N‐Methyl‐d‐aspartate receptor co‐agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse. (23rd November 2017)

• Record Type: Journal Article
• Authors: Puhl, Matthew D.; Desai, Rajeev I.; Takagi, Shunsuke; Presti, Kendall T.; Doyle, Michelle R.; Donahue, Rachel J.; Landino, Samantha M.; Bergman, Jack; Carlezon, William A.; Coyle, Joseph T.
• Is Part Of: Addiction biology. Volume 24:Number 1(2019)
• Page Start: 40
• Page End: 50
• Publication Date: 2017-11-23
• Subjects: addiction -- d‐serine -- N‐methyl‐d‐aspartate receptor -- schizophrenia -- serine racemase; Substance abuse -- Periodicals; Substance abuse -- Physiological aspects -- Periodicals; Substance-Related Disorders -- periodicals; 616.86
• DOI: 10.1111/adb.12577
• Languages: English
• ISSNs: 1355-6215

Abstract

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‐agonistd ‐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 ofd ‐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 drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction. Abstract : The high prevalence of substance abuse in schizophrenia could be due to shared risk genes that impair NMDA receptor function. We studied mice with hypofunctional NMDA receptors caused by genetic inactivation of serine racemase (SR−/− a schizophrenia risk gene. We found that SR−/−mice had decreased sensitivity to cocaine's hedonic effects mediated by blunted accumbens dopamine release. NMDAR hypofunction in schizophrenics may render abused substances less effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated dependence/addiction.