Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine.
BACKGROUND
Recent studies using phencyclidine (PCP) as a model for psychosis have implicated metabotropic glutamate (mGlu) receptors in schizophrenia. We have shown, using an automated motor activity monitoring system, that selective group II mGlu receptor agonists attenuate PCP (5 mg/kg)-evoked increases in ambulations and fine motor movements with similar profiles to the atypical antipsychotic, clozapine.


OBJECTIVE
Because the automated system does not discriminate between specific PCP-evoked behaviors, in this paper we examined the effects of the potent mGlu2/3 receptor agonist LY379268 on PCP-evoked behaviors as assessed by observational methods. Furthermore, we have compared the actions of LY379268 to the atypical antipsychotic clozapine.


RESULTS
LY379268 and clozapine reduced the expression of PCP-induced falling, turning and back pedaling in a dose-dependent manner. Thirty minutes post-PCP administration, 1 mg/kg LY379269 reduced falls and turns by 89% and 53%, respectively, and 1 mg/kg clozapine attenuated turning by 70%. Interestingly, low doses of clozapine increased PCP-elicited falls. Back-pedaling was particularly sensitive to LY379268 and clozapine, with 1 mg/kg of either agent completely abolishing back-pedaling 30 min after PCP administration. However, in contrast to LY379268, attenuation of these behaviors by clozapine only occurred at doses that augmented PCP-evoked ataxia. Furthermore, LY379268 did not affect PCP-evoked forepaw treading.


CONCLUSIONS
These results indicate that mGlu2/3 receptors do not mediate a generalized reduction in motor activity, but instead selectively modulate specific PCP behaviors, further implicating group II mGlu receptors as viable drug targets in the treatment of schizophrenia.
Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
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Cartmell
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Monn
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Schoepp
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006213:Hallucinogens / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*
D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D006213:Hallucinogens; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D010622:Phencyclidine; D003024:Clozapine