Date of Award
11-1986
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
First Advisor
Elliot Stein
Second Advisor
Archie Vomachka
Third Advisor
Bela Piacsek
Fourth Advisor
Donald Czech
Fifth Advisor
Joel Myerson
Abstract
The major effects of the opiate alkaloids are produced by interactions with the receptors of endogenous opioid peptide systems found throughout the central nervous system. Regional modifications of neuronal activity produced by systemic heroin, and heroin-conditioned auditory stimuli were measured in conscious rats using autoradiographic tracers of cerebral blood flow and free fatty acid metabolism. Regional cerebral blood flow (RCBF) was quantified in conscious, restrained rats shortly after intravenous infusion of heroin, the opiate antagonist naloxone, or heroin following naloxone pretreatment. These values were compared to similarly treated, saline-injected animals. Heroin elevated blood flow an average 36% in 37 of the 40 brain regions analyzed, and this regional hyperemia was reversed by pretreatment with naloxone. Infusions of naloxone produced slight reduction in RCBF. Since RCBF is coupled to local metabolic rate related to functional activity, these results suggest that heroin activates neural function in several brain regions. This effect was not limited to brain areas containing dense populations of opiate receptors. Cerebral activity was measured using the free-fatty acid 1-('14)C octanoate as a fast functional tracer in conscious, unrestrained rats 5 minutes after intravenous injection of heroin, cocaine or saline vehicle. Regional changes of octanoate labeling density in the autoradiograms relative to saline-injected animals were used to determine the functional activity effects of each drug. Heroin and cocaine each produced a distinctive pattern of activity increases and suppression throughout the rat brain. Similar regional changes induced by both drugs were found in limbic brain regions implicated in drug reinforcement. Labeled octanoate autoradiography was used to measure the cerebral functional response to a tone that had previously been paired to heroin injections. Rats were trained in groups of three consisting of one heroin self-administration animal, and two animals receiving yoked infusions of heroin or saline. A tone was paired with each infusion during training. Behavioral experiments in similarly trained rats demonstrated that these training conditions impart secondary reinforcing properties to the tone in animals previously self-administering heroin, while the tone remains behaviorally neutral in yoked-infusion rats. Cerebral functional activity was measured during presentation of the tone without drug infusion. Octanoate labeling density changed in fifteen brain areas in response to the tone previously paired to heroin without response contingency. Labeling density was significantly modified in sixteen regions as a result of previously pairing the tone to response-contingent heroin infusions.