R. Fred Westbrook

Evidence that GABA transmission mediates context-specific extinction of learned fear

Abstract Six experiments used rats to study the effects of the β-carboline FG 7142 on extinction of fear responses (freezing) to an auditory cue that had signalled footshock. Subcutaneous injection of FG 7142 interfered with the development of extinction without having any detectable effect on the rats’ levels of fear prior to extinction. Injection of FG 7142 also reversed extinction, partially reinstating fear responses that had been extinguished previously. A similar reinstatement of extinguished fear was seen when rats were tested for fear of the cue in a different chamber. The reinstatement produced by FG 7142 and that caused by context shift were not additive: FG 7142 did not increase extinguished fear if rats were tested in the different chamber. Finally, FG 7142 had no detectable effect on the latent inhibition of fear produced by repeatedly presenting the cue alone before conditioning with shock, even though this inhibition, like extinction, was affected by a shift in context. The present findings indicate that GABA transmission at GABAA receptors is involved in the inhibition of extinguished fear, and that this effect of GABA is regulated by those cues that constitute the extinction context.

Extended exposure to a palatable cafeteria diet alters gene expression in brain regions implicated in reward, and withdrawal from this diet alters gene expression in brain regions associated with stress

Like people, rodents exposed to energy-rich foods over-eat and become overweight. Removal of this diet activates stress systems, which may explain why people have difficulty dieting. We exposed rats to energy-rich foods in order to identify changes in the brain induced by that diet and by its removal. Sprague Dawley rats were fed lab-chow or an energy-rich cafeteria diet (plus chow). Following 6 or 15 weeks, half of each group was switched to the opposing diet. Rats were culled 48-h later. We measured fat mass, plasma hormones, and assessed brains for mRNA expression of several genes. Cafeteria-fed rats consumed more kilojoules, weighed more and had elevated leptin (plus reduced CORT at 15 weeks) relative to chow-fed rats. Fifteen weeks of cafeteria diet suppressed μ-opioid and CB1 receptor mRNA in the VTA, but elevated amygdala GR, and 6 weeks of cafeteria diet reduced BDNF, compared to chow-fed rats. Rats switched to the cafeteria diet ate similar amounts as rats maintained on the diet, and switching to cafeteria diet after 15 weeks reduced amygdala GR expression. Rats switched to chow ate less than rats maintained on chow, and switching to chow following 15 weeks of cafeteria diet increased hypothalamic CRH mRNA. Therefore, 15 weeks of cafeteria diet produced changes in brain regions implicated in reward processes. Switching these rats to chow activated the HPA axis, while switching chow-fed rats to the cafeteria diet decreased GR expression in the amygdala, a region associated with stress. These findings have implications for dieting in humans.

Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity.

In this study we sought to determine the effect of daily sucrose consumption in young rats on their subsequent performance in tasks that involve the prefrontal cortex and hippocampus. High levels of sugar consumption have been associated with the development of obesity, however less is known about how sugar consumption influences behavioral control and high-order cognitive processes. Of particular concern is the fact that sugar intake is greatest in adolescence, an important neurodevelopmental period. We provided sucrose to rats when they were progressing through puberty and adolescence. Cognitive performance was assessed in adulthood on a task related to executive function, a rodent analog of the Stroop task. We found that sucrose-exposed rats failed to show context-appropriate responding during incongruent stimulus compounds presented at test, indicative of impairments in prefrontal cortex function. Sucrose exposed rats also showed deficits in an on object-in-place recognition memory task, indicating that both prefrontal and hippocampal function was impaired. Analysis of brains showed a reduction in expression of parvalbumin-immunoreactive GABAergic interneurons in the hippocampus and prefrontal cortex, indicating that sucrose consumption during adolescence induced long-term pathology, potentially underpinning the cognitive deficits observed. These results suggest that consumption of high levels of sugar-sweetened beverages by adolescents may also impair neurocognitive functions affecting decision-making and memory, potentially rendering them at risk for developing mental health disorders.

Altered feeding patterns in rats exposed to a palatable cafeteria diet: increased snacking and its implications for development of obesity.

Background Rats prefer energy-rich foods over chow and eat them to excess. The pattern of eating elicited by this diet is unknown. We used the behavioral satiety sequence to classify an eating bout as a meal or snack and compared the eating patterns of rats fed an energy rich cafeteria diet or chow. Methods Eight week old male Sprague Dawley rats were exposed to lab chow or an energy-rich cafeteria diet (plus chow) for 16 weeks. After 5, 10 and 15 weeks, home-cage overnight feeding behavior was recorded. Eating followed by grooming then resting or sleeping was classified as a meal; whereas eating not followed by the full sequence was classified as a snack. Numbers of meals and snacks, their duration, and waiting times between feeding bouts were compared between the two conditions. Results Cafeteria-fed rats ate more protein, fat and carbohydrate, consistently ingesting double the energy of chow-fed rats, and were significantly heavier by week 4. Cafeteria-fed rats tended to take multiple snacks between meals and ate fewer meals than chow-fed rats. They also ate more snacks at 5 weeks, were less effective at compensating for snacking by reducing meals, and the number of snacks in the majority of the cafeteria-fed rats was positively related to terminal body weights. Conclusions Exposure to a palatable diet had long-term effects on feeding patterns. Rats became overweight because they initially ate more frequently and ultimately ate more of foods with higher energy density. The early increased snacking in young cafeteria-fed rats may represent the establishment of eating habits that promote weight gain.

Induction of Fos proteins in regions of the nucleus accumbens and ventrolateral striatum correlates with catalepsy and stereotypic behaviours induced by morphine

A history of intermittent exposures to drugs of abuse can cause long-term changes in acute behavioural responses to a subsequent drug exposure. In drug-naive rats, morphine can elicit intermittent cataleptic postures followed by sustained increases in locomotor activity. Chronic intermittent morphine treatment can reduce catalepsy and increase locomotor behaviour and stereotypy induced by morphine, even after prolonged periods of abstinence. The nucleus accumbens and limbic basal ganglia circuitry are implicated in the expression of various morphine-induced motor behaviours and catalepsy. We examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the basal ganglia following a subsequent morphine challenge administered after a period of drug abstinence. We found that such exposures increased c-Fos induced by a morphine challenge in accumbens core regions that were immunoreactive for the micro-opioid receptor, and this correlated with the frequency of stereotypic behaviours displayed by the rats. We also found that a history of morphine exposures increased c-Fos in the ventrolateral striatum in response to a morphine challenge following 14 d but not 24 h of drug abstinence. In contrast, such a history induced acute Fras in the nucleus accumbens in response to a morphine challenge following 24 h but not 14 d of morphine abstinence. These data provide further confirmation that psychomotor sensitisation induced by repetitive morphine exposure involves long-term neuroadaptations in basal ganglia circuitry particularly at the level of the nucleus accumbens.

Varenicline impairs extinction and enhances reinstatement across repeated cycles of nicotine self-administration in rats.

Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed.

Compound Stimulus Presentation Does Not Deepen Extinction in Human Causal Learning

Models of associative learning have proposed that cue-outcome learning critically depends on the degree of prediction error encountered during training. Two experiments examined the role of error-driven extinction learning in a human causal learning task. Target cues underwent extinction in the presence of additional cues, which differed in the degree to which they predicted the outcome, thereby manipulating outcome expectancy and, in the absence of any change in reinforcement, prediction error. These prediction error manipulations have each been shown to modulate extinction learning in aversive conditioning studies. While both manipulations resulted in increased prediction error during training, neither enhanced extinction in the present human learning task (one manipulation resulted in less extinction at test). The results are discussed with reference to the types of associations that are regulated by prediction error, the types of error terms involved in their regulation, and how these interact with parameters involved in training.