Date of Award

1979

Degree Type

Thesis

Degree Name

Master of Science in Pharmacology and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Harbans Lal

Abstract

Intravenous self-administration of drugs by experimental animals has importance as a laboratory model for the study of drug abuse and for the investigation of the neurochemical mechanisms underlying the reinforcing properties of drugs. Utilizing the drug self-administration technique, pharmacological investigations of the neurochemical basis of drug reinforcement suggest that opiate reinforcement is mediated through activation of central noradrenergic systems, whereas the reinforcing effects of psychomotor stimulants are mediated via activation of dopaminergic systems. The major purpose of the present study was to determine if the alpha noradrenergic receptor agonist, clonidine, would be self-administered by rats and furthermore to determine if clonidine is self-administered for its positive reinforcing effects. The latter was investigated by increasing the response requirement to obtain each clonidine injection. In view of the opiate-like effects of clonidine, the ability of clonidine to maintain self-administration behavior in rats self-administering the synthetic narcotic fentanyl was investigated. Also, the effect of response-contingent naloxone injections on clonidine-reinforced responding were compared with; their effect on fentanyl-reinforced responding. Since stimulation of the noradrenergic system is suggested to be involved in mediating the reinforcing effects of opiates, preliminary experiments compared the characteristics of clonidine-reinforced responding with the characteristics of fentanyl-reinforced responding by independently adding selected butyrophenones to the clonidine and fentanyl solutions. Under pentobarbital anesthesia male hooded rats of the Long-Evans strain were implanted with chronic indwelling jugular catheters and allowed to self-administer either clonidine (15 ug/Kg/injection), fentanyl (O.l and 1.0 ug/Kg/injection) or saline on a continuous reinforcement schedule. The drug solutions were delivered, in a constant volume of 100 ul/Kg, into the vein in less than one second. Subjects readily acquired the self-administration of clonidine and fentanyl (1 ug/Kg/injection) but not fentanyl (0.1 ug/Kg/injection) nor saline. Stable rates of clonidine and fentanyl-reinforced responding were attained after 3 or 5 days, respectively. When the fixed ratio (FR) requirement to obtain each clonidine injection was increased from 1 to 3, a significant increase in lever pressing was observed; however, total daily clonidine intake decreased significantly. When the FR requirement was further increased from 3 to 10, response rate increased so that total daily clonidine intake at the FR-3 and FR-10 schedules of clonidine reinforcement remained the same. Substitution of clonidine (15 ug/Kg/ injection but not clonidine (1 ug/Kg/injection) nor saline maintained self-administration behavior in rats previously self-administering fentanyl. Extinction of self-administration behavior was observed following the substitution of both clonidine (1 ug/Kg/injection) and saline for the fentanyl solution. Addition of naloxone (64 ug/Kg/injection) to the clonidine and fentanyl solutions significantly decreased fentanyl-reinforced responding but appeared to have no effect on clonidine-reinforced responding. Fentanyl reinforced responding returned to pre-naloxone rates following the removal of naloxone from the fentanyl solution. Addition of either haloperidol or azaperone to the clonidine and fentanyl solutions iso that the subjects received 64 ug/Kg/ injection, tended to decrease the rates of self-administration of rats previously self-administering either clonidine or fentanyl alone. Removal of haloperidol and azaperone from the clonidine and fentanyl solutions tended to result in a return to pre-haloperidol and pre-azaperone response rates. Addition of aceperone (64 ug/Kg/injection) produced no significant change in the rate of clonidine-reinforced responding but resulted in a significant increase in the rate of fentanyl-reinforced responding. Self-administration of clonidine by rats suggests that stimulation of central alpha-noradrenergic receptors results in positive reinforcement. Clonidine's self-administration by rats and its ability to maintain self-administration behavior in rats previously self-administering fentanyl suggests this drug may have abuse potential. Preliminary experiments suggest some similarities between clonidine- and fentanyl-reinforced responding; however, the exact nature of these similarities remain to be determined. The reinforcing effects of clonidine, unlike the reinforcing effects of fentanyl, seem to be mediated by opioid independent mechanisms.

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