The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice

Abstract

Rationale: Mice lacking metabotropic glutamate receptors 5 (mGluR5) exhibit reduced glutamatergic function and behavioral abnormalities, including deficits in prepulse inhibition (PPI) of the startle response that may be relevant to schizophrenia. Thus, these mice are an animal model that may be used for preclinical evaluation of potentially new classes of antipsychotic compounds. Recent clinical studies have suggested several compounds that modulate glutamatergic transmission through distinct mechanisms, such as potentiation of the N-methyl-D: -aspartate (NMDA) receptor glycine site, activation of group II mGluR, and activation of glutamate-cysteine antiporters, as being efficacious in the treatment of schizophrenia.

Objectives: The aim of this work is to evaluate the effects of sarcosine (a selective inhibitor of the glycine transporter 1 [GlyT1]), LY379268 (a group II mGluR agonist), and N-acetylcysteine (a cysteine prodrug that indirectly activates cystine-glutamate antiporters to increase glutamate levels in the extrasynaptic space) on PPI deficits in mGluR5 knockout mice.

Results: Sarcosine and N-acetylcysteine, but not LY379268, ameliorated PPI deficits in mGluR5 knockout mice. The ability of N-acetylcysteine to restore PPI deficits was not blocked by the group II mGluR antagonist LY341495, indicating that the effects of N-acetylcysteine were not attributable to activation of group II mGluRs by glutamate.

Conclusions: These findings provide evidence that the interactions between mGluR5 and NMDA receptors are involved in the regulation of PPI and suggest that activation of glutamate receptors, other than group II receptors, by increased endogenous glutamate transmission, may ameliorate the behavioral abnormalities associated with mGluR5 deficiency.

Fig. 1

Effects of sarcosine on PPI in mGluR5^+/+ and mGluR^−/− mice. Percentage of PPI (a) and startle amplitude (b) at each of three prepulse levels (69, 73, and 77 dB) are presented. Data are expressed as mean ± SEM (n = 8). * p < 0.05, compared with vehicle-treated group of the same genotype; # p < 0.05, compared with the same treatment group of wild-type mice

Fig. 2

Effects of the mGluR2/3 agonist LY379268 on PPI in mGluR5^+/+ and mGluR^−/− mice. Percentage of PPI (a) and startle amplitude (b) at each of three prepulse levels (69, 73, and 77 dB) are presented. Data are expressed as mean ± SEM (n = 7). # p < 0.05, compared with the same treatment group of wild-type mice

Fig. 3

Effects of N-acetylcysteine on PPI in mGluR5^+/+ and mGluR^−/− mice. Percentage of PPI (a) and startle amplitude (b) at each of three prepulse levels (69, 73, and 77 dB) are presented. Data are expressed as mean ± SEM (n = 8). * p < 0.05, compared with the vehicle-treated group of the same genotype; # p < 0.05, compared with the same treatment group of wild-type mice

Fig. 4

Effects of co-treatment of LY341495 and N-acetylcysteine on PPI in mGluR^−/− mice. Percentage of PPI (a) and startle amplitude (b) at each of three prepulse levels (69, 73, and 77 dB) are presented. Data are expressed as mean ± SEM (n = 8). * p < 0.05, compared with the vehicle-treated group