dizocilpine-maleate and 2-4-methanoglutamate

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

Unilateral and bilateral injections of cis-2,4-methanoglutamate, a potent and selective NMDA agonist, were made into the striatum of rats. Unilateral injections elicited MK-801-sensitive dose-related increases in contralateral turning, beginning 10-15 min after injection. Bilateral injections elicited typical seizure-like behaviours commencing approximately 80 min postinjection. Forty-eight hours after unilateral injection, and presumably after lesion development, no spontaneous preference for turning was seen. Upon challenge with apomorphine (1 mg/kg SC), ipsilateral turning lasting approximately 60 min was seen. Correlates are drawn between this model and some of the features of Huntington's disease.

Topics: Animals; Apomorphine; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Injections; Male; Motor Activity; Neostriatum; Rats; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

Lipocortin-1 (annexin-1), an endogenous phospholipid and calcium binding protein, has been shown to significantly attenuate the damage produced by focal cerebral ischaemia in the rat. In the present study we have therefore investigated its effect on N-methyl-D-aspartate (NMDA) induced neuronal damage. Unilateral intrastriatal infusion of a potent and selective NMDA agonist, cis-2,4-methanoglutamate (MGlu), induced an extensive lesion of the striatum in the rat, which was inhibited (greater than 80%) by prior injection of MK801 (4 mg/kg, i.p.). Infusion of 1.2 micrograms of an active fragment of lipocortin-1 (N-terminal 1-188 aa) immediately after MGlu significantly reduced the extent of damage by 44.2 +/- 8.0%. In contrast, infusion of 3 microliters of neutralizing anti-lipocortin-1 antibody with MGlu increased lesion size by 158.9 +/- 22.0%. These findings indicate that the damage produced by intrastriatal infusion of MGlu is mediated by the NMDA receptor. Lipocortin-1 fragment markedly attenuated, and the neutralizing antibody increased, this NMDA mediated neuronal damage. These observations may explain the neuroprotective action of lipocortin following cerebral ischaemia.

Topics: Animals; Annexins; Calcium-Binding Proteins; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Male; Nerve Degeneration; Neurons; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate