dizocilpine-maleate and Cocaine-Related-Disorders

Blocking N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) prevents cocaine locomotor sensitization, but facilitates escalation of cocaine self-administration and produces ambiguous effects on acquisition of cocaine self-administration. This study used a recently described model of acquisition and escalation to test the hypothesis that continuous NMDAR antagonism functionally increases the effects of a given dose of cocaine.. We assessed acquisition of cocaine self-administration (0.6 mg/kg/infusion) in rats treated continuously with either vehicle or the NMDAR antagonist dizocilpine (0.4 mg/kg/day) for 14 consecutive 2h fixed ratio 1 (FR1) sessions. In a separate experiment that assessed the effect of dizocilpine treatment on escalation of cocaine self-administration, rats acquired cocaine self-administration (0.6 mg/kg/infusion) prior to vehicle or dizocilpine treatment. Then, immediately post-acquisition, rats were treated continuously with either vehicle or dizocilpine and allowed to self-administer either 0.6 or 1.2mg/kg/infusion cocaine for an additional seven consecutive 2h FR1 sessions.. Relative to vehicle-treated rats, a significantly greater percentage of dizocilpine-treated rats acquired cocaine self-administration. During the escalation experiment, both vehicle- and dizocilpine-treated rats escalated intake of 1.2mg/kg/infusion cocaine. Whereas vehicle-treated rats exhibited stable intake of 0.6 mg/kg/infusion cocaine, dizocilpine-treated rats escalated intake of this moderate cocaine dose to levels indistinguishable from intake levels produced by self-administration of the high cocaine dose (i.e., 1.2mg/kg/infusion).. These findings suggest that chronic NMDAR blockade potentiates, rather than attenuates, cocaine's effects and argue for reconsideration of the role of NMDARs in cocaine "addiction-like" behavior.

Topics: Animals; Cocaine; Cocaine-Related Disorders; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Infusions, Subcutaneous; Male; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Reinforcement Schedule; Self Administration

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

The stimulation of glutamate receptors plays a relevant role in the development of behavioral sensitization to psychostimulants, while less clear results have been obtained on their role in morphine sensitization. We addressed this issue by comparing the development of cocaine and morphine sensitization under a continuous s.c. infusion of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (0.1 mg/kg/24 h). Moreover, we studied the expression of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunits in discrete limbic areas of rats sensitized to morphine or cocaine with or without the concomitant dizocilpine infusion. It was observed that dizocilpine infusion did not prevent the development of morphine sensitization, while it prevented the development of tolerance to morphine-induced analgesia. Finally, morphine-sensitized animals did not present any modification in the subunit expression of glutamate receptors in the brain areas examined. In agreement with previous results, we found that dizocilpine infusion prevented the development of cocaine sensitization. Moreover, we observed that rats sensitized to cocaine presented a significant increase in the levels of GLUR1, NR1 and NR2B, in the nucleus accumbens, and of NR2B in the hippocampus compared to control animals. Such modifications were absent in rats administered cocaine under dizocilpine infusion. We conclude that: (i) morphine sensitization is a neuroadaptive phenomenon which does not appear to require NMDA receptor activity in order to develop; (ii) cocaine sensitization is clearly dependent on NMDA receptor activity, as dizocilpine infusion prevented the occurrence of glutamate receptors modifications as well as the development of sensitization.

Topics: Animals; Blotting, Western; Cocaine; Cocaine-Related Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Excitatory Amino Acid Antagonists; Hippocampus; Limbic System; Male; Morphine; Morphine Dependence; Nucleus Accumbens; Pain Measurement; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

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

Previous work has established that the development of cocaine sensitization is prevented by co-administration of the non-competitive NMDA receptor antagonist MK-801 or by prior ibotenic acid lesions of the medial prefrontal cortex (PFC). The present study examined the effect of these treatments on the expression of cocaine sensitization. Rats were treated with 15 mg/kg cocaine for 5 days and then challenged with cocaine 3 days later to establish the presence of sensitization. The next day, rats received 0.1 mg/kg MK-801 30 min before cocaine challenge. This dose of MK-801, which is sufficient to prevent the development of cocaine sensitization, did not prevent its expression. Rather, it augmented the response of sensitized rats to cocaine challenge and produced a non-significant trend towards augmentation of the acute response to cocaine in saline-pretreated rats. For PFC lesion experiments, rats were sensitized to cocaine and then received either ibotenic acid or sham lesions of the PFC. One week later, all rats were challenged with cocaine. Sham lesioned and ibotenic acid lesioned rats exhibited the same degree of sensitization. Thus, neither NMDA receptor transmission nor PFC projections appear necessary for the expression of cocaine sensitization.

Topics: Animals; Behavior, Animal; Cocaine; Cocaine-Related Disorders; Dizocilpine Maleate; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Ibotenic Acid; Male; Microinjections; Motor Activity; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Cocaine, 10 mg/kg, I.P., twice daily, was given to rats for 1 week. At 1 and 4 weeks following discontinuation of cocaine, the initial rate of 3,4-dihydroxyphenylacetic acid (DOPAC) formation was assessed. The initial rate of DOPAC formation was found to be decreased in the frontal and cingulate cortices at 1 week, but was only decreased in the frontal cortex at 4 weeks. When administered in conjunction with cocaine, haloperidol, clozapine, and vitamin E, but not MK-801, were found to prevent cocaine's effects. In addition to the potential value these findings have for further understanding cocaine abuse, it is proposed that the alteration in dopamine metabolism produced by cocaine, and the ability of haloperidol, clozapine and vitamin E to decrease cocaine's effects, model some biochemical aspects of schizophrenia.

Topics: Aged; Animals; Antipsychotic Agents; Brain; Cocaine; Cocaine-Related Disorders; Dizocilpine Maleate; Dopamine; Humans; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Time Factors; Vitamin E