Arrestin 2B plays a key role in a pharmacological model of psychosis

CAITLIN MCORMISH; JAMES HANKS; NOELIA V WEISSTAUB; JAY A GINGRICH

Chicago

Conferencia; 39th annual meeting of the Society for Neuroscience; 2009

Society for Neuroscience

NTRODUCTION: NMDAR antagonists such as PCP, MK801 and ketamine induce or worsen schizophrenia-like symptomatology and are considered the foremost pharmacological model for psychosis in animals. The mechanism by which these non-competitive NMDAR antagonists mediate their effects has not been elucidated and constitutes a question of central importance to psychiatric research.Previous research has implicated serotonergic and non-ionotropic glutamatergic receptors in the actions of MK801 on behavior. Namely, the serotonin 2A receptor (5-HT2AR) and the metabotropic glutamate receptor 2 (mGlu2), both 7TM GPCRs, have been demonstrated to modulate the phenotypes induced by MK801 (disrupted locomotor behavior, and prepulse inhibition). However the downstream components of these (and additional) interacting systems remains an open question.Arrestin proteins can regulate the signal transduction of GPCRs, such as the 5-HT2AR, by binding to the receptor preventing further signaling, targeting the receptor for internalization, redirecting signaling to other G protein dependent pathways, and can themselves act as G-protein independent signaling molecules. Here, we present further investigations into the molecular candidates responsible for psychosis-like behavior induced by MK801, specifically, whether the beta-arrestin 2 protein influences behavioral response to MK801. Furthermore, based on preliminary data, we investigated whether metabotropic glutamate receptor 2/3 agonists would be effective in these mice.METHODS: Wildtype (WT) and beta-arrestin 2 knockout mice (b-arr KO) were treated with 0.3mg/kg MK801, and the 3mg/kg of mGlu2 agonist LY379 268. Locomotor activity was assessed for 2.5 hrs.RESULTS: As has been previously shown, WT mice showed increased locomotor response to MK801 treatment which was abolished by an agonist of mGlu2 (LY379 268). B-arr KO mice show decreased locomotor activation following MK801 treatment, relative to WT animals, which was not responsive to LY379 268.CONCLUSION: This study reveals a complex involvement of beta-arrestin in MK801 induced locomotion. In the absence of beta-arrestin2, mice remain responsive to MK801 - albeit at a greatly reduced level - however, in its absence, the ability to completely attenuate the hyperactivity by LY379 268 is absent.Demonstrating new mechanisms by which MK801 elicits its effects is a critical step towards understanding how psychotic symptoms may be elicited via interactions between multiple neurotransmitter systems, and may go some way towards bridging the glutamatergic and dopaminergic hypotheses of schizophrenia