| Popis: |
The neurodevelopmental hypothesis of a schizophrenia emphasised that that the pathophysiology underlining the disease arises from abnormalities in brain development and do not manifest until adolescence and early adulthood. The postweaning social isolation rearing model employs early-life adversity that elicits the neurodevelopmental aetiology of schizophrenia. The overall aim of this thesis was to deduce whether manipulations of cholinergic, serotonergic and cannabinoid pathways account for some behavioural alterations seen in isolation-reared rats. This was probed by evaluating behavioural effects of different pharmacological compounds including CBI receptor agonist THC, CB2 receptor antagonist AM630, 5-HT6 receptor antagonist SB-271046, Donepezil an acetylcholinesterase inhibitor and nAChR agonists GTS-21, Varenicline and PNU-282987 in this model. Results confirmed that rearing rats in isolation produced an array of behavioural deficits III the adult rats. Concomitant treatment of /19_ tetrahydrocannabinol (THC) did not aggravate the isolation-induced locomotor responses and deficits in object recognition memory and associative learning in conditioned emotion paradigm, but disrupted the associative learning in grouphoused rats. Furthermore, isolation-rearing induced deficits were not reversed by concomitant treatment with the CB2 receptor antagonist, AM630 suggesting that CB2 receptors do not play significant role in isolation-induced deficits. Acute systemic administration of 5-HT6 receptor antagonist has been shown to reverses the isolation rearing -induced impairments in object recognition memory and conditioned emotional learning suggesting the altered serotonergic neurotransmission in isolates and blockade of serotonergic neurotransmission in :1 j :1 I isolation-reared rats by selective 5-HT6 antagonists may have beneficial effects on cognitive performance in this model. The important finding of the present study is that donepezil, when administered acutely reversed the hyperactivity, deficit in object recognition memory and impairment in associative learning. The effects of donepezil in isolation-reared and group-housed rats were further investigated by coupling in vivo microdialysis in rats performing novel object recognition task. No significant changes in acetylcholine overflow were observed in medial prefrontal cortex of rats while performing object recognition task suggesting the reversal of deficits seen in object recognition tasks are unlikely to cholinergic enhancement in prefrontal cortex but warrants further investigation as drug was not perfused locally in mPFC. Finally, administration of GTS-21 (a7 partial agonist) reversed the deficits in object recognition memory. Varenicline (a7 full agonist and a4~2 partial agonist) reversed the isolation-induced hyperactivity and partially restored the deficits in conditioned emotion response. PNU-29287 (selective a7 full agonist) also restored isolation-rearing induced deficits in novel object recognition and conditioned emotion response task. These results suggest the alterations in the function and/or expression of a7 and a4p2 receptors may contribute to the components of cognitive deficits produced in isolation-reared rats Clearly these data suggest that the behavioural deficits seen in isolation-rearing model of schizophrenia can be reversed by the acute administration of variety of compounds modulating cholinergic and serotonergic neurotransmission and the possible mechanisms underlying these effects are discussed. |
