The mesocorticolimbic dopamine(Drug information on dopamine) system is central to our understanding of addiction. Nonetheless, glutamate is also of interest because it modulates dopamine activity and is involved in the development and maintenance of drug dependence, particularly in reinstatement to drug-seeking behavior.10 Decreasing glutamatergic transmission by modulation of glutamate receptors may be effective in attenuating the reinforcing effects of drugs of abuse and in preventing reinstatement to drug-seeking behavior.11
Murray and colleagues12 looked at the effects of N-acetylcysteine (NAC), a glutamate modulator that acts on the glutamate/cysteine exchanger, on cocaine seeking in the early and late stages of the acquisition and maintenance of cocaine self-administration in rats. NAC dose-dependently decreased the propensity to seek cocaine but had no effect on the reinforcing properties of cocaine. The researchers suggest that NAC can decrease the tendency to relapse and may also help break drug cue–elicited cocaine-seeking habits.
It is interesting to note that NAC was effective in decreasing marijuana use during an 8-week, double-blind, randomized, placebo-controlled trial for treatment-seeking cannabis-dependent adolescents.13 NAC was well tolerated and associated with minimal adverse effects. In contrast, a controlled clinical trial failed to demonstrate an ability of D-cycloserine to boost relapse prevention outcomes when combined with cognitive-behavioral therapy.14 Thus, pharmacological modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors.
The finding that noncompetitive NMDA-R antagonists such as phencyclidine and ketamine(Drug information on ketamine) can elicit the positive, negative, and cognitive symptoms of schizophrenia in healthy individuals gave rise to the hypothesis of impaired NMDA-R functioning in psychosis. A number of compounds licensed for medical conditions, including several NMDA-R and mGluR agents, may have antipsychotic effects, but none has proved overall benefit over risks (adverse effect, tolerability).15
The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) found no beneficial effect of glycine(Drug information on glycine) as an add-on treatment in chronic schizophrenia. Nonetheless, given a clear role for glutamate in the neurobiology of psychosis, it remains an active target for drug development.16
One of the most promising therapeutic strategies for treatment-induced dyskinesias in Parkinson disease (PD) is mGluR5 antagonism.17 Morin and colleagues18 found an antidyskinetic effect of mGluR5 antagonism in de novo l-dopa–treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Glutamate dysregulation may also be involved in fragile X syndrome (FXS). The FXS mental retardation gene (Fmr1) encodes fragile X mental retardation protein (FMRP), which alters the cascade-regulating glutamate homeostasis in the brain.
In early clinical trials, mGluR5 antagonists have shown evidence of efficacy in treating neurobehavioral symptoms associated with FXS.19 Moreover, acute treatment with mGlu5 inhibitor in the Fmr1 knockout mouse suggests that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype.20 This glutamate-based therapeutic strategy may have important implications for management of such neuropsychiatric disorders as PD and FXS in the future.
Might targeting glutamate lead to new approved treatments in psychiatry? Understanding the pathophysiology of glutamate systems has yielded tremendous progress, which we hope will translate into novel and exciting neurotherapeutics. Increasing our understanding of biological vulnerability factors such as glutamate function in psychiatric disorders is important, but such advances should be combined with psychosocial interventions to yield optimal outcomes. The future is bright for developing neurotherapeutics based on the brain glutamate systems—so, up, up and away!