Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates "dual-hit" neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal- and drug-evoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT6 antagonist-evoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.
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PMID:Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia. 3253 66

Social behaviour is frequently impaired in schizophrenic patients, and current antipsychotics appear poorly effective in alleviating this deficit. SSR181507 is a selective dopamine D2 receptor antagonist and 5-HT1A receptor agonist [Neuropsychopharmacology 28 (2003) 2064] with an atypical antipsychotic profile and additional antidepressant/anxiolytic activities [Neuropsycho pharmacology 28 (2003) 1889]. Here, we sought to assess the efficacy of SSR181507, and of reference antipsychotics and antidepressant/anxiolytics, to counteract phencyclidine (PCP)-induced social interaction deficit in rats. Pairs of unfamiliar rats were placed for 10 min each day into a dimly lit arena, during four consecutive days. On the test day (5th day), each pair was placed into the arena 30 min after i.p. treatment with PCP (or vehicle) and a challenge compound or vehicle (same for both rats, i.p. or s.c.). The time spent in social interaction was scored during 10 min. PCP (1 mg/kg) decreased social interaction time by about 35%. This effect was fully antagonized by pre-treatment with SSR181507 (1 mg/kg). In contrast, neither haloperidol (0.05 and 0.1 mg/kg) nor clozapine (0.3 and 1 mg/kg) antagonized this PCP-induced deficit. The selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 and 0.05 mg/kg s.c.), but not the anxiolytic diazepam (0.75 and 1.5 mg/kg), also improved social interaction impairment in PCP-treated rats: this would indicate that the 5-HT1A receptor agonist properties of SSR181507 are responsible for the reversal of PCP-induced social deficit. These data suggest that, in addition to its atypical antipsychotic profile and antidepressant/anxiolytic activities, SSR181507 has a potential therapeutic activity in another key feature of schizophrenia poorly controlled by current antipsychotics, namely deterioration in social functioning.
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PMID:SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats. 3258 85


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