Recent anatomical and functional studies have renewed interest in the lateral habenula (LHb), a critical brain region that works in an opponent manner to modulate aversive and appetitive processes. In particular, increased LHb activation is believed to drive anxiogenic states during stressful conditions. Here, we reversibly inactivated the LHb with GABA receptor agonists (baclofen/muscimol) in rats prior to testing in an open field, elevated plus maze, and defensive burying task in the presence or absence of yohimbine, a noradrenergic ?2-receptor antagonist that acts as an anxiogenic stressor. In a second set of experiments using a cocaine self-administration and reinstatement model, we inactivated the LHb during extinction responding and cue-induced reinstatement of cocaine seeking in the presence or absence of yohimbine pretreatment. Inactivation of the LHb after yohimbine treatment attenuated anxiogenic behavior by increasing time spent in the open arms and reducing the time spent burying. Inactivation of the LHb also reduced cocaine seeking when cue-induced reinstatement occurred in the presence of yohimbine, but did not affect extinction responding or cue-induced reinstatement by itself. These data demonstrate that the LHb critically regulates states of heightened anxiety during both unconditioned behavior and conditioned appetitive processes.
Rats reared in enriched environmental conditions (EC) show altered responding for visual novelty and psychostimulants compared with rats reared in isolated conditions (IC). This study investigated whether response rate was altered in EC and IC rats when a visual stimulus was or was not paired with sucrose delivery in food-deprived and free-fed rats. Male Sprague-Dawley rats were reared in EC, IC, or social conditions (SC) before training to lever press for liquid sucrose on a fixed ratio 5 schedule. Food-deprived EC rats responded significantly more than IC rats during acquisition and when cue lights were removed, these results were reversed in free-fed rats. In the absence of the cue light, IC food-deprived rats took more time to extinguish responding and showed greater reinstatement compared with EC rats. These results reveal differences between EC and IC rats in response to incentive value and learning abilities. During all phases, responding for SC rats was generally between EC and IC rats. These studies suggest that differences in the incentive value of the stimulus contribute to differential responding in EC, IC, and SC rats for sucrose paired with a cue-light reinforcer.
3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP) is a metabotropic glutamate receptor 5 (mGluR5) antagonist that may alter drug sensitivity in differentially reared rats due to its involvement in the psychostimulant reward pathway and plasticity.
As there is currently no licensed vaccine against Francisella tularensis, the causative agent of tularaemia, the bacterium is an agent of concern as a potential bioweapon. Although F. tularensis has a low infectious dose and high associated mortality, it possesses few classical virulence factors. An analysis of the F. tularensis subspecies tularensis genome sequence has revealed the presence of a region containing genes with low sequence homology to part of the capBCADE operon of Bacillus anthracis. We have generated an isogenic capB mutant of F. tularensis subspecies tularensis SchuS4 and shown it to be attenuated. Furthermore, using BALB/c mice, we have demonstrated that this capB strain affords protection against significant homologous challenge with the wild-type strain. These data have important implications for the development of a defined and efficacious tularaemia vaccine.
Rats classified as high responders (HR) based on their response to an inescapable novel environment self-administer more amphetamine and have greater amphetamine-induced sensitization than rats classified as low responders (LR). Recent research suggests that the central nucleus of the amygdala (ACe) contributes to the elevated self-administration in HR rats. Therefore, the current study examined the role of the ACe in the expression of both amphetamine-induced sensitization and conditioned hyperactivity in HR and LR rats. Male Sprague-Dawley rats were screened for their response to inescapable novelty and classified as HR or LR rats. Rats were implanted with bilateral cannulae into the ACe and received amphetamine (1.0 mg/kg, s.c.) or saline injections immediately prior to 1-h locomotor sessions. Following five training sessions, all rats received an infusion of muscimol (0.5 microg/0.5 microl) or phosphate buffered saline (PBS) followed by a saline injection to measure conditioned hyperactivity. HR rats displayed conditioned hyperactivity, while LR rats did not, suggesting that HR and LR rats differ in the expression of conditioned hyperactivity. While ACe inactivation attenuated the expression of conditioned hyperactivity, it did not differentially affect HR and LR rats. Following additional training and a 10-day rest period, all rats were then tested for amphetamine-induced sensitization (1.0 mg/kg) following an infusion of muscimol or PBS. Inactivation of the ACe attenuated the expression of sensitization only in HR rats. These results suggest the ACe contributes to the greater amphetamine sensitization in HR rats.
Differential rearing decreases psychostimulant-induced hyperactivity. In general, environmental enrichment decreases the locomotor response to low unit doses of psychostimuluants, whereas isolation increases the response. It is not clear whether the changes in locomotor activity are due to an enrichment-induced decrease or an isolation-induced increase. Therefore, the current experiments examined the ability of enrichment rearing, as compared with isolation and standard rearing, to attenuate amphetamine-induced hyperactivity following acute administration, repeated administration, and sensitization of a low (0.3 mg/kg) and moderate (1.0 mg/kg) dose of amphetamine. Rats were reared under enriched, isolated, or standard conditions. Enrichment slowed the acquisition of amphetamine-induced hyperactivity and attenuated the expression of amphetamine-induced sensitization, but only at the low unit dose. Enrichment did not protect against the expression of conditioned hyperactivity at either of the doses tested. The behavior of standard condition rats was generally closer to that of isolated condition rats than enriched condition rats, suggesting that the enrichment attenuates the response to amphetamine as opposed to isolation rearing increasing the response to amphetamine. These results suggest that the effects of enrichment are because of enrichment manipulation and not simply a contrast from the effects of isolation.
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