Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

Perirhinal to prefrontal circuit in methamphetamine induced recognition memory deficits.

Return to methamphetamine (meth) use is part of an overarching addictive disorder hallmarked by cognitive sequela and cortical dysfunction in individuals who use meth chronically. In rats, long access meth self-administration produces object recognition memory deficits due to drug-induced plasticity within the perirhinal cortex (PRH). PRH projections are numerous and include the medial prefrontal cortex (mPFC). To evaluate the role of the PRH-mPFC reciprocal circuit in novel object recognition memory, a rgAAV encoding GFP-tagged Cre recombinase was infused into the PRH or the mPFC and rats were tested for recognition memory. On test day, one group explored both familiar and novel objects. A second group explored only familiar objects. GFP and Fos expression were visualized in the mPFC or PRH. During exploration, PRH neurons receiving input from the mPFC were equally activated by exploration of novel and familiar objects. In contrast, PRH neurons that provide input to the mPFC were disproportionately activated by novel objects. Further, the percent of Fos + cells in the PRH positively correlated with recognition memory. As such, the flow of communication appears to be from the PRH to the mPFC. In agreement with this proposed directionality, chemogenetic inhibition of the PRH-mPFC circuit impaired object recognition memory, whereas chemogenetic activation in animals with a history of long access meth self-administration reversed the meth-induced recognition memory deficit. This finding informs future work aimed at understanding the role of the PRH, mPFC, and their connectivity in meth associated memory deficits. These data suggest a more complex circuitry governing recognition memory than previously indicated with anatomical or lesion studies.

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.

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.

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).

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.

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.

Stereoselective effects of the second-generation synthetic cathinone α-pyrrolidinopentiophenone (α-PVP): assessments of conditioned taste avoidance in rats.

RATIONALE: Work with α-pyrrolidinopentiophenone (α-PVP), a second-generation synthetic cathinone, has been generally limited to the racemate. Given that with other synthetic cathinones, there are behavioral and neurochemical differences between their enantiomers, differences may also be seen with α-PVP. OBJECTIVES: The present study assessed the relative contribution of each enantiomer to the aversive effects of racemic-α-PVP by comparing their ability to induce a conditioned taste avoidance. METHODS: Adult male Sprague-Dawley rats were exposed every other day for four exposures to a novel saccharin solution followed immediately by an injection of 0 (saline vehicle) or 1.5, 3, or 6 mg/kg of S-, R-, or racemic-α-PVP (IP). On alternating days, all subjects were given access to water to assess any unconditioned effects of α-PVP on general fluid consumption. RESULTS: Rats injected with the racemate and S-isomer of α-PVP displayed avoidance of the drug-associated saccharin solution, although this avoidance was dose-dependent only for the subjects injected with the racemate. There was no evidence of taste avoidance in animals injected with the R-enantiomer at any dose tested. Animals injected with 3 mg/kg racemic-α-PVP did not differ in avoidance from those treated with 1.5 mg/kg of the S-enantiomer, but subjects treated with 6 mg/kg racemic-α-PVP displayed a significantly stronger avoidance than those treated with 3 mg/kg S-α-PVP. CONCLUSIONS: The present work suggests that the aversive effects of racemic α-PVP are mediated primarily by its S-isomer. The fact that at the highest dose tested (6 mg/kg), the racemate induces an avoidance greater than the simple additive effects of the S- and R-isomers (at 3 mg/kg) suggests that while the R-isomer may not induce taste avoidance at this dose, it may interact synergistically with the S-isomer in mediating the effects of the racemic mixture. These results were discussed in terms of similar effects with other behavioral and physiological endpoints reported with a number of psychostimulants and suggest that the enantiomers of α-PVP are an important variable in characterizing its behavioral effects.

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

Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy.

Background: While cranial radiation therapy (CRT) is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed, and inhibition control are impaired. These deficits appear months to years after CRT and impair quality of life. Exercise has been shown to rejuvenate the brain and aid in recovery post-injury through its effects on neurogenesis and cognition. Methods: We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31 days old) were irradiated with a fractionated dose of 4 Gy × 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-choice serial reaction time task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry. Results: CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, as well as causing stunting of growth and changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, and processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared with sedentary CRT values. Further, exercise partially restored global connectome organization, including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs. Conclusions: Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.

Conditioned taste avoidance, conditioned place preference and hyperthermia induced by the second generation 'bath salt' α-pyrrolidinopentiophenone (α-PVP).

BACKGROUND: α-Pyrrolidinopentiophenone (α-PVP) has been reported to be rewarding in a variety of pre-clinical models. Given that a number of drugs of abuse have both rewarding and aversive effects, the balance of which influences addiction potential, the present study examined the aversive properties of α-PVP by assessing its ability to induce taste avoidance. This assessment was made in a combined taste avoidance/place conditioning design that also allowed an evaluation of the relationship between α-PVP's aversive and rewarding effects. METHODS: Male Sprague-Dawley rats were exposed to a novel saccharin solution, injected with one of four doses of α-PVP (0, 0.3, 1.0 and 3.0mg/kg) (IP) and placed on one side of a place conditioning apparatus. The next day, they were injected with vehicle, given access to water and placed on the other side. Following four conditioning cycles, saccharin avoidance and place preferences were then assessed. The effects of α-PVP on body temperature were also examined. RESULTS: α-PVP induced dose-dependent taste avoidance as well as significant increases in time spent on the drug-paired side (although this effect was not dependent on dose). α-PVP also induced dose- and time-dependent hyperthermia. CONCLUSIONS: α-PVP induced significant taste avoidance whose strength relative to the psychostimulants methylenedioxypyrovalerone (MDPV) and cocaine paralleled their relative binding to the dopamine transporter. Similar to other drugs of abuse, α-PVP has both aversive and rewarding effects. It will be important to assess how various experiential and subject variables impact these effects and their balance to predict abuse liability.

Effects of 3,4-methylenedioxypyrovalerone (MDPV) pre-exposure on the aversive effects of MDPV, cocaine and lithium chloride: Implications for abuse vulnerability.

BACKGROUND: Drug use is thought to be a balance of the rewarding and aversive effects of drugs. Understanding how various factors impact these properties and their relative balance may provide insight into their abuse potential. In this context, the present study attempted to evaluate the effects of drug history on the aversive effects of 3,4-methylenedioxypyrovalerone (MDPV), one of a variety of synthetic cathinones (collectively known as "bath salts"). METHODS: Different groups of male Sprague-Dawley rats were exposed to either vehicle or MDPV (1.8mg/kg) once every fourth day for five total injections prior to taste avoidance conditioning in which a novel saccharin solution was repeatedly paired with either vehicle, MDPV (1.8mg/kg), the related psychostimulant cocaine (18mg/kg) or the emetic lithium chloride (LiCl) (13.65mg/kg). RESULTS: In animals pre-exposed to vehicle, all three drugs induced significant and comparable taste avoidance relative to animals injected with vehicle during conditioning. MDPV pre-exposure attenuated the avoidance induced by both MDPV and cocaine (greater attenuation for MDPV than cocaine), but had no effect on that induced by LiCl. CONCLUSIONS: These findings suggest that a history of MDPV use may reduce or attenuate MDPV and cocaine's (but not LiCl's) aversive effects. The implications for such changes in MDPV's aversive effects to its potential use and abuse were discussed.