REFERENCES

1. DISCUSSION • WIN 55,212-2 had been shown to disrupt Pre Pulse Inhibition (PPI) in rat- a measure of sensory motor gating (Schneider & Koch, 2002). However the effect of WIN 55,212-2 on auditory gating has not been examined before. • The results of this study suggest the possibility of using cannabinoid agonists to pharmacologically model the gating deficits seen in schizophrenic patients. • WIN 55,212-2 and PCP failed to show any effect on non-gating rats. Whether or not non-gating rats represent a sub-population with inherent cognitive deficits, comparable to those seen in schizophrenia remains to be addressed. • The CA3 region of the rat hippocampus gates auditory responses. Some rats fail to gate responses to auditory stimuli under basal conditions. • Single administration of non selective cannabinoid agonist WIN55,212-2 and PCP disrupt sensory gating but WIN55,212-2 caused a greater disruption than PCP. • With both drugs the disruption of gating was brought about by a significant increase in the test response amplitude with no significant change in the conditioning response amplitude. • Single administration of either WIN or PCP failed to induce any significant change in the T/C ratios in non-gating rats. ABOLITION OF SENSORY GATING BY THE CANNABINOID WIN55, 212-2 IN THE RAT HIPPOCAMPUS Dissanayake WDN1, Zachariou M2, Marsden CA1 and Mason R1 School of Biomedical Sciences1, School of Mathematical sciences2, University of Nottingham Medical School, QMC, UK. • METHODS • Male Lister-hooded rats (n=11) were anaesthetised with isoflurane & N2O:O2 (50%:50%). • Stereotactically manipulated 16-channel microwire electrode arrays (2x8 array running medio-laterally; NB Labs, USA) were centred on the hippocampal CA3 region and dentate gyrus (Paxinos & Watson, 1998). • Paired auditory stimuli (3kHz tones, intensity 90dB, duration 10ms) separated by 0.5s were binaurally presented through hollow ear bars repeatedly for 128 trials with an inter-trial interval of 10s. • Simultaneous multiple single unit and local field potential (LFP) activity was recorded using a Plexon Multineuron Acquisition Processor (MAP) system (Plexon Inc., Texas, USA). Neural signals were split at the Plexon PBX preamplifier, amplified x1000 and filtered (LFPs: 0.1-170Hz; spikes: 500Hz-5kHz). • The effect of WIN55,212-2 (1.2mg/kg, i.p) and PCP (1mg/kg,i.p) on sensory gating were compared. • Data were analysed using NEX v3 (Neuroexplorer Inc.,USA) and Matlab v7.2. • Gating was assessed by measuring the ratio of the N40 LFP amplitude of the test (T) to the conditioning (C) response; a T/C ratio < 50% indicates gating was present. • INTRODUCTION • Sensory gatingis a mechanism which allows filtering of irrelevant sensory information, so enabling efficient information processing within the CNS. • Sensory gating can be assessed using an auditory Conditioning-Test paradigm which measures the reduction in the auditory evoked response (AER) produced by a test stimulus following an initial conditioning stimulus (Bickford-Wimer et al, 1990) . • Schizophrenic patients demonstrate a lack of attenuation of the test response measured electrophysiologically by the P50 wave component of the cortical evoked potential. • In rats, a similar defect in the N40 wave, recorded from the CA3 region of the hippocampus, has been observed in pharmacologically-induced -e.g. amphetamine, phencyclidine(PCP)- models of schizophrenia (Joy et al, 2004; Dissanayake et al , 2005 ). • Cannabinoids may produce schizophrenic symptoms in human subjects and cause relevant behavioural changes in rats (Schneider , Koch ,2002). • This study examined auditory gating in the rat hippocampus following a single dose of non selective cannabinoid agonist WIN55,212-2. FIG 2: Effects of WIN 55,212-2 on gating compared with the effects of PCP FIG 1: Hippocampal auditory-evoked LFP responses Stimuli A LFP1 Basal (WIN-control) T/C = 20 ± 8% Basal (PCP control) T/C = 25 ± 3% LFP2 LFP2 Averaged over 128 trials 500ms Peri-event rasters 1 B WIN 1.2mg/kg i.p Trials PCP 1mg/Kg i.p 128 Averaged LFPS N40 (C) N40 (T) Amplitude mV Time sec T/C = 81 ± 3% p<0.001 T/C = 114 ± 21% p<0.005 TS CS (A) Representative recording of auditory-evoked responses illustrating local field potentials from dentate gyrus (LFP1) and CA3 (LFP2). (B) Averaged local field potentials recorded from CA3 for 128 stimulus presentation trials demonstrated a reduction in test (T) response amplitude compared to conditioning (C) response amplitude; CS = Conditioning stimulus, TS = Test stimulus. Averaged LFPs and peri-event LFP rasters recorded from CA3 in gating rats; basal recording compared with effect of WIN 55,212-2 and PCP 45 minutes after administration of each drug. Both averaged LFPS and rasters demonstrated a significant drug induced disruption of gating in CA3 with a higher T/C ratio seen after WIN.55,212-2. ( N40 responses ) Test Stimulus Conditioning Stimulus FIG 4: Effects of (A) WIN 55,212-2 and (B) PCP on conditioning response (Camp) and test response (Tamp) amplitudes compared with the T/C ratios 15 and 45mins after drug administration FIG 3:Effects of WIN 55,212-2 on Non gating rats compared with the effects of PCP A Basal (PCP control) T/C = 87±8% Basal (WIN control) T/C = 97 ± 9% * ** * WIN 1.2mg/kg i.p PCP 1mg/kg i.p B ** T/C = 93 ± 7% p>0.05 ** T/C = 94 ± 6% p>0.05 *** *** A There was a significant increase in the Tamp (p<0.05) accompanied with a significant increase in the T/C ratio 45mins after administration of WIN. There was no significant change in Camp. B There was a significant increase in the Tamp accompanied with a significant increase in the T/C ratio both 15 (p<0.01) and 45mins (p<0.01) after administration of PCP. There was no significant change in Camp. Averaged LFPs and peri-event LFP rasters recorded from CA3 in non-gating rats; basal recording compared with effect of WIN 55,212-2 and PCP, 45 minutes after administration of each drug. Both averaged LFPS and rasters showed no significant drug induced changes in T/C ratios. ACKNOWLEDGEMENTS WDN Dissanayake was supported by the government of Sri Lanka and the University of Nottingham International Office and M Zachariou by the Institute of Neuroscience University of Nottingham. Harvey Wiggins and team at Plexon Inc USA. REFERENCES Bickford-Wimer PC, et al (1990) Auditory sensory gating in hippocampal neurons: A model system in the rat. Biol. Psychiatry27: 183-192. Joy B, McMahon RP & Sheppard PD (2004) Effects of acute and chronic clozapine on D-amphetamine induced disruption of auditory gating in the rat. Psychopharmacology174: 274-82 Paxinos G & Watson C (1998) The Rat Brain in stereotaxic coordinates, 4th edition, Academic Press. Dissanayake WDN, Marsden CA & Mason R (2005) Effect of phencyclidine on hippocampal sensory gating under isoflurane anaesthesia in the rat Brit J Pharmacol. http://www.pa2online.org/abstracts/Vol3Issue4abst163P.pdf Schneider M, Koch M (2002). The cannabinoid agonist WIN 55,212-2 reduces sensorimotor gating and recognition memory in rats. Behav Pharmacol13: 29-37