed.

Conditioned flavor aversions: assessment of drug-induced suppression of food intake.

Administration of a drug following ingestion of a novel food or solution often suppresses subsequent intake of the new food or solution. This suppression is associative, in that consumption is not suppressed when there is no temporal relationship between consumption and drug administration. The robust nature of aversion learning has made this procedure a sensitive and widely used behavioral index of drug side effects. The procedures described in this unit are suitable for work with rodents, and may require modifications, e.g., in presentation of the ingesta and drug for other species. Familiar and novel foods may be used instead of solutions, with similar results.

Morphine-induced conditioned taste aversions: assessment of sexual dimorphism.

Although sex differences in taste aversions have been reported with emetics such as lithium chloride (LiCl), little is known whether such findings generalize to other aversion-inducing drugs, including recreational compounds. One particular class of recreational compounds that induces taste aversions but that has not been examined for sex differences in its aversive properties is the opioids. To assess sex differences in the aversive properties of the opioids, Experiment 1 examined the acquisition and extinction of morphine-induced taste aversions in male and female rats. To determine whether the specific parametric conditions used in Experiment 1 would support sex differences in general, Experiment 2 examined possible sex differences in the acquisition and extinction of LiCl-induced taste aversions, a compound for which sex differences have been previously reported. During acquisition, male and female rats were given 20-min access to a novel saccharin solution and injected with either morphine (0, 10, 18 and 32 mg/kg s.c.; Experiment 1) or LiCl (0, 0.3, 0.6 and 1.2 mEq s.c.; Experiment 2) every fourth day for a total of four conditioning trials. During extinction, subjects were allowed access to saccharin but were not injected (for a total of eight trials). There were no sex differences in acquisition with either morphine or LiCl. There were also no sex differences in extinction with morphine; however, sex differences were found with LiCl, an effect consistent with prior assessments with this drug. The basis for and implications of the differences in the effects of sex on morphine- and LiCl-induced taste aversions were discussed.

Strain-dependent differences in schedule-induced polydipsia: an assessment in Lewis and Fischer rats.

Strain-dependent differences have been used to highlight unknown genetic contributions to important behavioral and physiological end points. In this regard, the Fischer (F344) and Lewis (LEW) rat strains have often been studied because they exhibit a myriad of behavioral and physiological differences. Recently, schedule-induced polydipsia (SIP), a potential model of stress and drug abuse, has been reported to differ between the two strains (see [Pharmacol. Biochem. Behav. 67 (2002) 809]) with F344 rats displaying greater levels of consumption than LEW rats. Given the importance of SIP as a behavioral model of stress and of drug abuse, the present study further explored SIP in F344 and LEW strains by assessing the acquisition and steady-state performance of SIP (under a fixed-time 30 schedule of food delivery; FT30), its characteristic postprandial temporal licking pattern and its modulation by variations in the food delivery schedule (FT15, FT30 and FT60). F344 rats acquired SIP at a faster rate and drank at a higher asymptotic level than LEW rats. Both strains displayed the typical inverted U-shaped post-pellet pattern of drinking and changes in levels of consumption (and displacement of the initiation of post-pellet drinking) with changes in the FT value, supporting the position that the increased drinking seen in both groups was schedule induced. These strain differences in SIP are consistent with the fact that the F344 and LEW strains differ on other behavioral and physiological indices of stress and raise the issue of the use of this model in the assessment of differential drug intake between the two strains.