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 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.

Keywords: N-methyl-d-aspartate receptor; addiction; d-serine; schizophrenia; serine racemase.

Figure 1

Mean minimum current (μA) required to maintain ICSS responding in WT (n=16) and SR−/− (n=5), mice.

Figure 2

Mean ICSS threshold (T₀) expressed as a percentage of baseline for WT (n=16) and SR−/− (n=5) mice following treatment with 0, 3, 6, and 12 mg/kg cocaine. * indicates statistical significance (p<0.01) compared to saline (0 mg/kg) treatment.

Figure 3

Mean ICSS maximum response rate expressed as a percentage of baseline for WT (n=16) and SR−/− (n=5) mice following treatment with 0, 3, 6, and 12 mg/kg cocaine. * indicates statistical significance (p<0.01) compared to saline (0 mg/kg) treatment.

Figure 4

Drawings of the forebrain sections based on Paxinos and Franklin (2001) with superimposed rectangles that show the confines within which the microdialysis probe tracks were considered to be in the nucleus accumbens shell or core. Data were only included from all subjects with probe tracts within the rectangles. The anterior coordinate (measured from the bregma) is located on each section.

Figure 5

Top Panels: Time course of the effects of cumulative administration of cocaine (3.2–56 mg/kg) on the extracellular levels of DA (A), glutamate (B), and GABA (C) in the nucleus accumbens of WT (n = 5) and SR−/− (n=5/6) mice. Dialysate samples were taken from the nucleus accumbens every twenty minutes. Each arrow indicates time points at which incremental cumulative injections of cocaine were administered. Ordinates; percentage of basal DA, glutamate, and GABA level; abscissae, time in minutes after injection. Each point indicates the mean (±SEM) effect shown as of percentage of basal DA, glutamate, or GABA levels; levels were uncorrected for probe recovery. Bottom Panels: Cumulative dose-response. Changes in extracellular levels of DA (D), glutamate (E), and GABA (F) in the nucleus accumbens of WT (n = 5) and SR−/− (n=5/6) mice after administration of cocaine are shown. Ordinates, percentage of basal DA, glutamate, and GABA levels; abscissae cumulative drug dose in milligrams per kilogram. Each data point represents the mean (±SEM) of at least two dialysate samples taken from all WT and SR−/− subjects immediately following administration of each cumulative dose. Filled symbols represents values that are significantly different from basal or vehicle values (i.e., at time point “0”). Significant differences between genotypes, * = P<0.05.