Binge cocaine administration in adolescent rats affects amygdalar gene expression patterns and alters anxiety-related behavior in adulthood.

BACKGROUND: Administration of cocaine during adolescence alters neurotransmission and behavioral sensitization in adulthood, but the effect on the acquisition of fear memories and the development of emotion-based neuronal circuits is unknown. METHODS: We examined fear learning and anxiety-related behaviors in adult male rats that were subjected to binge cocaine treatment during adolescence. We furthermore conducted gene expression analyses of the amygdala 22 hours after the last cocaine injection to identify molecular patterns that might lead to altered emotional processing. RESULTS: Rats injected with cocaine during adolescence displayed less anxiety in adulthood than their vehicle-injected counterparts. In addition, cocaine-exposed animals were deficient in their ability to develop contextual fear responses. Cocaine administration caused transient gene expression changes in the Wnt signaling pathway, of axon guidance molecules, and of synaptic proteins, suggesting that cocaine perturbs dendritic structures and synapses in the amygdala. Phosphorylation of glycogen synthase kinase 3 beta, a kinase in the Wnt signaling pathway, was altered immediately following the binge cocaine paradigm and returned to normal levels 22 hours after the last cocaine injection. CONCLUSIONS: Cocaine exposure during adolescence leads to molecular changes in the amygdala and decreases fear learning and anxiety in adulthood.

Protective effect of metabotropic glutamate mGluR5 receptor elimination in a 6-hydroxydopamine model of Parkinson's disease.

Pharmacologic or genetic blockade of metabotropic glutamate mGlu5 receptors (mGluR5) has been shown to attenuate parkinsonian motor deficits and protect nigrostriatal neurons from damage in the acute MPTP model of Parkinson's disease (PD), suggesting that therapeutically targeting the mGluR5 receptor may offer a novel approach to improving motor symptoms and/or slowing neurodegeneration in PD. This study further explored the neuroprotective potential of targeting mGluR5 receptors. We examined the behavioral and neurochemical effects of receptor elimination on toxicity induced by intra-striatal application of 6-hydroxydopamine (6-OHDA), thought to represent a comparatively progressive model of PD. mGluR5 knockout (KO) mice and wild-type (WT) littermates received unilateral 6-OHDA infusions. Reflecting the imbalance expected following unilateral infusion, WT but not KO mice demonstrated predominantly ipsilateral forepaw use and robust ipsilateral amphetamine-induced rotation. Further, performance on the vertical pole descent task was profoundly impaired in WT mice, while KO mice completed the task significantly faster. Consistent with the behavioral observations, neurochemical analyses of striatal dopamine depletion showed significantly diminished severity in KO mice with only 64% of striatal dopamine lost, compared to 92% in WT mice. The absence of brain mGluR5 receptors in living KO mice was verified using positron emission tomography (PET). Our findings substantiate the key role of mGluR5 receptors in animal models of PD, strengthening the rationale for the development of mGluR5 antagonists for their neuroprotective, as well as symptomatic, benefit.

Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats.

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.

Altered attention and prefrontal cortex gene expression in rats after binge-like exposure to cocaine during adolescence.

Illicit use of drugs frequently begins and escalates during adolescence, with long-term adverse consequences. Because it is increasingly accepted that neural development continues through adolescence, addiction research has become more invested in understanding the behavioral and molecular consequences of early exposure to drugs of abuse. In a novel binge administration paradigm designed to model the pattern of human adolescent drug use, we administered ascending doses of cocaine or saline during a 12-d developmental period [postnatal day 35 (P35) to P46] corresponding to human adolescence. During adulthood (P70), rats treated with this regimen displayed increased responsiveness to the stimulant effects of cocaine. Adult rats also displayed abnormally rapid shifts in attention when performing an attentional set-shifting task, which measures the ability to shift attention between stimuli and whose performance requires an intact prefrontal cortex (PFC). Treatment with cocaine during adolescence also caused acute alterations in the expression of genes encoding cell adhesion molecules and transcription factors within the PFC. Furthermore, we observed decreases in histone methylation, which may indicate a role for chromatin remodeling in the observed changes in gene expression patterns. These findings suggest that exposure to cocaine during adolescence has far-reaching molecular and behavioral consequences in the rat PFC that develop over time and endure long after drug administration has ceased.

Complementary tasks to measure working memory in distinct prefrontal cortex subregions in rats.

Acquisition of odor-guided or visually-guided delayed win-shift behavior was evaluated in rats after lidocaine-induced inactivation within the agranular insular area of the prefrontal cortex (PFC) or the prelimbic area of the PFC. Additional sites and tasks were used to control for neuroanatomical and behavioral specificity of lidocaine inactivation of the agranular insular and prelimbic areas. Results showed that acquisition of the odor-guided delayed win-shift task was dependent on the agranular insular area, whereas acquisition of the visually-guided version was dependent on the prelimbic area. This dissociation suggests that the stimulus modality used is critical for revealing working memory functions of different PFC subregions. The described methods provide a complementary means to study working memory in PFC subregions using a radial-arm maze.

Hippocampal memory system function and the regulation of cocaine self-administration behavior in rats.

There is considerable interest in elucidating neurocognitive mechanisms of cocaine addiction. This report focuses on the hippocampal memory system. Using food reward, two cognitive tasks were examined after lidocaine inactivation of the dorsal (dSUB) or ventral (vSUB) subiculum, the primary hippocampal output regions in rats. These tasks were conducted to first identify functionally relevant stereotaxic coordinates within the hippocampal memory system, in order to then examine its role in regulating drug-seeking and drug-taking behavior studied under a contextually discriminable FI 5-min(FR5:S) second-order schedule of cocaine and brief stimulus delivery. Inactivation of the dSUB and vSUB with 10microg lidocaine impaired hippocampal-dependent win-shift performance. Amygdalar-dependant conditioned cue preference, used as a test for behavioral specificity of lidocaine, was not affected following inactivation of either site. Inactivation of the dSUB with 100 microg lidocaine significantly reduced drug-seeking and drug-taking behavior studied during the cocaine self-administration maintenance phase. Following extinction, inactivation of neither the dSUB nor vSUB influenced reinstatement of drug-seeking behavior induced by drug-paired cues presented alone or with a cocaine priming injection. The impairments in win-shift performance are consistent with the spatial processing functions of the dSUB and vSUB, and the reduction in drug-taking behavior is consistent with the non-spatial temporal processing functions of the dSUB. The lack of an effect of dSUB and vSUB inactivation on reinstatement of drug-seeking behavior may relate to the fact that the contextual associations with cocaine were well-practiced at the time of cue reinstatement testing, and therefore, drug-seeking behavior was likely regulated by nonhippocampal-dependent mechanisms.

Stimulus-response functions of the lateral dorsal striatum and regulation of behavior studied in a cocaine maintenance/cue reinstatement model in rats.

RATIONALE: To investigate potential neurocognitive mechanisms underlying drug-seeking and drug-taking behavior, the effects of reversible lidocaine-induced inactivation of the lateral dorsal striatum (DST) on behavior studied in a drug maintenance/cue reinstatement model were evaluated. This region of the DST was investigated because it selectively regulates stimulus-response learning that is disrupted by 10 microg of bilaterally infused lidocaine. METHODS: Rats ( n=6) were trained to self-administer 1 mg/kg per infusion cocaine under a second-order schedule of drug delivery. The effects of bilateral lidocaine (30-100 microg) inactivation of the lateral DST were evaluated during drug maintenance tests as well as during tests in which responding was reinstated by cocaine-associated cues presented in combination with a cocaine priming injection. The lower 10 microg dose was used to examine the effects of lidocaine on reinstatement of responding induced by presentation of cues alone. RESULTS: During drug maintenance tests, drug-seeking behavior was significantly increased after inactivation by 100 microg lidocaine. The number of infusions earned did not change. During cue-induced reinstatement tests preceded by a cocaine priming injection, 100 microg lidocaine significantly decreased both drug-seeking behavior and the number of infusion-paired light deliveries earned. During reinstatement tests with cues presented alone, inactivation of the lateral DST by 10 microg lidocaine did not influence either behavior. CONCLUSIONS: These findings suggest that stimulus-response functions of the lateral DST may regulate the dose-related effects of self-administered cocaine because the lidocaine-induced changes in behavior during the maintenance and cocaine priming tests resembled the effects of exposure to increasingly lower doses of cocaine, respectively. Given the lack of an effect of lidocaine during the cues-alone tests, the lateral DST does not appear to regulate drug-seeking behavior per se (i.e., responding maintained by drug-associated cues at times when drug is not available).

Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats.

Cocaine addiction is a chronically relapsing brain disease, but its neural basis is not yet well understood. Clinical reports underscore the possible importance of associative processes for regulating at least some aspects of cocaine addiction. The present study reports the effects of reversible lidocaine-induced inactivation of rostral basolateral amygdala (rBLA) and caudal basolateral amygdala (cBLA) regions on the maintenance and reinstatement of drug-seeking behavior in rats trained to self-administer 1 mg/kg cocaine under a second order schedule of drug delivery. Both regions of the basolateral amygdala were investigated because they have dissociable effects on cognitive task performance. Results demonstrated that after self-administration training and a period of extinction and abstinence, lidocaine inactivation of the rBLA and cBLA attenuated the reinstatement of drug-seeking behavior induced by cocaine-associated cues examined in conjunction with a single priming injection of cocaine. In contrast, lidocaine inactivation of only the rBLA blocked reinstatement of drug-seeking behavior induced by cocaine-associated cues examined alone. Additional differences were shown during cocaine maintenance testing where inactivation of only the cBLA attenuated drug-seeking behavior. Drug intake was not altered. Thus, the rBLA and cBLA appear to selectively and dissociably regulate drug-seeking behavior under conditions of cocaine abstinence (cue-induced reinstatement) and repeated cocaine use (maintenance), respectively. These findings suggest that the basolateral amygdala may be more functionally heterogeneous than commonly thought for regulating drug-seeking behavior. The basis for this dissociation might be related to neuroanatomical connections of the rBLA and cBLA with segregated, but parallel, corticostriatalpallidothalamic circuits.