Neither Amphetamine nor Sub-Anesthetic Ketamine Treatment during Adolescence Impairs Devaluation in Rats Tested during Adulthood.

BACKGROUND: Much of the existing animal literature on the devaluation task suggests that prior repeated exposure to drugs of abuse during adulthood can impair goal-directed action, but the literature on human drug users is mixed. Also, the initiation of drug use often occurs during adolescence, but examinations of the effects of drug exposure during adolescence on behavior in the devaluation task are lacking. METHODS: We examined whether repeated exposure during adolescence to amphetamine (3 mg/kg injections every-other day from post-natal day 27-45) or ketamine (twice daily 30 mg/kg injections from post-natal day 35-44) would impair behavior in a devaluation test when tested drug-free in adulthood. Rats were trained to press a left lever with a steady cue-light above it for one reinforcer and a right lever with a flashing cue-light above it for a different reinforcer. We tested whether any impairments in goal-directed action could be overcome by compensation between strategies by giving rats information based on lever-location and cue-lights during the test that was either congruent (allowing compensation) or incongruent (preventing compensation between strategies) with the configurations during training. RESULTS: Our results provided no evidence for impairment of goal-directed action during adulthood after adolescent amphetamine or ketamine exposure. CONCLUSIONS: We discuss possible reasons for this discrepancy with the prior literature, including (1) the age of exposure and (2) the pattern in the previous literature that most previous demonstrations of drug exposure impairing devaluation in laboratory animals may be attributed to either drug-associated cues present in the testing environment and/or accelerated habit learning in tasks that predispose laboratory animals towards habit formation with extended training (with training procedures that should resist the formation of habits in the current experiment). However, additional research is needed to examine the effects of these factors, as well a potential role for the particular doses and washout periods to determine the cause of our finding of no devaluation impairment after drug exposure.

Examination of onset trajectories and persistence of binge-like eating behavior in mice after intermittent palatable food exposure.

Binge eating is a persistent behavior associated with a chronic course of illness and poor treatment outcomes. While clinical research is unable to capture the full course of binge eating, preclinical approaches offer the opportunity to examine binge-like eating from onset through chronic durations, allowing identification of factors contributing to binge eating persistence. The present study quantified the trajectories of binge-like eating onset and modeled cycles of abstinence/relapse to develop a translational model for binge eating persistence. Adult male and female C57Bl6/J mice were randomized to a binge-like palatable food access schedule (daily 2-hr, 3×/week) or continuous, nonbinge like palatable food access for 12 days (Experiment 1). Persistence of palatable food consumption in both binge-like palatable food access groups was then examined across three cycles of forced abstinence and reexposure to palatable food (incubation) to model the persistence of binge eating in clinical populations. Mice with daily 2-hr palatable food access escalated their intake more than mice in the 3×/week or continuous groups (Experiment 1). This pattern was more pronounced in females. In addition, this pattern of palatable food intake reemerged across multiple cycles of behavioral incubation (Experiment 2). These findings provide a model of binge-like eating in mice that can be used in future studies examining both environmental factors and neural mechanisms contributing to binge eating persistence. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Corticostriatal dynamics underlying components of binge-like consumption of palatable food in mice.

Binge eating (BE) is a maladaptive repetitive feeding behavior present across nearly all eating disorder diagnoses. Despite the substantial negative impact of BE on psychological and physiological health, its underlying neural mechanisms are largely unknown. Other repetitive behavior disorders (e.g., obsessive compulsive disorder) show dysfunction within corticostriatal circuitry. However, to date, no work has investigated the in vivo neural dynamics underlying corticostriatal activity during BE episodes. The aim of the current study was to longitudinally examine in vivo neural activity within corticostriatal regions - the infralimbic cortex (IL) and dorsolateral striatum (DLS)- in a robust pre-clinical model for BE. Female C57BL6/J mice (N = 32) were randomized to receive: 1) intermittent (daily, 2-h) binge-like access to palatable food (sweetened condensed milk) (BE), or 2) continuous, non-intermittent (24-h) access to palatable food (control). In vivo calcium imaging was performed via fiber photometry at baseline and after chronic (4 weeks) engagement in the model for BE. Specific consummatory behaviors (feeding bout onset/offset) during recordings were captured using lickometers which generated TTL outputs for precise alignment of behavior to neural data. IL showed no specific changes in neural activity related to BE. However, BE animals showed decreased DLS activity at feeding onset and offset at the chronic timepoint when compared to activity at the baseline timepoint. Additionally, BE mice had significantly lower DLS activity at feeding onset and offset at the chronic timepoint compared to control mice. These results point to a role for DLS hypofunction in chronic BE, highlighting a potential target for future treatment intervention.

Pre-training naltrexone increases conditioned fear learning independent of adolescent alcohol consumption history.

Our previous research has shown a relationship between low voluntary alcohol consumption and high conditioned fear in male Long Evans rats. Here, we examined whether differences in the endogenous opioid systems might be responsible for these differences. Rats received 6 weeks of chronic intermittent to 20% alcohol (v/v) or water-only from PND 26-66. Based on their consumption during the last 2 weeks of alcohol access, the alcohol-access rats were divided into high drinking (>2.5 g/kg/24-h) or low drinking (<2 g/kg/24-h). Rats were then given injections of the preferential mu opioid receptor antagonist naltrexone (1 mg/kg, s.c.) or the selective kappa opioid receptor antagonist LY2456302 (10 mg/kg, s.c.) prior to fear conditioning and were then tested for conditioned fear 2 days later. Pre-training naltrexone increased conditioned suppression of lever-pressing during training and testing, with no differences between high versus low alcohol drinkers or between water-only versus alcohol access groups (averaged across drinking levels). There was no effect of LY2456302 on conditioned fear in any comparison. We also found no differences between high and low alcohol drinkers and no reliable effect of prior alcohol access (averaged across drinking levels) on conditioned fear. Our experiment replicates and extends previous demonstrations that a preferential MOR antagonist can increase fear learning using conditioned suppression of lever-pressing as a fear measure. However, additional research is needed to determine the cause of the differences in conditioned fear that we previously observed (as they were not observed in the current experiments).

Pre-training inactivation of basolateral amygdala and mediodorsal thalamus, but not orbitofrontal cortex or prelimbic cortex, impairs devaluation in a multiple-response/multiple-reinforcer cued operant task.

Reinforcer devaluation is a task often used to model flexible goal-directed behavior. Here, we inactivated basolateral amygdala (BLA), orbitofrontal cortex (OFC), mediodorsal thalamus (MD) (Exp. 1) and prelimbic cortex (PL) (Exp. 3) in rats during multiple-response/multiple-reinforcer operant training with levers available to earn reinforcers during cued trials. After two training days with each lever-food relationship, a reinforcer was devalued through selective satiety and devaluation was assessed in a choice test with the brain areas non-inactivated. The control and OFC and PL inactivation groups exhibited a devaluation effect, but the BLA or MD groups did not. Since the OFC is proposed to be required in devaluation tasks when a discrete cue signals an outcome and PL is proposed to be required when responses based on lever spatial-location guide behavior, we ran new rats through a cue-switching experiment (Exp. 2) to determine the strategy rats use to complete our task (attending to the discrete light cue or spatial lever location). Both groups (cue switched and cue normal) showed a devaluation effect based on the lever spatial location, suggesting that rats rely on the spatial lever location to guide behavior. Future studies will determine whether OFC and PL can compensate for each other to show intact devaluation when the functioning of one of them is impaired.

Voluntary alcohol access during adolescence/early adulthood, but not during adulthood, causes faster omission contingency learning.

In omission contingency training, rodents learn to suppress their natural tendency to approach or touch a reward-predictive cue (termed "autoshaping" or "sign-tracking" responses) if the approach/touching responses lead to the omission of the reward. Previous research has shown that high levels of alcohol exposure (through alcohol vapor exposure) or adolescent alcohol consumption (with some versions of the omission contingency task) can lead to faster omission contingency learning. However, the alcohol exposure procedures and/or omission contingency task parameters differed between these different demonstrations. It was unclear whether the same voluntary alcohol consumption procedures during adolescence/early adulthood and/or adulthood would lead to faster omission contingency learning in one or both age groups. Here, rats received 6 weeks of chronic intermittent access to 20% alcohol or water from PND 26-66 (adolescence/early adulthood in Exp. 1) or PND 68-108 (adulthood in Exp. 2) and began behavioral training (autoshaping training followed by omission contingency training) several days later. We found no evidence that alcohol access at either age altered the number of trials with a sign-tracking response on the levers during autoshaping training. However, alcohol access during adolescence/early adulthood, but not during adulthood, led to faster learning to withhold responding on the lever under omission contingencies during the subsequent phase. We also found no evidence that the level of alcohol consumption was correlated with sign-tracking behavior in the autoshaping phase or with the suppression of lever-pressing during the omission contingency phase. Our results suggest that adolescent/early adult rats have increased vulnerability, compared with adults, to some long-term behavioral effects of voluntary alcohol consumption.

Individual differences in conditioned fear are associated with levels of adolescent/early adult alcohol consumption and instrumental extinction.

Previous research has shown a relationship between alcohol exposure and conditioned fear, but the nature of this relationship remains unclear. We determined whether chronic intermittent access to alcohol during adolescence and early adulthood would alter or be associated with the level of conditioned fear to an auditory cue in male Long Evans rats. Rats received 6 weeks of chronic intermittent access to 20% alcohol or water from PND 26-66 and began behavioral testing 10 days later. We found no evidence that voluntary alcohol consumption altered fear. However, we found that rats that consumed more alcohol had lower fear, as measured with conditioned suppression of lever-pressing and conditioned freezing to an auditory cue. We have previously shown that higher levels of alcohol consumption are correlated with faster instrumental extinction learning. Therefore, we determined whether instrumental extinction would be directly associated with conditioned fear in rats never given alcohol access. As predicted, we found that rats that exhibited faster instrumental extinction also exhibited lower conditioned fear, as measured with conditioned suppression of lever-pressing and conditioned freezing. Our results suggest that at least part of the relationship between alcohol consumption levels and fear learning differences may be due to pre-existing individual differences. In addition, our finding that conditioned fear and instrumental extinction abilities (both separately associated with alcohol consumption levels) are associated with each other suggests that alcohol consumption levels may be a marker that can distinguish two separate phenotypes that encompass a wide variety of learning traits.

Relationship of low doses of alcohol voluntarily consumed during adolescence and early adulthood with subsequent behavioral flexibility.

Previous alcohol use is associated with impaired decision-making and impulsivity in humans, but the relationship between alcohol use and decision-making/impulsivity is unclear. In two experiments, we determined whether chronic intermittent access to alcohol during adolescence and early adulthood would alter or be correlated with performance in a go/no-go reversal task, a devaluation task, or operant extinction. Rats received 6 weeks of chronic intermittent access to 20% alcohol or water from postnatal day 26 to 66 and then behavioral testing was initiated 1.5-2.5 weeks later. We found no evidence that voluntary alcohol consumption altered behavior in either task. However, we found that rats that consumed more alcohol made fewer commission errors in reversal learning compared with rats that drank less. There was no relationship between alcohol consumption and reversal learning omission errors. Alcohol consumption was not correlated with the magnitude of the devaluation effect, but rats that consumed more alcohol showed faster extinction during the devaluation test. Our results suggest that the relationships between behavioral flexibility and alcohol consumption may represent individual differences. Future work will determine the neurobiological and genetic bases of these behavioral differences.

Subchronic anesthetic ketamine injections in rats impair choice reversal learning, but have no effect on reinforcer devaluation.

Previous exposure to a variety of drugs of abuse has been shown to cause long-term impairments in reversal learning and reinforcer devaluation tasks. However, there is mixed evidence in the literature for a long-term effect of ketamine exposure on reversal learning and the long-term effect of ketamine exposure on devaluation is not known. We determined whether repeated injections of an anesthetic dose of ketamine would lead to impairments in choice reversal learning after discrimination learning or impairments in reinforcer devaluation. In two experiments, rats received three injections once-daily of ketamine (100 mg/kg, intraperitoneally) or saline and then began behavioral training 19 days later so that the key reversal learning and devaluation tests would occur about 1 month after the final ketamine injection. This ketamine exposure regimen did not impair learning in our discrimination task, but led to an increase in perseverative errors in reversal learning. However, the same ketamine exposure regimen (or injections of a lower 50 mg/kg dose) had no effect on behavior in the devaluation task. The behavioral patterns observed suggest possible neural mechanisms for the effects of ketamine, but future neurobiological investigations will be needed to isolate these mechanisms.

Prior alcohol consumption does not impair go/no-go discrimination learning, but causes over-responding on go trials, in rats.

Prior alcohol use is associated with impaired response inhibition in humans, including in laboratory go/no-go discrimination tasks. In two experiments, we determined whether chronic intermittent access to alcohol would alter go/no-go discrimination learning. Rats received 4-6 weeks of chronic intermittent access to 20% alcohol (alone or accompanied by saline or 1.5g/kg alcohol injections) or water. Rats then began discrimination training 4-5days after the end of the alcohol access. Each lever was available for 40s with one lever intermittently reinforced ("active lever") and the other lever non-reinforced ("inactive lever"). The rats given access to alcohol without concurrent alcohol injections drank ∼10g/kg/24-h on average during the last three weeks of alcohol access. The groups given alcohol injections (Alcohol+Injection groups) exhibited suppressed drinking, but the Alcohol+Injection groups exhibited higher blood alcohol spikes than all other alcohol groups (195 vs. 85-90mg/dl, respectively). We found no evidence for impaired go/no-go discrimination learning in either experiment. However, the alcohol access groups with moderate-to-high average alcohol consumption (>3g/kg/24-h) exhibited over-responding to the active lever compared to the water-only groups. One group given alcohol injections (Alcohol+Injection group) that exhibited very low voluntary drinking (<1g/kg/24-h) did not exhibit the over-responding effect, suggesting that the total 24-h alcohol dose matters more than short-lived blood alcohol spikes. Our findings are in accord with previous research showing that repeated alcohol withdrawal causes over-responding for responses that lead to limited reinforcement. Future work will determine the psychological and neurobiological basis of this behavioral change.