Effects of the Competitive N-Methyl-d-aspartate Receptor Antagonist, LY235959 [(-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic Acid], on Responding for Cocaine under Both Fixed and Progressive Ratio Schedules of Reinforcement

Abstract

It is difficult to determine the precise role of the N-methyl-Daspartate (NMDA) receptor system in the reinforcing effects of cocaine since uncompetitive NMDA receptor antagonists alter cocaine self-administration in different ways, depending on the antagonist examined and the behavior being measured. To increase understanding of the role of the NMDA system in cocaine's reinforcing effects, this study measured the effects of the competitive NMDA receptor antagonist, LY235959 [(Ϫ)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], in rats that self-administered cocaine under both fixed ratio (FR) 1 and progressive ratio (PR) schedules of reinforcement. Rats were trained to self-administer cocaine (0.33 mg/infusion) under an FR1 schedule of reinforcement. Thereafter, the effects of pretreatment with LY235959, or the uncompetitive antagonists dextromethorphan and dizocilpine, were examined. The number of infusions earned during the first 10 min of responding under the FR1 schedule was analyzed separately. When rats responded for 0.33 mg/infusion cocaine under an FR1 schedule of reinforcement, 3 mg/kg LY235959 decreased cocaine selfadministration only during the first 10 min of the responding. This effect was dose and time dependent and blocked by the competitive NMDA receptor agonist, NMDA. LY235959 (3 mg/ kg) decreased total responding for cocaine only when the selfadministered dose of cocaine was small (0.02-0.04 mg/infusion) or when responding was reinforced under the PR schedule. In contrast, dizocilpine decreased responding under the FR1 schedule but increased responding under the PR schedule. These data suggest that LY235959 decreased the reinforcing effectiveness of cocaine, a finding reported with systemically administered NMDA receptor antagonists other than dizocilpine.Data from animal studies show that self-administration of the psychomotor stimulant cocaine requires an intact mesolimbic dopamine system (Roberts and Koob, 1980;Pettit et al., 1984;Caine and Koob, 1994). In addition to the primary dopaminergic projection from the ventral tegmental area to the nucleus accumbens, the mesolimbic system receives extensive innervations from glutamatergic efferent projections originating in various cortical and subcortical structures, including the prefrontal cortex, hippocampus, and basolateral amygdala (for review, see Baker et al., 2002). Recent demonstrations that some forms of long-term potentiation are dependent upon the N-methyl-D-aspartate (NMDA) glutamate receptor system in the nucleus accumbens (Kombian and Malenka, 1994;Thomas et al., 2000) and ventral teg-

Continuous exposure to the competitive N-methyl-d-aspartate receptor antagonist, LY235959, facilitates escalation of cocaine consumption in Sprague–Dawley rats

“…Consistent with this finding, repeated daily injections of agmatine, a drug with NMDA receptor antagonist properties, also did not alter escalation of cocaine self-administration under long access conditions, though only a single dose was examined (Morgan et al 2002). We have shown also that single acute injections of LY235959 decrease self-administration of cocaine under both FR and PR schedules of reinforcement (Allen et al 2005), an effect replicated here in the LY235959-injection group during the first 6-h session.…”

“…During this escalation phase, rats were injected subcutaneously either with vehicle (n=8) or 6 mg/kg LY235959 (n=6) twice daily. Rats were injected immediately before the session (t=0) to avoid direct suppressing effects of LY235959 on load-up behavior (Allen et al 2005) and immediately after each session to ensure that LY235959 was active throughout cocaine exposure (LY235959 T 1/2 =1.6 h; Dahlem and Eckstein 1992). Fourteen 6 h cocaine self-administration sessions were conducted over 14-21 days, the range due to equipment failure during the experiment.…”

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

“…LY379268 has also been shown to reduce cocaine self-administration and to attenuate cueinduced reinstatement of cocaine seeking in rats (Baptista et al 2004). It is of interest that it has been shown recently that the NMDA receptor antagonist, LY235959, reduces cocaine self-administration early in the session (Allen et al 2005), suggesting that it reduces the effectiveness of drugrelated cues in a manner similar to that of buprenorphine seen in our study.…”

Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: comparison with dizocilpine

“…This change in responding for cocaine is similar to that which occurs when the dose of self-administered cocaine is increased, leading to the interpretation that the reinforcing effects of cocaine are enhanced rather than attenuated. This interpretation is supported by the observation that pretreatment with dizocilpine resulted in increased numbers of injections and breakpoints in rats self-administering cocaine under a progressive-ratio schedule (Ranaldi et al 1996;Hyytia et al 1999;Allen et al 2005). The reasons underlying the different effects of dizocilpine in the present study compared to studies in rats are unclear.…”

“…For example, in rats selfadministering cocaine under a FR schedule, dizocilpine has been shown to decrease the number of cocaine injections earned (Shoaib et al 1995;Pierce et al 1997;Hyytia et al 1999;Allen et al 2005). This change in responding for cocaine is similar to that which occurs when the dose of self-administered cocaine is increased, leading to the interpretation that the reinforcing effects of cocaine are enhanced rather than attenuated.…”