2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Cocaine-Related-Disorders

This study investigated the effects of the AMPA/Kainate receptor antagonist, NBQX, on cue-elicited cocaine-seeking behavior and concomitant changes in Fos protein expression. After cocaine self-administration training, rats underwent 24 days of abstinence during which they were exposed daily either to the self-administration environment with response-contingent cues previously paired with cocaine infusions available (Extinction group) or to an alternate environment (No Extinction group). Subsequently, rats were tested for cocaine-seeking behavior (i.e., operant responses without cocaine reinforcement) elicited by the cocaine-associated cues after pretreatment with either vehicle or NBQX (10 mg/kg, IP). NBQX markedly attenuated cue-elicited cocaine-seeking behavior relative to vehicle pretreatment in the No Extinction group and also decreased cue-elicited Fos protein expression in a region-specific manner in the anterior cingulate and orbitofrontal cortices, basolateral amygdala, nucleus accumbens core, and dorsal caudate-putamen, suggesting involvement of AMPA glutamate systems in specific subregions of the neuronal circuitry activated by cocaine cues.

Topics: Animals; Behavior, Animal; Brain Mapping; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Extinction, Psychological; Gene Expression Regulation; Male; Oncogene Proteins v-fos; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid; Self Administration; Time Factors

Cocaine strengthens behaviors associated with its administration. The stress response by individuals that are defeated in a brief aggressive confrontation can also promote enduring behavioral consequences similar to those of stimulants.. The study intends to find whether intermittent episodes of defeat promote cocaine's reinforcing effects by triggering N-methyl-D: -aspartic acid (NMDA)-receptor-mediated plasticity in the ventral tegmental area (VTA).. Long-Evans rats were investigated after four social defeats in three experiments. Two experiments examined systemic or intra-VTA antagonism of NMDA receptors during stress on the later expression of behavioral sensitization and cocaine self-administration during fixed and progressive ratio (PR) schedules of reinforcement (0.3 mg/kg/infusion), including a novel 24-h variable-dose continuous access binge (0.2, 0.4, and 0.8 mg/kg/infusion, delivered in an irregular sequence). Third, the expression of receptor proteins NR1 (NMDA) and GluR1 [alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)] were examined in VTA and nucleus accumbens.. Intermittent defeats augment locomotor responses to cocaine and increase cocaine taking. Rates of responding during binges are increased after defeat stress. These effects are prevented when NMDA or AMPA receptor antagonists are administered before defeats. VTA infusions of the NMDA antagonist AP-5 (5 nmol/side) before stress prevents locomotor sensitization to cocaine and intensified responding for cocaine during a PR schedule or binge. Episodic defeats increase GluR1 AMPA subunit protein expression in the VTA.. Social stress stimulates NMDA receptors in the VTA, and this neural action of defeat may be essential for prompting a later increase in cocaine intake during binges.

Topics: 2-Amino-5-phosphonovalerate; Animals; Blotting, Western; Cocaine-Related Disorders; Conditioning, Operant; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Quinoxalines; Rats; Rats, Long-Evans; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Reinforcement Schedule; Self Administration; Social Environment; Stress, Psychological; Ventral Tegmental Area