Effects of Serial Polydrug Use on the Rewarding and Aversive Effects of the Novel Synthetic Cathinone Eutylone.

BACKGROUND: As individual synthetic cathinones become scheduled and regulated by the Drug Enforcement Administration (DEA), new ones regularly are produced and distributed. One such compound is eutylone, a novel third-generation synthetic cathinone whose affective properties (and abuse potential) are largely unknown. The following experiments begin to characterize these effects and how they may be impacted by drug history (a factor affecting reward/aversion for other drugs of abuse). METHODS: Eutylone was assessed for its ability to induce conditioned taste avoidance (CTA; aversive effect) and conditioned place preference (CPP; rewarding effect) and their relationship (Experiment 1). Following this, the effects of exposure to cocaine or 3,4-methylenedioxymethamphetamine [MDMA] on eutylone's affective properties were investigated (Experiment 2). RESULTS: Eutylone produced dose-dependent CTA and CPP (Experiment 1), and these endpoints were unrelated. Pre-exposure to cocaine and MDMA differentially impacted taste avoidance induced by eutylone (MDMA > cocaine) and did not impact eutylone-induced place preference. CONCLUSIONS: These data indicate that eutylone, like other synthetic cathinones, has co-occurring, independent rewarding and aversive effects that may contribute to its abuse potential and that these effects are differentially impacted by drug history. Although these studies begin the characterization of eutylone, future studies should examine the impact of other factors on eutylone's affective properties and its eventual reinforcing effects (i.e., intravenous self-administration [IVSA]) to predict its use and abuse liability.

Western diet consumption does not impact the rewarding and aversive effects of morphine in male Sprague-Dawley rats.

The impacts of high-fat and/or high-sugar diets on opioid-induced effects are well documented; however, little is known about the effect of such diet on the affective responses to opiates. To address this issue, in the present experiment male Sprague-Dawley rats were given ad libitum access to a western-style diet (high in saturated fat and sugar) or a standard laboratory chow diet beginning in adolescence and continuing into adulthood at which point they were trained in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure to assess the aversive and rewarding effects of morphine, respectively. On four conditioning cycles, animals were given access to a novel saccharin solution, injected with morphine (1 mg/kg or 5 mg/kg), and then placed on one side of a place preference chamber. Animals were then tested for place preference and saccharin preference. All subjects injected with morphine displayed significant avoidance of the morphine-associated solution (CTA) and preferred the side associated with the drug (CPP). Furthermore, there were no differences between the two diet groups, indicating that chronic exposure to the western diet had no impact on the affective properties of morphine (despite increasing caloric intake, body weight, body fat and lean body mass). Given previously reported increases in drug self-administration in animals with a history of western-diet consumption, this study suggests that western-diet exposure may increase drug intake via mechanisms other than changes in the rewarding or aversive effects of the drug.

Serial feature positive and feature negative discrimination learning in a taste avoidance preparation: implications for interoceptive control of behavior.

BACKGROUND: Psychoactive drugs produce interoceptive stimuli that can guide appropriate behaviors by initiating or inhibiting responding. OBJECTIVE: The current study investigated whether an interoceptive morphine state produces similar patterns of serial feature positive (FP) and feature negative (FN) discrimination learning under comparable conditions in a taste avoidance design. METHODS: Male Sprague-Dawley rats were trained under 10 cycles of FP or FN discrimination. In the FP task, morphine (10 mg/kg, IP) signaled that a saccharin solution was followed by LiCl (1.2 mEq, IP), while the vehicle (saline) signaled that the LiCl was withheld. In the FN task, the contingency was reversed. RESULTS: The FP-trained rats acquired the discrimination after three training cycles, consuming significantly less saccharin on morphine, than on vehicle, sessions ( P  < 0.05). The FN-trained rats acquired the discrimination after six training cycles, consuming more on morphine than on vehicle sessions ( P < 0.05). However, FN-trained rats never recovered saccharin consumption to baseline levels and 40% of the rats continued to avoid saccharin (consuming 0 ml) on morphine sessions. Control rats that never received LiCl consumed high levels of saccharin on morphine and vehicle sessions, indicating that morphine did not produce unconditioned suppression of saccharin consumption. CONCLUSION: The difficulty to acquire FN discrimination might reflect the limitations of learning about safety contingencies in the taste avoidance design. The rapidity of FP learning when a drug state signals an aversive contingency may have implications for the general role of interoceptive stimuli in the control of behavior.

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.

Effects of Methylone Pre-Exposure on Fluoxetine-Induced Conditioned Taste Avoidance in Male and Female Sprague-Dawley Rats.

BACKGROUND: Prior work has reported that a drug's aversive effects (as indexed by taste avoidance conditioning) are attenuated when the pre-exposure and conditioning drugs are the same or different. The latter, otherwise known as cross-drug pre-exposure, is especially interesting as it has been used as a tool to assess mechanisms underlying the aversive effects of drugs. We previously reported that methylone pre-exposure differentially impacted the aversive effects of MDPV and MDMA (MDPV > MDMA), a difference consistent with the dopaminergic mediation of methylone's aversive effects. To examine the possible role of serotonin (5-HT) in methylone's aversive effects, the present study assessed the effects of methylone pre-exposure on taste avoidance induced by the 5-HT reuptake inhibitor fluoxetine. METHODS: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of 5 injections) prior to taste avoidance training with 10 mg/kg of fluoxetine. RESULTS: Fluoxetine induced significant taste avoidance (each p < 0.05) that was independent of sex. Methylone pre-exposure had no impact on avoidance produced by fluoxetine in either males or females (each p > 0.05). CONCLUSIONS: Methylone pre-exposure had no impact on fluoxetine-induced avoidance. These findings suggest that it is unlikely that 5-HT mediates the aversive effects of methylone. The implications of the present results for the mechanisms mediating methylone's aversive effects were discussed. Understanding such mechanisms is important in predictions relevant to drug history and abuse liability as a variety of subject and experiential factors known to affect (reduce) a drug's aversive effects may increase its use and potential for abuse.

Conditioned taste avoidance and conditioned place preference induced by the third-generation synthetic cathinone eutylone in female sprague-dawley rats.

Recently, use of the synthetic cathinone (aka "bath salt") eutylone has risen in the United States and globally. Due to its novelty in drug markets, its affective properties remain largely uninvestigated. In this context, drugs of abuse have both rewarding and aversive effects and understanding these effects, their relative balance, and factors that impact each are important to understanding the likelihood of drug use and abuse. This investigation attempted to characterize eutylone's rewarding and aversive effects in a combined conditioned taste avoidance/place preference assay. Female Sprague-Dawley rats were given 20-min access to saccharin, injected with one of five doses of eutylone (0, 3, 10, 18, 32 mg/kg; intraperitoneally; IP), and placed on one side of a place conditioning apparatus. On the following day, subjects were given 20-min access to water, injected IP with vehicle, and placed on the other side of the apparatus. After five conditioning cycles, place preference and saccharin avoidance were assessed. Eutylone induced significant taste avoidance but did not significantly increase time spent on the drug-paired side (relative to controls). Excluding animals with high initial side preference, however, eutylone induced a preference at all doses with the high dose group displaying higher preference than controls. There was no significant correlation between eutylone's aversive and rewarding effects. These data indicate that eutylone (like other synthetic cathinones) induces both rewarding and aversive effects and highlight the need to assess the impact of various factors on its affective properties (and their balance) and on their use and abuse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of fluoxetine preexposure on MDMA-induced taste avoidance in male and female rats.

The use of both prescription and illicit drugs creates the potential for drug interactions as a function of both pharmacokinetic and pharmacodynamic processes. One such interaction is that of fluoxetine and methylenedioxymethamphetamine (MDMA) in which fluoxetine attenuates the positive-like effects of MDMA. The present work extends the analysis of their interaction by examining the impact of fluoxetine on the aversive effects of MDMA which in balance with its rewarding effects may mediate its abuse potential. Male and female Sprague-Dawley rats were given fluoxetine (10 mg/kg every 4th day for five injections) prior to taste avoidance training with MDMA (3.2 mg/kg). MDMA induced taste avoidance in males and females (faster acquisition in females). Fluoxetine preexposure attenuated this avoidance in males, but not females. For males, the attenuation was partial as MDMA-conditioned animals with fluoxetine preexposure still displayed a significant reduction in fluid intake compared to controls. Consistent with prior work assessing the interaction of fluoxetine and MDMA, fluoxetine preexposure impacted the ability of MDMA to support taste avoidance learning, specifically attenuating the aversive effect of the drug. Prior work has shown that fluoxetine attenuates MDMA's positive effects which might lead to reduced intake of the drug; however, the concurrent reduction in the drug's aversive effects may still shift the overall affective balance of these two affective properties toward continued use and abuse. The fact that the attenuation was only evident in males needs further study to investigate the sex-dependent effects of drug history. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Methylone pre-exposure differentially impacts the aversive effects of MDPV and MDMA in male and female Sprague-Dawley rats: Implications for abuse vulnerability.

BACKGROUND: Polydrug use is well documented in synthetic cathinone users, although the consequences of such use are not well characterized. In pre-clinical research, a pre-exposure to a drug has been reported to attenuate the aversive effects of other drugs which has implications for their abuse potential. The goal of the present study was to investigate the impact of pre-exposure to the synthetic cathinone methylone on the aversive effects of MDPV and MDMA. METHOD: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of five injections) prior to taste avoidance training with 1.8 mg/kg of MDPV or 1 mg/kg of MDMA. RESULTS: MDPV and MDMA induced taste avoidance in males and females (all p's < 0.05). In males, methylone pre-exposure attenuated the avoidance induced by MDPV and MDMA (all p's < 0.05) with the attenuation greater with MDPV. In females, methylone pre-exposure attenuated avoidance induced by MDPV (all p's < 0.05), but it had no effect on those induced by MDMA (all p's > 0.05). CONCLUSIONS: The effects of exposure to methylone on taste avoidance induced by MDPV and MDMA were drug- (MDPV > MDMA) and sex- (MDMA only in males) dependent. The attenuating effects of methylone pre-exposure on MDPV and MDMA were discussed in terms of their shared neurochemical action. These findings suggest that a history of methylone use may reduce the aversive effects of MDPV and MDMA which may have implications for polydrug use involving the synthetic cathinones.

Impact of the Aversive Effects of Drugs on Their Use and Abuse.

Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.

Ethanol pre-exposure differentially impacts the rewarding and aversive effects of α-pyrrolidinopentiophenone (α-PVP): Implications for drug use and abuse.

RATIONALE: Exposure to a drug can subsequently impact its own reactivity as well as that of other drugs. Given that users of synthetic cathinones, i.e., "bath salts", typically have extensive and varied drug histories, an understanding of the effects of drug history on the behavioral and physiological consequences of synthetic cathiones may be important to their abuse liability. OBJECTIVES: The goal of the current work was to assess the effects of an ethanol pre-exposure on the rewarding and aversive effects of α-PVP. METHODS: Adult male Sprague Dawley rats were exposed to ethanol prior to combined conditioned taste avoidance/conditioned place preference training in which rats were injected with 1.5, 3 or 5 mg/kg of racemic α-PVP or vehicle. Following a 7-day washout period, rats were then tested for thermoregulatory effects of α-PVP using subcutaneous probes to measure body temperature changes over the course of 8 h. This was followed 10 days later by assessments for α-PVP-induced locomotor activity and stereotypies over a 1-h session. RESULTS: α-PVP induced significant dose- and trial-dependent taste avoidance that was significantly attenuated by ethanol history and dose- and time-dependent increases in locomotor activity that were significantly increased by ethanol. α-PVP also induced place preferences and dose- and time-dependent increases in body temperature, but these measures were unaffected by ethanol history. CONCLUSIONS: α-PVP's aversive effects (as measured by taste avoidance) were attenuated, while its rewarding effects (as indexed by place preference conditioning) were unaffected, by ethanol pre-exposure. Such a pattern may indicate increased α-PVP abuse liability, as changes in the balance of aversion and reward may impact overall drug effects and likelihood of drug intake. Future self-administration studies will be necessary to explore this possibility.

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.

Cross-generational THC Exposure Weakly Attenuates Cocaine's Rewarding Effects in Adult Male Offspring.

Adolescents represent a large demographic of marijuana consumers. Regrettably, use during this developmental period has been associated with above average health risks. A growing body of evidence suggests that adolescent drug use in the lifetime of a parent can modify behavior and neurochemistry in descendants without direct exposure. The current study was designed to evaluate the effects of pre-conception THC during adolescence on vulnerability to cocaine in adult male offspring. Male and female rats were given an intermittent THC (0 or 1.5 mg/kg) exposure regimen during the adolescent window and mated with drug group conspecifics in adulthood. F1-THC and F1-Veh pups were cross fostered to drug naïve control dams. In Experiment 1, adult offspring underwent cocaine (0 or 15 mg/kg) locomotor sensitization procedures and showed no effect of parental THC exposure on locomotor activity. In Experiment 2, intravenous catheters were implanted and subjects were tested under a number of reinforcement schedules with cocaine (FR1, FR5, FR10, PR, dose-response, extinction, cue + stress induced reinstatement). F1-THC subjects exhibited a slight decrease in cocaine responding during acquisition and a more rapid extinction, but they failed to produce significant differences on any other measure. These findings indicate that adolescent cannabis use likely has minimal effects on cocaine abuse liability in the next generation.

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.

Cross-Generational THC Exposure Alters Heroin Reinforcement in Adult Male Offspring.

BACKGROUND: An emerging area of preclinical research has investigated whether drug use in parents prior to conception influences drug responsivity in their offspring. The present work sought to further characterize such effects with cannabis by examining whether a parental THC history modified locomotor sensitization to morphine and self-administration of heroin in adult progeny. METHODS: Male and female Sprague Dawley rats were exposed to eight injections of 0 or 1.5 mg/kg THC during adolescence and bred with subjects from the same dose group. In Experiment 1, adult male and female offspring (F1-THC and F1-Veh) underwent locomotor sensitization procedures with morphine over five trials followed by a 5-day abstinence period and a final morphine challenge. In Experiment 2, subjects were trained to self-administer heroin and tested under a number of conditions (FR1, FR5, FR10, PR, dose response assessment, extinction, cue- + stress-induced reinstatement). RESULTS: Germline THC exposure had no effect on morphine locomotor sensitization. However, F1-THC males displayed a reduced motivation to self-administer heroin relative to F1-Veh males. CONCLUSIONS: The present data indicate that parental THC exposure alters the reinforcing properties of heroin in a sex-specific manner. As such, mild to moderate cannabis use during adolescence may alter heroin abuse liability for males in the subsequent generation, but have limited effects on females.

Hippocampal-Dependent Inhibitory Learning and Memory Processes in the Control of Eating and Drug Taking.

As manifestations of excessive and uncontrolled intake, obesity and drug addiction have generated much research aimed at identifying common neuroadaptations that could underlie both disorders. Much work has focused on changes in brain reward and motivational circuitry that can overexcite eating and drug-taking behaviors. We suggest that the regulation of both behaviors depends on balancing excitation produced by stimuli associated with food and drug rewards with the behavioral inhibition produced by physiological "satiety" and other stimuli that signal when those rewards are unavailable. Our main hypothesis is that dysregulated eating and drug use are consequences of diet- and drug-induced degradations in this inhibitory power. We first outline a learning and memory mechanism that could underlie the inhibition of both food and drug-intake, and we describe data that identifies the hippocampus as a brain substrate for this mechanism. We then present evidence that obesitypromoting western diets (WD) impair the operation of this process and generate pathophysiologies that disrupt hippocampal functioning. Next, we present parallel evidence that drugs of abuse also impair this same learning and memory process and generate similar hippocampal pathophysiologies. We also describe recent findings that prior WD intake elevates drug self-administration, and the implications of using drugs (i.e., glucagon-like peptide- 1 agonists) that enhance hippocampal functioning to treat both obesity and addiction are also considered. We conclude with a description of how both WD and drugs of abuse could initiate a "vicious-cycle" of hippocampal pathophysiology and impaired hippocampal-dependent behavioral inhibition.

Abuse potential and toxicity of the synthetic cathinones (i.e., "Bath salts").

The synthetic cathinones are derived from the naturally occurring drug cathinone found in the khat plant (Catha edulis) and have chemical structures and neurochemical consequences similar to other psychostimulants. This class of new psychoactive substances (NPS) also has potential for use and abuse coupled with a range of possible adverse effects including neurotoxicity and lethality. This review provides a general background of the synthetic cathinones in terms of the motivation for and patterns and demographics of their use as well as the behavioral and physiological effects that led to their spread as abused substances and consequent regulatory control. This background is followed by a review focusing on their rewarding and aversive effects as assessed in various pre-clinical animal models and the contribution of these effects to their self-administration (implicating their use and abuse potential). The review closes with an overview of the consequences of synthetic cathinone use and abuse in terms of their potential to produce neurotoxicity and lethality. These characterizations are discussed in the context of other classical psychostimulants.

Ad-libitum high fat diet consumption during adolescence and adulthood impacts the intravenous self-administration of cocaine in male Sprague-Dawley rats.

In preclinical populations, binge consumption of a high-fat diet (HFD) initiated during either adolescence or adulthood increases the intravenous self-administration (IVSA) of cocaine, whereas ad lib HFD consumption initiated during adulthood reduces or fails to influence cocaine intake. From this, it appears that binge exposure is a sufficient condition to increase cocaine IVSA and that such effects occur independent of the exposure period. It is not clear, however, if ad lib exposure would be sufficient to affect the IVSA of cocaine if initiated during adolescence, a developmental period associated with high-risk behavior. To investigate this question, the present experiment evaluated the effects of consumption of a HFD given throughout adolescence and adulthood on cocaine IVSA (0.75 mg/kg/infusion). Specifically, male Sprague-Dawley rats were maintained on either a HFD (n = 24) or chow diet (n = 15) beginning on postnatal day (PND) 21 and as adults underwent cocaine IVSA [Fixed Ratio (FR) 1, FR 5, FR 10, FR 20, Progressive Ratio (PR) and cue- and drug + cue-induced responding] from PNDs 77-126. Under all of these conditions, animals maintained on the HFD displayed higher rates of cocaine IVSA than those given access to chow. The present data demonstrate that under these specific conditions long-term exposure during the risk period of adolescence and extended throughout adulthood is capable of impacting the subsequent likelihood of cocaine self-administration and suggest that diet type and the duration of exposure may be important factors influencing the vulnerability to drug intake. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Ad libitum high fat diet consumption during adolescence and adulthood fails to impact the affective properties of cocaine in male Sprague-Dawley rats.

Recent research from our laboratories has demonstrated that long-term and ad libitum high fat diet (HFD) consumption during adolescence and adulthood increases the intravenous self-administration (IVSA) of cocaine in adult male Sprague-Dawley rats. One possible interpretation of these findings is that this dietary history influences the affective properties of cocaine, that is, cocaine's rewarding and/or aversive effects. In this context, our research and others suggest that the overall affective response to a drug, and its potential for use and abuse, reflects a balance between these properties in which the rewarding effects of a drug maintain its use and the aversive effects limit it. Accordingly, long-term HFD consumption might increase the rewarding effects of cocaine and/or decrease its aversive effects, resulting in greater IVSA. To examine this possibility, male Sprague-Dawley rats were maintained on either a HFD (n = 32) or chow diet (n = 32) beginning on postnatal day (PND) 21 and underwent combined cocaine-induced place preference and taste avoidance conditioning from PNDs 78-102. Under these conditions, cocaine (18 and 32 mg/kg, intraperitoneally [IP]), but not vehicle, was effective in inducing both a place preference and a taste avoidance; however, HFD- and chow-fed animals did not differ on either of these behavioral indices. These data suggest that the ability of ad libitum HFD consumption during adolescence to increase cocaine IVSA is not likely due to changes in the affective properties of cocaine. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Conditioned taste avoidance induced by the combination of heroin and cocaine: Implications for the use of speedball.

Speedball (heroin + cocaine) is a prevalent drug combination among intravenous drug users. Although its use is generally discussed to be a function of changes in the rewarding effects of either or both drugs, changes in the aversive effects of either drug may also be impacted (weakened) by the combination. To address this latter possibility and its potential role in the use of speedball, the present studies examined the interaction of cocaine and heroin in taste avoidance conditioning. In Experiment 1, male Sprague-Dawley rats were given access to a novel saccharin solution and then injected with either vehicle or heroin (3.2 mg/kg, IP) followed immediately by various doses of cocaine (10, 18 or 32 mg/kg, SC). At the two lowest doses of cocaine, only animals injected with the drug combination (H + C) displayed a taste avoidance relative to control subjects (taste avoidance was induced with both the combination and the high dose of cocaine). At no dose did animals injected with the combination of heroin and cocaine drink more than animals injected with cocaine alone. In Experiment 2, male Sprague-Dawley rats were similarly treated but injected with vehicle or cocaine (10 mg/kg) followed by injections of various doses of heroin (1.8, 3.2, 5.6 or 10 mg/kg). At the three highest doses of heroin, only animals injected with the drug combination (C + H) displayed significant avoidance relative to control subjects (no avoidance was evident with the combination of cocaine and the low dose of heroin). At no dose did animals injected with the combination of cocaine and heroin drink more than animals injected with heroin alone. Together, these results suggest that the aversive effects of heroin and cocaine are not attenuated by co-administration by cocaine and heroin, respectively. The importance of this for the use of speedball was discussed.

Sex differences in α-pyrrolidinopentiophenone (α-PVP)-induced taste avoidance, place preference, hyperthermia and locomotor activity in rats.

RATIONALE: The majority of synthetic cathinone research has used only male subjects, and as a result there are few studies assessing the impact of biological sex on their effects. OBJECTIVES: The current work extends the characterization of the second-generation synthetic cathinone, α-PVP, by investigating how biological sex impacts α-PVP's aversive and rewarding effects important to its use and potential abuse. METHODS: A combined conditioned taste avoidance/conditioned place preference preparation was utilized in which adult male and female Sprague Dawley rats were injected with 1.5, 3 or 6 mg/kg of racemic α-PVP or vehicle (saline) (IP). Following a 24-day washout period, rats were then tested for thermoregulatory effects of α-PVP using subcutaneous microchips to measure body temperature changes over the course of 8 h. This was followed 21 days later by assessments for α-PVP-induced locomotor activity and stereotypies over a 1-h session. RESULTS: Dose-dependent conditioned taste avoidance was evident in both males and females, although females displayed weaker avoidance at 3 mg/kg compared to males. Males displayed a dose-dependent conditioned place preference, while females did not form a place preference at any dose. α-PVP elicited dose- and time-dependent hyperthermia, with males displaying a faster on-set and delayed off-set compared to females. α-PVP also produced dose- and time-dependent increases in locomotor activity (F > M) and stereotypies (M > F). CONCLUSIONS: As described, males displayed greater rewarding (as indexed by place preference conditioning) and aversive (as indexed by taste avoidance, hyperthermia and stereotypies) effects of α-PVP. Although comparisons between males and females in α-PVP self-administration have not been reported, these data suggest that males may be more likely to use the drug. The implications for sex differences in human use of α-PVP were discussed.