Site-specific NMDA receptor antagonists produce differential effects on cocaine self-administration in rats
Introduction
Manipulation of glutamatergic neurotransmission produced by glutamate receptor antagonists alters a wide spectrum of functional responses in rodents, including lethality, convulsions, circulatory effects and locomotor stimulation following acute administration of cocaine and other psychostimulants (see Rockhold, 1998, for review). Glutamate receptor antagonists prevent also the development of sensitization to locomotor stimulation induced by repeated administration of cocaine (Karler et al., 1989); in addition, there is now increasing evidence for glutamatergic participation in the reinforcing actions of cocaine, assessed in various self-administration paradigms (Danysz and Parsons, 1998).
Alteration of cocaine self-administration by dizocilpine (MK-801), a non-competitive antagonist of the NMDA receptor, has been demonstrated best. Systemic pretreatment with dizocilpine reduced cocaine self-administration in rats maintained on a fixed ratio (FR) schedule in a manner similar to increasing the unit dose of cocaine (Pierce et al., 1997) and increased the breaking point of cocaine responding on a progressive ratio (PR) schedule (Ranaldi et al., 1996). Taken together, these findings suggest that dizocilpine enhances the reinforcing properties of cocaine. This effect, however, can be seen only in a very narrow dose range (0.1–0.15 mg/kg), whereas higher doses of dizocilpine produce a loss of discriminative responding for cocaine and motor impairment (Schenk et al., 1993). Furthermore, dizocilpine blocks enhanced acquisition of intravenous cocaine self-administration produced by pre-exposure to amphetamine (Schenk et al., 1993) and causes reinstatement of responding for cocaine following extinction (DeVries et al., 1998).
Attempts to modulate cocaine self-administration with other NMDA receptor antagonists than dizocilpine have produced conflicting results. For example, infusion of the competitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV), into the nucleus accumbens increased cocaine self-administration in rats, indicative of antagonism of cocaine reward by APV (Pulvirenti et al., 1992). In contrast, when the non-competitive antagonist, dextrometorphan, was given systemically, it reduced cocaine responding both on a continuous reinforcement and PR schedule (Pulvirenti et al., 1997).
Although these findings suggest that manipulation of NMDA receptor activity may alter the reinforcing properties of cocaine, little is known about the underlying neuropharmacological mechanisms involved in this phenomenon. Since antagonists acting at distinct modulatory sites of the NMDA receptor complex have different pharmacological and behavioural profiles, and could thus produce differential effects on cocaine reinforcement, the purpose of the present study was to examine how cocaine self-administration is modulated by CGP 39551 (Fagg et al., 1990), an antagonist acting competitively at the endogenous agonist recognition site, dizocilpine (Wong et al., 1986) and memantine (Bormann, 1989) that bind to a non-competitive site within the NMDA receptor channel, and L-701,324 (Kulagowski et al., 1994), an antagonist at the NMDA/glycine recognition site. In this study, dizocilpine and memantine were selected as representatives for high- and low-affinity channel blockers, respectively.
Section snippets
Subjects
Forty-two male Wistar rats (Wistar:Han/HY, Department of Laboratory Animals, University of Helsinki) weighing 140–160 g upon arrival were used. Animals were group housed (two per cage) in a room with controlled temperature (20±2°C) and humidity (55±5%) on a reverse 12-h light–dark cycle (lights on 6 p.m.–6 a.m.) with free access to tap water and RM1(E) pellet food (SDS, Witham, UK), except during initial food training (see Section 2.5). All behavioural testing occurred during the dark phase of
Results
Data presented in Fig. 1 show that both non-competitive NMDA receptor antagonists, dizocilpine and memantine, dose-dependently decreased cocaine self-administration during the 2-h sessions [main effects, dizocilpine: F(4,24)=18.16, P<0.0001; memantine: F(4,36)=12.06, P<0.0001]. In contrast, the competitive NMDA receptor antagonist CGP 39551 and the NMDA/glycine antagonist, L-701,324, failed to reliably alter the number of cocaine infusions [CGP 39551: F(4,28)=0.89, P>0.05; L-701,324: F
Discussion
In the present study, we investigated the modulation of intravenous cocaine self-administration by NMDA receptor antagonists acting at three different modulatory sites on the NMDA receptor: the site for the endogenous transmitter glutamate (CGP 39551), the non-competitive binding site within the NMDA receptor channel (dizocilpine, memantine) and the NMDA/glycine-specific binding site (L-701,324). The cocaine unit dose (0.25 mg/infusion) and the reinforcement schedule (FR5 TO 20-s) used in the
Acknowledgements
Supported by the Swedish Medical Research Council (Project No. 7688), and funds from the Karolinska Institutet (Stockholm) and the National Public Health Institute (Helsinki).
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