In conclusion, positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

In brain, nitric oxide (NO) is considered as a retrograde messenger involved in synaptic plasticity. The present study was undertaken to investigate whether mice lacking the neuronal nitric oxide synthase (nNOS) gene are protected from cocaine-induced behavioral sensitization. Mice were administered, IP. either saline or cocaine (15 mg/kg) for 5 days. Sensitization was determined as an increase in cocaine-induced locomotor activity on day 5 compared with day 1 and an amplified response of cocaine-experienced mice to a challenge cocaine injection given after a 10-day drug free period (e.g., on day 15). To investigate the development of a context-dependent locomotion (conditioning), the responses of cocaine- and saline-experienced mice to a saline injection were determined on day 17. Male homozygote nNOS(-/-) mice were sensitive to the acute effect of cocaine (15 mg/kg) on day 1; however, they developed neither a sensitized response to cocaine (on day 5 and 15) nor a conditioned locomotion. Female homozygote nNOS(-/-) mice neither were responsive to 15 mg/kg cocaine on day 1,5 and 15, nor did they develop a conditioned locomotion. In contrast, the same cocaine regimen delivered to male and female heterozygote nNOS(+/-) mice, and wild type mice (B6 J/sv129, C57BL/6 and sv129) resulted in sensitization to cocaine-induced locomotor activity and context-dependent locomotion. Investigation of [3H]cocaine disposition in the striatum and frontal cortex of the mice revealed neither gender nor strain differences in the drug disposition. Also, no major difference in striatal dopaminergic markers between homozygote nNOS(-/-) and wild type mice was observed. The most significant distinction, however, was the finding that nNOS(-/-) mice are completely deficient in striatal nNOS binding sites. Taken together, our results suggest that the resistance of homozygote nNOS(-/-) mice to cocaine-induced behavioral sensitization is primarily due to the deletion of the nNOS gene. Considering the role of NO in synaptic plasticity, it is conceivable that reduced brain NOS activity blunts the processes that underlie the development of sensitization to cocaine.

These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.

No abstract

No abstract

No abstract

No abstract

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo−/− mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.