Date of Award

1978

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacy and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Harbans Lal

Abstract

Narcotic dependence was established by continuous intravenous infusion of gradually increasing doses of morphine. Several days at the terminal concentration of morphine (100 mg/kg/day) was allowed prior to withdrawal. Morphine withdrawal body shakes were reliably observed upon the termination of continuous morphine infusion. The administration of morphine, methadone or _fentanyl, potent narcotic drugs, reliably abolished the occurrence of withdrawal body shakes 8 hours after the termination of morphine infusion. The narcotic antagonist naloxone or pentazocine had no significant effect on the rate of occurrence of withdrawal body shakes; however, there was a slight trend towards an increase in the frequency of this withdrawal index. A wide variety of neuroleptics were investigated for their ability to reduce withdrawal. The order of potency for reduction of withdrawal body shakes on a mg/kg basis for those neuroleptics tested was spiperone, benperidol, butaclarriol, loxapine, oxiperomide, haloperidol, spiramide, chlorpromazine, trifluoperazine, pimozide and pipamperone. The dopaminergic agonists amphetamine, apomorphine and L-IX>PA were also found to dose dependently reduce withdrawal• body shakes. Azaperone, a butyrophenone possessing high alpha noradrenergic blocking potency, reduces withdrawal body shakes in a dose related manner, while the alpha adrenergic blocker phenoxybenzamine and the beta adrenergic blocker propronalol failed to reduce withdrawal shakes to any significant extent. Dose dependent decreases in morphine withdrawal body shakes were produced by clonidine and desmethylimipramine, adrenergic agonists. Reserpine and alpha-methyl-p-tyrosine also reduced withdrawal shakes, but the effect was dose dependent for only reserpine. The serotoninergic agents fluoxetine, 5-HTP and methysergide were without effect on the occurrence of withdrawal body shakes at the doses tested. A slight but non-significant increase in the rate of withdrawal shakes was observed after the administration of the anticholinergic drugs atropine, benztropine, dexetimide and scopolamine. Conversely, the cholinergic agonists physostigmine and pilocarpine, reduced withdrawal body shakes in a dose related fashion. Modification of gabaminergic system by the administration of bicuculline, depakene and picrotoxin had no significant effect. Chlordiazepoxide, flurazepam and pentobarbital, sedativehypnotic agents, did not produce dose dependent effects on the occurrence of withdrawal shakes. However, the highest dose of each sedative hypnotic employed did reduce withdrawal body shakes. The exact mechanism by which neuroleptics reduce withdrawal is not known. Manipulation of each of the transmitters effect by neuroleptics indicates that dopamine and acetylcholine are involved in mediating the reduction in withdrawal body shakes. The fact that the antiwithdrawal activity of certain neuroleptics is reversed by the narcotic antagonist naloxone implicates opiate receptor mechanisms. However, not all neuroleptics were antagonized by naloxone, suggesting that neuroleptics may be working at more than one site to reduce withdrawal. Thus neuroleptics may be reducing withdrawal body shakes by several different mechanisms. The data gathered from these studies suggest a role for cholinergic, dopaminergic and narcotic mechanisms in the antiwithdrawal activity of neuroleptic drugs.

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