Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

Abstract

Rationale: Enhancement of N-methyl-D: -aspartate receptor (NMDAR) activity through its glycine modulatory site (GMS) is a novel therapeutic approach in schizophrenia. Brain concentrations of endogenous GMS agonist D: -serine and antagonist N-acetyl-aspartylglutamate are regulated by serine racemase (SR) and glutamic acid decarboxylase 2 (GCP2), respectively. Using mice genetically, under-expressing these enzymes may clarify the role of NMDAR-mediated neurotransmission in schizophrenia.

Objectives: We investigated the behavioral effects of two psychotomimetic drugs, the noncompetitive NMDAR antagonist, phencyclidine (PCP; 0, 1.0, 3.0, or 6.0 mg/kg), and the indirect dopamine receptor agonist, amphetamine (AMPH; 0, 1.0, 2.0, or 4.0 mg/kg), in SR -/- and GCP2 -/+ mice. Outcome measures were locomotor activity and prepulse inhibition (PPI) of the acoustic startle reflex. Acute effects of an exogenous GMS antagonist, gavestinel (0, 3.0, or 10.0 mg/kg), on PCP-induced behaviors were examined in wild-type mice for comparison to the mutants with reduced GMS activity.

Results: PCP-induced hyperactivity was increased in GCP2 -/+ mice, and PCP-enhanced startle reactivity was increased in SR -/- mice. PCP disruption of PPI was unaffected in either mutant. In contrast, gavestinel attenuated PCP-induced PPI disruption without effect on baseline PPI or locomotor activity. AMPH effects were similar to controls in both mutant strains.

Conclusions: The results of the PCP experiments demonstrate that convergence of pharmacological and genetic manipulations at NMDARs may confound the predictive validity of these preclinical assays for the effects of GMS activation in schizophrenia. The AMPH data provide additional evidence that hyperdopaminergia in schizophrenia may be distinct from NMDAR hypofunction.

Fig. 1

PCP dose-dependent blockade of PPI is unaltered in SR −/− and GCP2 −/+ mice. Mean PPI (± SEM) is shown at each prepulse intensity level; 3, 6, or 12 dB over 70 dB background noise. a PPI in SR −/− (solid bars) and WT littermate (open bars) mice (n=16–19) following PCP treatment (0, 1, 3, or 6 mg/kg, s.c.). b PPI in GCP2 −/+ (solid bars) and WT littermate (open bars) mice (n=18–21) following PCP treatment

Fig. 2

PCP dose-dependent effects on startle reactivity are differently altered in SR −/− and GCP2 −/+ mice. Mean startle reactivity (V_max ± SEM) is shown at each PCP dose. a Increased reactivity to a 120 dB startle stimulus in SR −/− (solid squares) as compared to WT littermate (open squares) mice (n=18–19) following PCP treatment (0, 1, 3, or 6 mg/kg, s.c.). *p<0.05 indicates significant difference between WT and SR −/− at that dose of PCP (Bonferroni post hoc test). b Decreased reactivity to a 120-dB startle stimulus in GCP2 −/+ (solid circles) as compared to WT littermate (open circles) mice (n= 20–21) following PCP treatment. *p<0.05 indicates significant difference between WT and GCP2 −/+ at that dose of PCP (Bonferroni post hoc test)

Fig. 3

AMPH dose-dependent blockade of PPI is unaltered in SR −/− and GCP2 −/+ mice. Mean PPI (± SEM) is shown at each prepulse intensity level; 3, 6, or 12 dB over 70 dB background noise. a PPI in SR −/− (solid bars) and WT littermate (open bars) mice (n=11–17) following AMPH treatment (0, 1, 2, or 46 mg/kg, s.c.). b PPI in GCP2 −/+ (solid bars) and WT littermate (open bars) mice (n=10–19) following AMPH treatment

Fig. 4

Increased efficacy of PCP to induce hyperactivity in GCP2 −/+ mice, but not in SR −/− mice. Data depicted are total distance traveled (mean ± SEM) in 90 min following PCP (0, 1, 3, or 6 mg/kg, s.c.) treatment (a and c) or distance traveled (mean ± SEM) in each 5-min time bin throughout the 120-min test session before and after 6.0 mg/kg PCP treatment (b and d). a PCP dose-dependent induction of activity in SR −/− (solid squares) and WT littermate (open squares) mice (n=19). b Activity in SR −/− and WT mice before and after treatment with 6.0 mg/kg PCP. c PCP dose-dependent induction of activity in GCP2 −/+ (solid circles) and WT littermate (open circles) mice (n=21). d Activity in GCP2 −/+ and WT mice before and after treatment with 6.0 mg/kg PCP. Arrows indicate time of PCP treatment. *p<0.05 indicates significant difference between WT and GCP2 −/+ at that dose of PCP (Bonferroni post hoc test)

Fig. 5

Unaltered efficacy of AMPH to induce hyperactivity in SR −/− and GCP2 −/+ mice. Data depicted are total distance traveled (mean ± SEM) in the 90 min following AMPH (0, 1, 2, or 4 mg/kg, s.c.) treatment. a AMPH dose-dependent induction of activity in SR −/− (solid squares) and WT littermate (open squares) mice (n=16–17). b AMPH dose-dependent induction of activity in GCP2 −/+ (solid circles) and WT littermate (open circles) mice (n=20–21). Arrows indicate time of AMPH treatment

Fig. 6

Gavestinel reverses PCP-induced blockade of PPI, without affecting baseline PPI (vehicle treatment). Mean PPI (± SEM) is shown at each prepulse intensity level; 3, 6, or 12 dB over 70 dB background noise. The dose-dependent effects of gavestinel (0, 3, or 10 mg/kg, i.p.) were investigated in the presence of 3.0 mg/kg PCP (solid bars) or vehicle treatment (open bars) in WT mice (n=13–15)