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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.

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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


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