N ‐Methyl‐d‐aspartate receptor co‐agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse

Abstract Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N‐methyl‐d‐aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co‐agonist d‐serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d‐serine on motivated behavior by using intracranial self‐stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild‐type mice, SR−/− mice exhibited similar baseline intracranial self‐stimulation thresholds but were less sensitive to the threshold‐lowering (rewarding) and the performance‐elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR−/− mice, cocaine‐induced increases in DA and glutamate release were blunted. γ‐Amino‐butyric acid efflux was unaffected in the SR−/− mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the dru...
Source: Addiction Biology - Category: Addiction Authors: Tags: Original Article Source Type: research