REFERENCESBickford-Wimer PC, et al (1990) Auditory sensory gating in hippocampal neurons: A model system in the rat. Biol. Psychiatry 27: 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. Psychopharmacology 174: 274-82

Paxinos G & Watson C (1998) The Rat Brain in stereotaxic coordinates, 4 th 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 Pharmacol 13: 29-37

ACKNOWLEDGEMENTSWDN 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.

• 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.

• 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.

DISCUSSION

Neuronal Networks

Laboratory

Neuronal Networks

Laboratory

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. (

FIG 1: Hippocampal auditory-evoked LFP responses

(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.

Peri-event rasters

LFP2 Averaged over 128 trials

Averaged LFPS

A

B

FIG 3: Effects of WIN 55,212-2 on Non gating rats compared with the effects of PCP

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.

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

Dissanayake WDN1, Zachariou M2, Marsden CA1 and Mason R1

School of Biomedical Sciences1, School of Mathematical sciences2, University of Nottingham Medical School, QMC, UK.

ABOLITION OF SENSORY GATING BY THE CANNABINOID WIN55, 212-2 IN THE RAT HIPPOCAMPUS

INTRODUCTION

• Sensory gating is 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.

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.

FIG 2: Effects of WIN 55,212-2 on gating compared with the effects of PCP

Basal (WIN-control)

T/C = 20 ± 8%

T/C = 114 ± 21%

p<0.005

T/C = 81 ± 3%

p<0.001

Basal (PCP control)

T/C = 25 ± 3%

Basal (WIN control)

T/C = 97 ± 9%

Basal (PCP control)

T/C = 87±8%

T/C = 93 ± 7%

p>0.05

T/C = 94 ± 6%

p>0.05

N40 (C) N40 (T)

0 15 450

50

100

150

200

250

300

350WIN Camp

WIN Tamp WIN T/C ratio

0

100

200

300

Am

pli

tud

eV T

/C R

atio

0 15 450

100

200

300

400PCP CampPCP Tamp

PCP T/C ratio

0

100

200

300

400

Time mins

Am

pli

tud

eV T

/C ra

tio

A

B

*

*

**

****

*** ***

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.

Conditioning Stimulus Test Stimulus N40 responses )

Amplitude mV Time sec

CS TS

500ms

Stimuli

LFP1

LFP2

1

128

Trials

WIN 1.2mg/kg i.p PCP 1mg/kg i.p

WIN 1.2mg/kg i.p PCP 1mg/Kg i.p