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.

Failure of NMDA receptor hypofunction to induce a pathological reduction in PV-positive GABAergic cell markers

“…Neither PCP nor ketamine significantly altered PV expression levels in the frontal cortex, producing only modest non-significant decreases at the highest treatment doses (16.0 % and 14.8% respectively) as compared to vehicle treatment (Table 2). We have observed these doses of PCP to alter behavior acutely ([9]). Similarly, no significant effect was found in the hippocampus (Table 2).…”

1‐cyclohexyl‐x‐methoxybenzene derivatives, novel psychoactive substances seized on the internet market. Synthesis and in vivo pharmacological studies in mice

“…It is interesting to note that 1‐cyclohexyl‐x‐methoxybenzene derivatives did not impair Rotarod test performance (Figure ) as well as tramadol (Ozdogan et al, ) but differently by PCP. In fact, PCP caused dose‐dependent increases in locomotor activity, assessed in rodents as well as increases in horizontal locomotion, vertical movements such as rearing, and/or stereotypies (Benneyworth, Basu, and Coyle ).…”

Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse

“…Furthermore, the effects of gavestinel treatment seem to indicate competitive binding between glycine, which is increased in GlyT1 1/2 mice, and gavestinel, given that treatment attenuated the acquisition of CPP, resulting in quicker extinction due to the weakened drug-cue association, and blunted cocaine-induced reinstatement. Although we have previously demonstrated the ability of gavestinel to reverse phencyclidine-induced attenuation of prepulse inhibition (Benneyworth et al, 2011), these studies are the first to investigate its effects on psychostimulantinduced place preference and locomotor sensitization. As such, additional studies must be conducted to examine whether gavestinel affects baseline behavioral motivation or interacts with other substances of abuse.…”