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.

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).

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.

Cocaine impairs serial-feature negative learning and blood-brain barrier integrity.

Previous research has shown that diets high in fat and sugar [a.k.a., Western diets (WD)] can impair performance of rats on hippocampal-dependent learning and memory problems, an effect that is accompanied by selective increases in hippocampal blood brain barrier (BBB) permeability. Based on these types of findings, it has been proposed that overeating of a WD (and its resulting obesity) may be, in part, a consequence of impairments in these anatomical substrates and cognitive processes. Given that drug use (and addiction) represents another behavioral excess, the present experiments assessed if similar outcomes might occur with drug exposure by evaluating the effects of cocaine administration on hippocampal-dependent memory and on the integrity of the BBB. Experiment 1 of the present series of studies found that systemic cocaine administration in rats also appears to have disruptive effects on the same hippocampal-dependent learning and memory mechanism that has been proposed to underlie the inhibition of food intake. Experiment 2 demonstrated that the same regimen of cocaine exposure that produced disruptions in learning and memory in Experiment 1 also produced increased BBB permeability in the hippocampus, but not in the striatum. Although the predominant focus of previous research investigating the etiologies of substance use and abuse has been on the brain circuits that underlie the motivational properties of drugs, the current investigation implicates the possible involvement of hippocampal memory systems in such behaviors. It is important to note that these positions are not mutually exclusive and that neuroadaptations in these two circuits might occur in parallel that generate dysregulated drug use in a manner similar to that of excessive eating.

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

Conditioned Taste Avoidance Drug Discrimination Procedure: Assessments and Applications.

In the present chapter, we summarize much of the work on the taste avoidance drug discrimination procedure, presenting the logic for its initial introduction and the extension of the procedure in the investigation of the discriminative properties of various drugs. Results from these assessments parallel those from more traditional operant and maze designs in classifying and characterizing the discriminative properties of drug. At the same time, this design reveals a procedure that is sensitive in such assessments by indexing these stimulus properties more rapidly and at lower doses than in the more traditional procedures (in some cases for drugs heretofore resistant in their detection). Importantly, much remains to be learned about the taste avoidance procedure in that the nature of such learning remains unknown and the specific parameters under which it can be established and generalized and its neurochemical and neuroanatomical bases are largely unexplored. The application of drug discrimination learning to human drug abuse continues to be an important consideration for this specific design (as well as that of drug discrimination procedures in general), and recent parallels between drug use and food intake in terms of its regulation by interoceptive stimuli suggests a possible role of the loss of stimulus control in drug escalation and addiction (with possible therapeutic implications via the modulation of these interoceptive cues).

Sex as a biological variable: Drug use and abuse.

The study of sex as a biological variable is a necessary emphasis across a wide array of endpoints, including basic neuroscience, medicine, mental health, physiology and behavior. The present review summarizes work from clinical and preclinical populations on sex differences in drug use and abuse, ranging from initiation to escalation/dysregulation and from drug cessation/abstinence to relapse. These differences are analyzed in the context of the addiction cycle conceptualization of Koob and his colleagues and address patterns of drug use (binge/intoxication), motivation underlying its use (withdrawal/negative affect) and likelihood and causes of craving and relapse of drug taking (preoccupation/anticipation). Following this overview, an assessment of the basis for the reported sex differences is discussed in the context of the affective (rewarding and aversive) properties of drugs of abuse and how such properties and their balance vary with sex and contribute to drug intake. Finally, the interaction of sex with several experiential (drug history) and subject (age) factors and how these interactions affect reward and aversion are discussed to highlight the importance of understanding such interactions in predicting drug use and abuse. We note that sex as a biological variable remains one of critical evaluation and that such investigations of sex differences in drug use and abuse continue and be expanded to assess all facets of their mediation, including these affective properties, how their balance may be impacted by the multiple conditions under which drugs are taken and how this overall balance affects drug use and addiction vulnerability.

Antagonism of the kappa opioid receptor attenuates THC-induced place aversions in adult male Sprague-Dawley rats.

RATIONALE: Prior research with transgenic mice in which the kappa opioid receptor (KOR) has been suppressed or activated suggests that the aversive effects of THC are mediated by activity of this receptor subtype. If the activity of the KOR system is responsible for mediating the THC's aversive effects, then selective antagonism of the KOR by norBNI should block such aversive effects. To test this hypothesis, rats were pretreated with norBNI 24h prior to place conditioning with THC to assess its effect on the acquisition of THC-induced place aversions. METHODS: In Experiment 1, rats pretreated with norBNI (0 or 15mg/kg) were exposed 24h later to one side of a place conditioning chamber and injected with THC (0, 0.56, 1 and 3.2mg/kg). On the next day, they were injected with vehicle and placed on the opposite side of the chamber. This was repeated for a total of five cycles followed by a test of the animal's aversion to the THC-paired side. In Experiment 2, rats were pretreated with norBNI (0 or 30mg/kg) prior to place conditioning 24h later with THC (0 or 3.2mg/kg). RESULTS: In Experiment 1, THC produced dose-dependent place aversions that were unaffected by norBNI (15mg/kg). In Experiment 2, THC induced significant place aversions that were fully attenuated by norBNI (30mg/kg). CONCLUSIONS: Although 15mg/kg norBNI was ineffective in antagonizing the aversive effects of THC, 30mg/kg norBNI blocked the ability of THC to induce a place aversion. The results of the latter assessment are consistent with prior research with transgenic manipulations of the KOR and provide further evidence for the role of the KOR system in the aversive properties of THC.

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

Despite widespread cannabis use in humans, few rodent models exist demonstrating significant Δ9-tetrahydrocannabinol (THC) self-administration, possibly due to THC's co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse. (PsycINFO Database Record

Pre-exposure to cocaine or morphine attenuates taste avoidance conditioning in adolescent rats: Drug specificity in the US pre-exposure effect.

Although the attenuating effects of drug history on conditioned taste avoidance (CTA) learning have been widely investigated in adults, such effects in adolescents have not been well characterized. Recent research has suggested that the display of the drug pre-exposure effect during adolescence may be drug dependent given that pre-exposure to ethanol attenuates subsequent conditioning, whereas pre-exposure to the classic emetic lithium chloride (LiCl) fails to do so. The present study began investigating the possible drug-dependent nature of the effects of drug pre-exposure by pre-exposing and conditioning adolescent male Sprague-Dawley rats to drugs from two additional classes, specifically psychostimulants (cocaine; Experiment 1) and opioids (morphine; Experiment 2). Consistent with prior work with ethanol (but not LiCl), prior exposure to both cocaine and morphine attenuated taste avoidance induced by these compounds. Although this work supports the view of drug-dependent pre-exposure effects on taste avoidance learning during adolescence, research is needed to assess its mechanisms.

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.

Adolescent rats fail to demonstrate a LiCl-induced pre-exposure effect: Implications for the balance of drug reward and aversion in adolescence.

Adolescents display weaker taste avoidance induced by both abused and non-abused drugs than adults. Drug history attenuates avoidance learning in adults (the drug pre-exposure effect), but little is known about this phenomenon in adolescents. Given that the weaker taste avoidance in adolescence is thought to be a function of their relative insensitivity to the drug's aversive effects, it might be expected that the drug pre-exposure effect would be weaker in adolescents given that for some drugs this effect is mediated by associative blocking that depends on the association of environmental cues with the drug's aversive effects. To address this, in the present studies male adolescent (Experiment 1) and adult (Experiment 2) rats were given five spaced injections of LiCl prior to subsequent taste avoidance conditioning with LiCl. Consistent with past reports, adolescents displayed weaker taste avoidance than adults. While adults displayed attenuated LiCl-induced taste avoidance following LiCl pre-exposure, adolescents showed no evidence of this pre-exposure. This work is consistent with the view that adolescents are relatively insensitive to the aversive effects of drugs, an insensitivity potentially important in subsequent intake of drugs of abuse given that such intake is a function of the balance of their rewarding and aversive effects.

Delta-9-tetrahydrocannabinol (THC) history fails to affect THC's ability to induce place preferences in rats.

RATIONALE: In pre-clinical models of marijuana abuse, there is relatively limited evidence of delta-9-tetrahydrocannabinol's (THC) rewarding effects, as indexed by its general inability to induce a place preference. One explanation for this failure is that its rewarding effects are masked by its concurrently occurring aversive properties. Consistent with this explanation, THC pre-exposure, which presumably weakens its aversive effects, induces place preferences. Such demonstrations are limited to mice and given reported species differences in THC reactivity, it is unknown to what extent the same shift in affective properties would be evident in rats. METHODS: The present experiment examined the effect of THC history (3.2mg/kg) on THC (1 or 3.2mg/kg) induced place preference conditioning in rats. An assessment of taste avoidance was also run to independently characterize THC's aversive effects and any changes that occurred with drug pre-exposure. These assessments were made in a combined taste avoidance/place preference procedure in which a novel saccharin solution and environment were paired with THC (0, 1 or 3.2mg/kg). RESULTS: THC did not induce place conditioning, and a history of THC was ineffective in increasing THC's ability to do so, despite the fact that this same history significantly attenuated the aversive effects of THC. CONCLUSIONS: The failure of THC to consistently induce place preferences has been argued to be a function of its concurrently occurring aversive effects masking its rewarding properties. The fact that pre-exposure to THC significantly reduced its aversive effects without impacting THC's ability to induce place preferences suggests that THC has weak rewarding effects and/or its residual aversive affects may have still masked its rewarding properties. An important area for future work will be characterizing under what conditions THC is rewarding and whether its overall reinforcing effects are impacted by the relationship between its affective properties.