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Abstract The introduction of beta-adrenergic blockers in clinical medicine was recognized as one of the major therapeutic advances of this century. Beta-adrenergic blockers which have been used for many years in general medicine are still being explored for new indications. One of such areas is the effect of beta-blockers on the central nervous system. There are many reports on the effective use of propranolol in controlling neuroleptic-induced extrapyramidal manifestations. Akathisia for example is a frequent and often disabling side effect of treatment with neuroleptic drugs. The traditional treatment of neuroleptic-induced akathisia has been disappointing. Beta-blockers especially the non-selective members may induce hypoglycemia particularly in diabetics under therapy due to impairement of the normal sympathetic-mediated homeostatic mechanisms for maintaining the blood sugar. The symptoms of hypoglycemia as mediated by the sympathetic system will not occur. Such a prolonged-non detected Summary and Conclusion 151 decrease in brain fuel may be expected to affect brain functions such as learning and memory. The aim of the present work was to study the effects of beta-blockers (either non selective as propranolol or selective as metoprolol) on two important aspects of brain functions namely motor behavior and learning process. This works consists of two parts : Part r : This part concerned with the study of the effect of propranolol and metoprolol versus benztropine on motor behavior. An animal model of Parkinsonism was made by a single s.c. injection of fluphenazine in rats (10 mg/kg B.W.). Propranolol (in doses of 5, 10, 20 & 40 mg/kg), metoprolol (in doses of 7.5, 15, 30 & 60 mg/kg) or benztropine (1 mg/kg) were injected s.c. for 15 days either concomitantly (as prophylaxis) with/or on the third day following fluphenazine injection (as treatment). Motor coordination was determined using the Rotord test (Hoore and Rech, 19”), as the time in seconds that the rat can keep its posture on a rolling bar. After 15 days all animals are sacrified and their brains were extracted and dissected, whole brain, thalamus and hypothalamus contents of Summary and Conclusion 152 acetylcholine and dopamine were estimated biologically according to Richter and crossland (1949) for acetylcholine and with the flurometric method of Bourke and Murphy (1965) for dopamine. We found that benztropine (1 mg/kg) and propranolol (40 mg/Kg) medicated groups were non-significant from the control non-medicated group from the 1st day indicating a prophylactic effect. other doses of propranolol produced the effect in later days. Metoprolol on the other hand failed to produce this effect in all doses used but still significant from the fluphenazine group. Regarding brain transmitters, both benztropine (1 mg/kg) and propranolol (40 mg/kg) could increase dopamine level to reach that of the non-medicated control group. Metorpolol (60 mg/kg) could not produce this effect. Regarding Ach, only benztropine offered levels nonsignificant from the non-medicated control group, while propranolol and metorpolol could not produce this effect. Benz tropine (1 mg/kg) and propranolol (40 mg/kg) could produce a curative effect from the 1st day. Propranolol (10 & 20 mg/kg) produced this effects after few -- - ---_.-- ~_- Summary and Conclusion 153 days while propranolol (5 mg/kg) and metoprolol in all used doses had no curative effect. The -corresponding brain neurotransmitters are also estimated. Regarding dopamine, both benztropine (1 mg/kg) and propranolol (40 mg/kg) could increase its levels to those of non-medicated controls while metoprolol failed to produce this effect. Regarding acetylcholine only benz tropine could reduce its level to be non-significant with those of non-medicated control group. Part II : to study the effect of propranolol and metoprolol on the learning process using the learned conditioned reflex according to the same rules described by Grant (1964) in normal and insulin-induced hypoglycemic rats in order to investigate the implication of hypoglycemia in the process of B-blockers induced amnesia. Animals were administered a daily S.C. injections of insulin (2.5 and 5 I.U/kg) and/or beta-blockers (propranolol in doses of 10, 20 & 40 mg/kg or metoprolol in doses of 15, 30 & 60 mg/kg). Animals were tested for the learned conditioned reflex 5 times a day for each animal. After conditioning reinforcement was given by 3 days trials ---- --- -- --------- - ------------------ summary and Conclusion 154 till the time of experiment for extinction. The latency period in days till the animal learned the reflex as well as the number of positive trials needed to get rid of the reflex (extinction) were recorded. Serum glucose level was estimated utilizing the methods of Trinder (1969), before drug administration and after testing of each animal. We found that propranolol (10 mg/kg), metoprolol (15 mg/kg), insulin (2.5 1.U/kg), insulin + propranolol or metoprolol (same doses) failed to produce any significant effect on latency period of rats to acquire the conditioned reflex. On the other hand in all these groups, except the group received metoprolol alone, extinction was significantly reduced. The corresponding serum glucose level showed a significant reduction in all groups allover the experiment except with those administered propranolol or metoprolol. with high doses (5 I.U/Kg insulin, 20 mg/kg propranolol and 30 mg/kg metoprolol, the group receiving insulin and propranolol together increased significantly the latency period for rats to develop the reflex while other results was about the same with smaller doses. The corresponding serum glucose level still shows a significant summary and Ccnclusion 155 reduction among all grcups receiving insulin but not with those administered propranolol or metoprolol alone. with more higher doses of propranolol (40 mg/kg) and metoprolol (60 mq/kg) and the same dose of insulin (5 I.U/kg), the group receiving insulin and metoprolol together could significantly prolong latency period and the group administered metoprolol alone could significantly prolong extinction while other results were similar to those with smaller doses. The corresponding serum glucose level still shows a significant reduction among all groups administered insulin but not in the groups of B-blockers alone. So it can be said that propranolol may be used as curative and prophylactic against antipsychotic inducedextrapyramidal manifestations as alternative to the usually used anticholinergic drugs especially in cardiac patients and in cases where anticholinergic proved contra-indicated or uneffective. Also, we can conclude that B2 adrenoceptors are important in the process of learning, and hypoglycemia shares in part in disturbing this process. So when insulin and B-blockers are to be given in combination, a cardioselective B-blocker is preferred to avoid the implication of B1-blockade on learning and memory. |