An issue that deserves dedicated attention is the possibility that the relative contribution of excitatory amino acid neurotransmitters may become particularly significant during specific periods of exposure to cocaine. Excitatory amino acids are considered critical mediators of neural plasticity within the central nervous system, and this makes them ideal candidates as participating agents in the development of adaptive changes, which may represent integral parts of the addictive process
Glutamate dependence is a feature of long-term potentiation (LTP), a form of synaptic enhancement associated with repeated use of specific synaptic connections (74). Originally described within the hippocampus, more recent studies have shown LTP in other brain areas, including the nucleus accumbens. Tetanic stimulation of allocortical afferent fibers making monosynaptic connections with nucleus accumbens cells produced LTP in a slice preparation and in the intact animal effects that seemed to be mediated by activation of ionotropic glutamate receptors (75-76). Excitatory amino acid-dependent synaptic changes in the nucleus accumbens is of enormous potential importance because it reveals that forms of synaptic enhancement may occur within this structure, and these changes may be relevant for the development of the addictive process.
In experiments where behavioral techniques were used in combination with electrophysiological analysis, evoked field responses measured in the nucleus accumens shell after stimulation of fimbria afferents were examined in rats exposed to the very first days of self-administration of cocaine. Significantly increased paired-pulse facilitaion of a specific component of the potential (a long-latency component termed P25) as well as a marked potentiation of the same potential after tetanic stimulation of the fimbria were observed in rats self-administering cocaine, but not in yoked controls. These effects were prevented by systemic administration of the NMDA antagonist CGS 19755 and the non-NMDA antagonist NBQX (77). Hence, the modifications of nucleus accumbens synaptic efficacy produced by repeated stimulation of the neural firing of fimbric origin may be part of the neural plastic changes representing the early critical events leading to the development of cocaine addiction. The fact that these changes depend on excitatory amino acid neurotransmission suggests the hypothesis that pharmacological manipulation of glutamate receptors may effectively modify at least part of the neuroadaptive phenomena that occur during the course of drug addiction.
As discussed earlier, the natural history of drug addiction consists of several phases that include the acquisition and the maintenance of stable drug intake, the transition from moderate to excessive drug intake, and extinction and relapse. The protracted withdrawal state, in particular, is of importance becasue, during this period, phenomena such as drug-craving, cue-precipitated drug-seeking behavior, and conditioned reinforcement may occur and these lead into relapse of drug abuse both in animals and in humans (77-79).
One of the major precipitating factors leading into relapse of drug use is exposure to enteroceptive and environmental cues previously associated with the abused drug. Reinstatement of drug-seeking behavior induced by a priming systemic administration of the abused drug or by environmental cues have been well characterized in rodents. Although the intimate neurobiological determinants of this phenomenon have not been fully explored, nucleus accumbens dopamine seems to facilitate operant responding elicited by a conditioned stimulus (80). Interestingly, excitotoxic lesions of the amygala disrupt conditioned responding for food and sexual reinforcement (81) and, moreover, intranucleus accumbens infusion of AP-5 reduced the facilitatory effects of amphetamine coinfused within the nucleus accumbens on conditioned reinforcement (50). Taken together, these results suggest that neural messages from the amygdala reaching the nucleus accumbens, and probably other areas of the limbic system, are capable of reinstating responding for the primary reinforcer in the presence of a conditioned stimulus. This is probably through the activation of a glutamate mechanism. Considering that activation of nucleus accumbens dopamine neurotransmission elicits is similar effects (82), it is possible that excitatory amino acid afferents to the nucleus accumbens may primarily drive neural activity of nucleus accumbens neurons, allowing allocortical messages to find access to the motivational/motor effectors of the ventral striatum. The various forms of excitatory amino acid-dependent neural plasticity shown to occur within the nucleus accumbens may, therefore, participate in the concert of cellular events whose behavioral outcome may ultimately be represented by drug-seeking behavior or drug-craving. Indeed recent observations suggest a specific role for glutamate-containing pathways in relapse into cocaine self-administration. Theta-burst electrical stimulation of hippocampal glutamatergic fibers produced reinstatement of operant responses associated with cocaine in rats previously trained to self-administer the drug (83). Interestingly, in the same study, stimulation of the medial forebrain bundle, a pathway critical for reinforcement, did not elicit reinstatement of cocaine-seeking behavior. This suggests that separate neural systems may subserve drug-induced positive reinforcement and incentive properties. Glutamate-containing pathways originating from the hippocampus appear to be more specifically involved in the incentive-motivational aspects of drug addiction, thought to be important for relapse. Interestingly, however, glutamate blockade within the basolateral amygdala failed to affect relapse of cocaine-seeking behavior (84), thus suggesting a specificity for allocortico-limbic glutamate pathways in reinstatement of cocaine-seeking behavior and, possibly, craving. Further studies on the role played by specific excitatory amino acids receptor subtypes on selected aspects of these phases of the cocaine-addiction cycle will permit a closer analysis of the cellular mechanisms through which excitatory amino acids modulate specific aspects of cocaine-seeking behavior when the drug is no longer available.
Through activation of NMDA receptors, glutamate promotes the influx of calcium into the postsynaptic neuron, which, binding to calmodulin, stimulates the activity of nitric oxide synthase (18). Nitric oxide (NO) is a gaseous neurotransmitter that acts as a retrograde messenger and affects the release of various neurotransmitters via increases in cyclic GMP (18). Therefore, NO acts as an important intracellular effector of excitatory amino acid neurotransmission through NMDA receptors. Elec-trophysiological and behavioral evidence suggests that nitric oxide plays a significant role in various forms of synaptic plasticity and in learning and memory (85). More recently, evidence from different experimental approaches indicates that NO may play a role in the behavioral effects of psychostimulant drugs. Neurochemical studies indicate that endogenous NO facilitates the efflux of dopamine within the striatum (86) and perfusion of the nucleus accumbens with NMDA through a microdialysis probe produced a NO-dependent increase of dopamine release (87). In addition, methamphetamine-induced dopamine release in the caudate/putamen of the rat can be reduced by concurrent administration of the NO synthase inhibitor l-NAME (88). Further evidence for a functional interaction between endogenous glutamate neurotransmission, NO, and dopamine within the striatal complex comes from the observation that the glutamate reuptake inhibitor PDC potentiates endogenous NO-facilitated dopamine efflux in the rat striatum (89). Electrophysiological evidence suggests that blockade of NO synthesis with l-NAME reduced NMDA-induced burst firing of rat midbrain dopamine neurons (90). Behavioral studies, in addition, suggest that functional integrity of NO signaling is essential for the full expression of cocaine-induced behavior, including locomotion and conditioned place preference, psychostimulant sensitization, and cocaine kindling (91-94). Within the context of cocaine addiction, earlier studies have shown that administration of l-NAME reduced responding for cocaine in both a fixed-ratio and a progressive-ratio schedule (95). In addition, l-NAME appears to reduce the increase in responding for cocaine during the extinction phase (96). These effects of blockade of NO synthase on cocaine self-administration suggest the possibility that nitric oxide may represent an important component of the cocaine-abuse cycle.
In conclusion, the recent development of pharmacological probes allowing the selective exploration of specific aspects of glutamate neurotransmission will allow a better characterization of still unexplored aspects of excitatory amino acid neurotransmission in the context of addiction. This includes the role played by metabotropic receptors, intracellular effects of NMDA activation such as NO, and the availability of drugs reducing glutamate release. Importantly, these studies will be critical for the characterization of novel potential therapeutic perspective, strategically tailored to affect specific aspects of synaptic plasticity associated with the different phases of the cocaine-abuse cycle.
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