6-cyano-7-nitroquinoxaline-2-3-dione and Cocaine-Related-Disorders

While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a nonaddicted or an addicted phenotype.. Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended-access self-administration.. Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended-access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group.. These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Excitatory Amino Acid Antagonists; Extinction, Psychological; Female; Glutamic Acid; Male; Motivation; Nucleus Accumbens; Phenotype; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Reinforcement Schedule; Self Administration

The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 µl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 µg/0.3 µl /hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual cocaine-seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity or food-reinforced instrumental behavior in control experiments. Thus, glutamate-mediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Behavior, Animal; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Drug-Seeking Behavior; Extinction, Psychological; Feeding Behavior; Male; Motivation; Motor Activity; Nucleus Accumbens; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate; Recurrence; Reinforcement, Psychology; Self Administration

Dopamine and glutamate are thought to interact in the ventral striatum and to play important roles there in the cocaine-seeking of cocaine-experienced animals.. We sought to determine the relative roles of the two transmitters in the two major zones of the nucleus accumbens (NAS), the core and shell subregions.. We assessed the effects of dopamine and glutamate receptor blockade in the core and shell on intravenous cocaine self-administration in rats. Trained animals were allowed to self-administer cocaine for an initial hour, and then D1-type or D2-type dopamine receptor blockers or NMDA-type or AMPA-type glutamate receptor blockers were infused by reverse microdialysis into one of the two regions for an additional 3 h of testing.. The D1-type antagonist SCH23390 and the D2-type antagonist raclopride each increased cocaine intake whereas the AMPA-type antagonist CNQX decreased responding when infused into the core. SCH23390 increased cocaine intake less strongly when infused into the shell, while raclopride and CNQX were each ineffective when infused into the shell. The NMDA-antagonist CPP failed to affect cocaine self-administration when infused into either site.. These findings implicate the core of NAS in the maintenance of established cocaine self-administration in trained animals, despite the fact that the reinforcement of responding in untrained animals appears to results from cocaine actions in the olfactory tubercle and medial shell and not the core of accumbens.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Behavior, Addictive; Cocaine; Cocaine-Related Disorders; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Glutamic Acid; Male; Microdialysis; Nucleus Accumbens; Olfactory Pathways; Rats; Rats, Long-Evans; Receptors, AMPA; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Reinforcement Schedule; Self Administration

The direct glutamatergic projection from the medial prefrontal cortex (mPFC) to the nucleus accumbens plays a critical role in mediating the reinstatement of cocaine seeking behavior. The mPFC also sends glutamatergic projections to the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDT), which in turn send glutamatergic and cholinergic efferents to the ventral tegmental area (VTA) where they synapse on dopaminergic cells that innervate limbic structures including the nucleus accumbens. The goal of these experiments was to examine a potential role for the PPTg/LDT in the reinstatement of cocaine seeking. All rats were trained to self-administer cocaine (0.25 mg, i.v.) on a fixed-ratio 5 schedule of reinforcement. Cocaine self-administration behavior was extinguished and a series of subsequent pharmacological experiments were performed to assess the potential role of the mPFC, PPTg/LDT and VTA in the reinstatement of cocaine seeking. Administration of the D1-like dopamine receptor agonist SKF-81297 (1.0 microg) directly into the mPFC produced a small, but statistically significant, increase in cocaine seeking behavior. Furthermore, microinjection of the ionotropic glutamate receptor antagonist CNQX (0.3 microg) into the PPTg/LDT attenuated the reinstatement of drug seeking induced by a priming injection of cocaine (10 mg/kg, i.p.). Intra-VTA administration of CNQX, the nicotinic receptor antagonist mecamylamine (10.0 microg) or the muscarinic receptor antagonist scopolamine (24.0 microg) also blocked cocaine seeking. Taken together, these results suggest that cocaine priming-induced reinstatement of drug seeking is mediated in part by a serial polysynaptic limbic subcircuit encompassing the mPFC, PPTg/LDT and VTA.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Benzazepines; Cocaine; Cocaine-Related Disorders; Dopamine Agonists; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Extinction, Psychological; Male; Muscarinic Antagonists; Pedunculopontine Tegmental Nucleus; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Scopolamine; Self Administration; Tegmentum Mesencephali; Ventral Tegmental Area

A growing body of evidence indicates that enhanced AMPA-mediated glutamate transmission in the core of the nucleus accumbens is critically involved in cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. However, the extent to which increased glutamate transmission in the other major subregion of the nucleus accumbens, the shell, contributes to the reinstatement of cocaine seeking remains unclear. In the present experiments, administration of the AMPA/kainate receptor antagonist CNQX (0, 0.03, or 0.3 mug) into either the core or the shell of the nucleus accumbens before a systemic cocaine priming injection (10 mg/kg, i.p.) dose-dependently attenuated the reinstatement of drug seeking. Cocaine priming-induced reinstatement of cocaine seeking also was associated with increases in GluR2-pSer880 in the nucleus accumbens shell. The phosphorylation of GluR2 by PKC at Ser880 plays an important role in the trafficking of GluR2-containing AMPA receptors from the plasma membrane. The current results showed that administration of a cell-permeable peptide that disrupts GluR2 trafficking (Pep2-EVKI) into either the accumbens core or shell attenuated cocaine-induced reinstatement of drug seeking. Together, these findings indicate that changes in AMPA receptor-mediated glutamate transmission in both the nucleus accumbens core and shell are necessary for the reinstatement of drug seeking induced by a priming injection of cocaine. The present results also demonstrate that the reinstatement of cocaine seeking is associated with increases in the phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Behavior, Animal; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Food Preferences; Male; Nucleus Accumbens; Phosphorylation; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Reinforcement Schedule; Reinforcement, Psychology; Self Administration; Serine

Nucleus accumbens glutamate transmission has been implicated in drug-seeking behavior, but the involvement of glutamate receptor subtypes in drug seeking maintained by drug-associated cues has not been fully investigated.. This study examined the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-D-aspartate (NMDA) and mGlu5 receptor blockade in the nucleus accumbens core on cue-induced reinstatement of cocaine seeking.. Wistar rats were trained to self-administer cocaine and associate a compound stimulus (light and tone) with the drug under an FR4(FR5:S) second-order schedule of reinforcement. After extinction, during which neither cocaine nor the compound stimulus was available, responding was reinstated by contingent presentations of the compound stimulus. The effects of the intra-accumbal AMPA/kainate receptor antagonist 6-cyano-7-nitro-quinoxaline-2, 3-dione (CNQX; 0, 0.01, and 0.03 microg/side), the NMDA antagonist D-2-amino-5-phosphonopentanoate (D-AP5; 0, 1, and 2 microg/side), and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 0, 0.5, and 1 microg/side) on reinstatement were examined in a within-subjects design.. CNQX and D-AP5 attenuated cue-induced reinstatement of cocaine seeking dose-dependently. MPEP, however, decreased cocaine seeking only relative to baseline because also the saline vehicle included in the within-subjects series of injections decreased responding, possibly reflecting conditioned anhedonic effects of MPEP. In additional experiments, none of the antagonists attenuated locomotor activity or responding for sucrose pellets.. The results suggest that cue-induced reinstatement of cocaine seeking after a period of withdrawal from cocaine is sensitive to AMPA/kainate and NMDA receptor antagonism in the nucleus accumbens core and give further evidence for the role of the accumbal glutamate transmission in modulation of drug-seeking behavior.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cocaine; Cocaine-Related Disorders; Conditioning, Psychological; Cues; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Extinction, Psychological; Male; Motor Activity; Nucleus Accumbens; Pyridines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Self Administration

Cocaine administration induces glutamatergic activation within the mesolimbic-accumbens system. This activation has been linked to the behavioral effects of cocaine and recently to the induction of long-term potentiation in dopamine neurons within the ventral tegmental area (VTA). We sought to determine if glutamate receptor activation is also crucial to the development of a conditioned place preference (CPP) to cocaine's rewarding effects. Two groups of rats were given intra-VTA injections of either vehicle or a combination of NMDA (N-methyl-D-aspartate) and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonists (AP5 0.24 nmol plus CNQX 0.12 nmol per side) prior to each cocaine place-conditioning trial. Microinjections of the glutamate antagonists completely blocked the development of a cocaine CPP when given within, but not when given outside of, the VTA. These data indicate that glutamatergic activity in the VTA may be crucial for learning to associate environmental stimuli with cocaine exposure.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cocaine; Cocaine-Related Disorders; Cues; Environment; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Microinjections; Motor Activity; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Ventral Tegmental Area

It has been suggested previously that conditioned effects on drug-seeking behaviour are in part mediated through glutamatergic neurotransmission.. To optimise a second-order schedule of IV cocaine reinforcement in Wistar rats and investigate the effects of the systemic AMPA/kainate receptor antagonist CNQX on cocaine-seeking behaviour under this schedule.. Free-feeding Wistar rats were trained to respond for an IV cocaine infusion (0.25 mg/infusion) under a FI15 min(FR7:S) schedule, whereby the completion of FR7 responses led to the presentation of a conditioned stimulus (CS). After two 15-min fixed intervals, rats were allowed to respond for cocaine under an FR4(FR7:S) second-order schedule for another 120 min. After acquisition of stable responding, the cocaine unit dose was increased to 0.50 mg/infusion. The effects of CNQX (0, 0.75, 1.5, and 3 mg/kg IP) on cocaine seeking were then examined using a within-subjects design.. Increasing the cocaine unit dose increased responding during the first and second intervals, with a decrease in the latency to the first CS. CNQX decreased the number of cocaine responses in a dose-dependent manner during the first 15-min cocaine-free interval, but did not affect cocaine responding during either the second interval or the latter part of the session under the FR4(FR7:S) schedule. In the locomotor activity test, reductions in rearing were produced by higher CNQX doses than those that attenuated significantly responding during the first fixed interval.. These results suggest that AMPA/kainate receptors are involved in mediation of cocaine-seeking behaviour controlled partly by cocaine-associated cues.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Behavior, Animal; Cocaine-Related Disorders; Conditioning, Psychological; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Extinction, Psychological; Male; Motor Activity; Rats; Rats, Wistar; Reaction Time; Receptors, AMPA; Receptors, Kainic Acid; Reinforcement Schedule; Self Administration

In the medial prefrontal cortex, repeated cocaine produces tolerance of the extracellular dopamine response to subsequent cocaine injection. These studies characterized the influence of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors on the medial prefrontal cortex dopamine response to acute cocaine, amphetamine and potassium chloride as a first step to assess whether these receptor subtypes may be candidates for mediating dopamine tolerance after repeated cocaine. Local infusion of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) produced an approximate 40% increase in dopamine levels in the medial prefrontal cortex, while a 30 microM dose did not alter basal levels infused over a 3-h period. Thus, 30 microM CNQX was chosen for the remaining experiments, and was infused for 1 h prior to and during all in vivo treatments. Local medial prefrontal cortex infusion of the 30 microM dose blocked the small increase in dopamine levels elicited by systemic saline injection (maximum of 26%), as well as the much larger increase in response to acute cocaine injection (maximum of 340%). Local infusion of D-amphetamine (3 and 30 microM) through the probe increased dopamine to 300 and 600% of basal levels, respectively. Co-infusion of CNQX partially blocked the response for the first 40 min, but dopamine levels recovered by 60 min later. Local infusion of 100 mM potassium chloride elicited a 600% increase in dopamine levels, which was attenuated approximately 50% by CNQX co-infusion. Potassium-stimulated release of dopamine was also measured in vitro in medial prefrontal cortical and striatal tissue. By 30 s after potassium addition, dopamine levels increased to 800% above baseline in the medial prefrontal cortex, and this increase was blocked by the presence of 30 microM CNQX. In contrast, potassium-stimulated dopamine release in striatal tissue was approximately 250% above basal levels, with no effect of CNQX on dopamine release. Locomotor behavior collected during dialysis experiments demonstrated that increased activity induced by local infusion of potassium chloride was severely attenuated by co-infusion of 30 microM CNQX, while no effects of this drug were found for cocaine-elicited behavior. These results suggest a potent influence of glutamate via alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors on extracellular dopamine in the medial prefrontal cortex, and these receptors may regulate dopamine release through a

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamine; Animals; Cocaine; Cocaine-Related Disorders; Dopamine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Motor Activity; Neostriatum; Neurons; Potassium Chloride; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Reward; Stress, Physiological; Synaptic Transmission; Up-Regulation

G-protein-coupled metabotropic glutamate receptors (mGluRs) are being implicated in various forms of neuroplasticity and CNS disorders. This study examined whether the sensitivities of mGluR agonists are modulated in a distinct fashion in different models of synaptic plasticity, specifically, kindling and chronic cocaine treatment. The influence of kindling and chronic cocaine exposure in vivo was examined in vitro on the modulation of synaptic transmission by group II and III metabotropic glutamate receptors using whole cell voltage-clamp recordings of central amygdala (CeA) neurons. Synaptic transmission was evoked by electrical stimulation of the basolateral amygdala (BLA) and ventral amygdaloid pathway (VAP) afferents in brain slices from control rats and from rats treated with cocaine or exposed to three to five stage-five kindled seizures. This study shows that after chemical stimulation with chronic cocaine exposure or after electrical stimulation with kindling the receptor sensitivities for mGluR agonists are altered in opposite ways. In slices from control rats, group II agonists, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1) and (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), depressed neurotransmission more potently at the BLA-CeA than at the VAP-CeA synapse while group III agonist, L(+)-2-amino-4-phosphonobutyrate (LAP4), depressed neurotransmission more potently at the VAP-CeA synapse than at the BLA-CeA. These agonist actions were not seen (were absent) in amygdala neurons from chronic cocaine-treated animals. In contrast, after kindling, concentration response relationships for LCCG1 and LAP4 were shifted to the left, suggesting that sensitivity to these agonists is increased. Except at high concentrations, LCCG1, LY354740, and LAP4 neither induced membrane currents nor changed current-voltage relationships. Loss of mGluR inhibition with chronic cocaine treatment may contribute to counter-adaptive changes including anxiety and depression in cocaine withdrawal. Drugs that restore the inhibitory effects of group II and III mGluRs may be novel tools in the treatment of cocaine dependence. The enhanced sensitivity to group II and III mGluR agonists in kindling is similar to that recorded at the lateral to BLA synapse in the amygdala where they reduce epileptiform bursting. These findings suggest that drugs modifying mGluRs may prove useful in the treatment of cocaine withdrawal or epilepsy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids, Dicarboxylic; Aminobutyrates; Amygdala; Animals; Bridged Bicyclo Compounds; Cell Membrane; Chromones; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Kindling, Neurologic; Male; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Synapses; Synaptic Transmission

This study investigated the effect of ionotropic glutamate receptor agonist or antagonist administration into the nucleus accumbens on the maintenance of cocaine self-administration and the reinstatement of cocaine-seeking behavior. The stimulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or N-methyl-D-aspartate glutamate receptors in the nucleus accumbens with either alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or 1-aminocyclobutane-cis-1,3-dicarboxylic acid, respectively, decreased the number of cocaine-reinforced responses, suggesting an enhancement in the rewarding properties of cocaine. In contrast, blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors with N-methyl-D-aspartate, or N-methyl-D-aspartate receptors with dizocilpine maleate or 2-amino-5-phosphonovaleric acid had no selective effect on the maintenance of cocaine self-administration. Following one week of extinction from the reinforcing cue of the drug-paired lever, both alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid and 1-aminocyclobutane-cis-1,3-dicarboxylic acid treatment in the nucleus accumbens reinstated cocaine-seeking behavior. However, alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid treatment increased responding only on the drug-paired lever, while 1-aminocyclobutane-cis-1,3-dicarboxylic acid increased responding on both the drug-paired and non-drug-paired levers. These results suggest that stimulation of glutamate receptors in the nucleus accumbens augments the reinforcing effect of cocaine, yet glutamate transmission is not required to maintain cocaine self-administration. In addition, increased glutamate transmission in the nucleus accumbens may be involved in facilitating the relapse to cocaine-seeking behavior.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Anesthetics, Local; Animals; Behavior, Addictive; Behavior, Animal; Benzazepines; Cocaine; Cocaine-Related Disorders; Dizocilpine Maleate; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Feeding Behavior; Glutamates; Glutamic Acid; Male; Nucleus Accumbens; Procaine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recurrence; Self Administration; Synaptic Transmission