الفهرس | Only 14 pages are availabe for public view |
Abstract -218- SUMMARY AND CONCLUSIONS Schizophrenia 1s a major psychotic disturbance of non clear aetiology that results in severe and ’ prolonged mental disturbance. The cause of schizophrenia may be due to genetic, and environmental factors, or biochemical changes. The drug treatment can eleminate or reduce symptoms of schizophrenia. Neuroleptics drug therapy is the commonset component used for treating schizophrenic disorders, but there are many reports on the effective use of propranolol in controlling schizophrenic symptoms, and neuroleptic induced extrapyramidal manifestations. The aim of the present work was to evaluate the amphetamine model of induction of schizophrenia in rats, and to study the neurotransmitter pattern namely norepinephrine, GABA, dopamine and serotonin , as well as to suggest the causative mechanism of the disease in this model. Moreover the effect of a single dose of chlorpromazine, and propranolol singly or 1n combination on tested neurotransmitters in the whole brain and its areas (namely cerebral cortex, Thalamus, hypothalamus, midbrain and -219- hindbrain}. The experimental findings were assessed in terms of their relevance to the therapeutic usefullness and side effects. Male albino rats of about 100-120 gm were chosen 1n this study. Animals were divided into 5 groups each consists of 60 rats, the first group was several as a normal control group, in the second group schizophrenia was induced by a single S. C. injection of amphetamine (5 mg/kg B. W. }, the third, fourth, and fifth groups of amphetamine induced schizophrenic rats served to study the effect of chlorpromazine ( 12, mgjkg B. W.,s. C. ) , propranolol ( 30 mgjkg B. W.,L P.), and combined drug respectively on norepinephrine, GABA, dopamine, and Serotonin in the whole brain and its different areas namely cerebral cortex, thalamus-hypothalamus, midbrain and hindbrain. The choice of the dose based on pilot experiment and published literature. The method of Sourkes and Murphy, (1965) were adopted for the determination of norepinephrine and dopamine, while that of Weissbach, {1965) was used for serotonin evaluation,and the concentration of GABA was assessed by using the chromatographic method of Consden et al, {1944). The findings in this study revealed that amphetamine induced schizophrenic rats showed a significant increase of norepinephrine, dOPamine, and serotonin concentrations, this increase may be attributed to increasing release, of monoamines and/or inhibiting of their reuptake, to the monoamine oxidase inhibitory effect of moreover the increased level of GABA may be due in addition amphetamine, to its a 1 adrenoceptor stimulant effect of amphetamine. The results of this work may indicate that the elevated synaptic concentration of norepinephrine probably gives rise to excitation, and that of dOPamine may be responsible for locemotor hyperactivity, and while the r1se in synaptic concentration of serotonin may explain alerteness, elevated mood and depressed appetite in schizophrenic psychosis. The rised GABA level may act as a compensatory mechanism to reduce excitatony state of schizophrenia. Administration of chlorpromazine normalization of dopamine concentration resulted through adrenoceptor blockade, as well as,significantly reduce in level of norepinephrine through presynaptic a adrenoceptor 2 blockade, in addition GABA concentration was increased through blocking its reuptake.The above mentioned effect may be contribute the antipsychotic effect of chlorpromazine. -221- Tbe da~a of the present work may explain extrapyramidal syndrome and gynaecomastia, induced by chlorpromazine, these effects may be due to D 2 receptor blockade. The sedative effect of the drug may be due to decreased norepinephrine and eleveted GABA concentration in cerebral cortex. The hypotensive effect of the drug may result from increased levels of GABA and serotonin in thalamun and hypothalamus, in addition to increased GABA and decrease serotonin concentrations in hindbrain. the rise in serotonin level in thalamus and hypothalamus may explain inhibition of ovulation induced by chlorpromazine. Propranolol exerted its antipsychotic effect by the same mechanism as chlorpromazine {significantly decrease norepinephrine, normalization of dopamine concentrations through increasing release of these transmilters, increased GABA level through B 1 adrenoceptor blockade) but extrapyramidal symptoms that are common with chlorpromazine do not occur with propranolol, this may be due to increased level of serotonin. Also from the data of the present work, we may conclude that the sedative effect of propranolol may be due to -222- decreased norepinephrine, increased GABA and concentrations in cerebral cortex. serotonin The anithypertensive effect of propranolol may be due to increased release of norepinephrine which then stimulate a adrenergic receptors 1n hindbrain to lower systemic 2 arteral blood pressure. The concomitant administration of propranolol and chlorpromazine run in the same line and produce transmitter pattern similar to that of propranolol but differs from that of chlorpromazine in elevating serotonin level and this may explain the low incidence of extrapyramidal symptoms with the combined therapy. A further study is needed to determine the local concentration of each drug in brain and its areas, together with determination of the receptor density in amphetamine model of schizophrenia. A further study is also needed to compare equipotent doses of chlorpromazine and propranolol, and studying the side effects of long use of combined drug therapy. |