The Search For Novel Approaches To Antipsychotic Medication: Behavioural And Neurochemical Studies On Drugs Acting At Dopamine D4 And D3 Receptors

<p dir="ltr">Schizophrenia is a serious mental illness that affects around 0.5% of the population. Despite the population of people diagnosed with schizophrenia, the neurochemical basis of the mental illness is poorly understood. Different antipsychotic drugs have been administered in the past, but these drugs are not efficient, leaving the patients with severe side effects from the drugs. About 50 - 70% of patients administered these antipsychotic drugs do not respond well, resulting in a series of side effects from the drugs. This study uses several behavioural, neurochemical and histological approaches to study the role of drugs affecting dopamine D4 receptors (D4-R) and their effects on changes evoked by phencyclidine (PCP) pretreatment, modelling schizophrenia, in the context of their possible applicability as novel antipsychotics. Also, preliminary experiments investigated the actions of drugs affecting dopamine D3 receptors (D3-R), which have also been suggested as potential novel antipsychotic drugs, on behaviour and stimulated dopamine release. A pharmacological model of schizophrenia, using PCP treatment, was adopted, which evokes behavioural changes in rats that resemble abnormal behaviours expressed by schizophrenic patients. This research aimed to investigate the effects of the D4-R agonist A412997 on electrically-stimulated dopamine release in nucleus accumbens shell (NAc), also to assess whether PCP treatment modelling schizophreniaaffected changes induced by D4-R, to study the action of dopamine D3 and D4 receptor mechanisms in behaviour and neuronal function, in the context of possible abnormalities in signaling in schizophrenia. To achieve this, a series of experiments were carried out: Effect of drugs affecting D3 and D4 receptors on dopamine release fast scan cyclic voltammetry (FSCV); Effect of PCP Pretreatment and drugs affecting D3-R and D4-R on behaviours modelling schizophrenia; Effect of PCP on local brain area activity (measured by c-fos in post-mortem tissue); Effect of PCP and D4-R agonist (A412997) on regional neurochemical function (high performance liquid chromatography: HPLC). The outcome of this study using FSCV revealed that the D4-R agonist, A412997, caused a concentration-dependent attenuation in electrically stimulated dopamine release at both high and low stimulation frequency, which was abolished by L741,742 (a D4-R antagonist). Clozapine is another D4-R antagonist that was used to check its ability to reverse the actions of A412997 in the NAc, it only caused a fractional effect on dopamine release but failed to completely abolish the attenuation caused by A412997. Under both high and low frequency stimulations, PCP failed to abolish the attenuation caused by 30 μM A412997, but the attenuation caused by a higher concentration of A412997 (100μM) was abolished by PCP, though the PCP effect was frequency dependent. D3-R agonist evoked a concentration-dependent attenuation of dopamine-stimulated release, which PCP failed to abolish at both high and low frequency stimulations. The Latent Inhibition (LI) experiment revealed that there was an indication of LI effect in animals in the preexposed (PE) groups that were treated with A412997. The Spatial Object Recognition (SOR) experiment revealed that PCP has no effect on SOR: the SOR effect remained intact in PCP pretreated animals. A412997 abolished SOR in saline-treated animals but has no effect in PCP-treated animals. D3-R antagonist restored Novel Object Recognition (NOR), though it was a weak effect, but D3-R agonist PD128907 had no effect on NOR using two different Inter-Trial Intervals (ITI) of 1 min and 4 hours. D4-R agonist (A412997) on neurotransmitter (dopamine, DOPAC, 5HT and HVA) regional differences was investigated in five different brain regions of interest: the frontal cortex, nucleus accumbens , dorsal striatum , ventral tegmental area and amygdala , using HPLC. The data revealed that A412997 caused a brain regional difference in the neurotransmitters studied. This study also investigated a PCP-pretreatment effect to ,check the effect of PCP in causing regional differences in neurotransmitters. The PCP caused regional neurotransmitter differences in the dopaminergic system. The outcome of the experiments done in this ,study provided behavioural and neurochemical evidence supporting a potential antipsychotic role for D3-R and D4-R agonists and, importantly, provided neurochemical evidence of a possible mechanism through which the behavioural actions may be mediated.</p>