Date of Award

1975

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Harbans Lal

Abstract

Lesioning the nigro-striatal dopamine neuron system produces aphagia and adipsia with an intensity proportional to the size of the lesion. Those rats which received small lesions produced by a 1 mA current for a 15 second duration of the nigro-striatal system initially lost weight and then spontaneously recovered from that loss. Pretreatment with alpha-methyl-para-tyrosine (50 mg/kg) or haloperidol (0.4 mg/kg) given twice a day for a three-day period prior to lesioning facilitated the recovery. When large lesions (2mA for 30 sec) were used to destroy this dopaminergic neuron system, a severe aphagia and adipsia resulting in death occurred in all saline treated animals. Haloperidol (2 mg/kg) or morphine sulfate (30 mg/kg) injected twice a day for six days preceding extensive nigrostriatal destruction promoted survival. The pharmacological denervation of dopaminergic receptors produced by haloperidol, morphine sulfate, or alpha-methyl-para-tyrosine prior to surgical destruction of the nigro-striatal pathway is felt to facilitate recovery. Symptoms of morphine withdrawal such as, wet shakes, ptosis, weight loss and hypothermia were enhanced when lesions were made in the nigro-striatal tract prior to and following the production of morphine dependence. This exacerbation of the primary abstinence syndrome was seen at either of two different terminal doses of morphine sulfate. Apomorphine, a dopamine receptor stimulant,- was effective in reducing the withdrawal wet shakes in these lesioned animals. The administration of apomorphine to intact withdrawn rats also resulted in a significant decrease in wet shakes. The intensity of morphine withdrawal aggression observed in response to social grouping of the animals seventy-two hours after the termination of morphine administration was decreased by nigro-striatal lesioning. Destruction of the medial forebrain bundle in morphine dependent rats results in increased withdrawal ptosis, temperature and weight loss. These results suggest a role for brain noradrenergic and dopaminergic neuronal systems in morphine withdrawal. In particular, withdrawal wet shakes seem to be related to dopaminergic mechanisms.

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