Larry Reid - US grants

Despite the considerable social and health costs associated with drinking alcoholic beverages, little is known, in detail, especially in neuroscience terms, about why ethanol reinforces ethanol-intake. Relatedly, little is known concerning why certain individuals consistently drink to the point of toxicity, i.e., lose control of drinking. The basic question of why individuals drinks is central to eventually developing prevention-programs and therapy directed toward remediating alcohol abuse and alcholism. Modern theories of addictions stress the capability of addicting agents, including ethanol, to be positively reinforcing. The plan is to develop a procedure so that ethanol's positively reinforcing characteristics can be reliably indexed and, therefore, set the stage for studying the neural mechanisms of that positive reinforcement. Among the planned studies is to ask which antagonists of neurochemical systems would reduce alcohol's capability to be reinforcing. Preliminary data-collection demonstrate conclusively that small doses of certain opioids increase rats' propensity to drink alcoholic beverages. These findings add to a considerable body of research indicating that alcohol may interact with endogenous opioid systems to achieve some of its effects, particularly those associated with propensity to drink large amounts of alcohol. Research is planned that extends the initial findings that certain opioids increase propensity to drink alcoholic beverages. In particular, there is a plan to extend the finding that large doses of morphine given with diprenorphine, an antagonist for many of morphine's effects, lead to much greater intakes than small or large doses of morphine by themselves, a finding indicating only one type of opioid receptor may be involved in opioid-potential of propensity to drink alcoholic beverages. In the experimental situation used and under the influence of certain drugs, the rats drink to point of showing clear signs of intoxication. The proposed research, therefore, is seen as part of an effort to understand why individuals drink to the point of engendering considerable risk to health and social well-being.

Preliminary data-collections indicate there may be a specific type of opioid receptor related to opioid's ability to reinforce its own intake. The possibility of a specific receptor became apparent by studying diprenorphine, a mixed agonist-antagonist which antagonizes many events of morphine but which shows signs of having capability to elicit opioid-positive-affect. The research to be done will follow the preliminary findings and explore the dimensions of diprenorphine's effects as well as studying diprenorphine's site to action. Among people, TRC, the active ingredient of marijuana, clearly produces signs of positive affect. Yet, we have little or no capability of studying THC-elicited positive affect in laboratory subjects, such as rats. Consequently, we have little information concerning how THC may induce positive affect which is one the features by which THC sustains its own intake. Research will be done leading to the capability of measuring THC-elicited positive affect among rats and, thereby, begin the process of studying how THC achieves its positively reinforcing effects. It is clearly a possibility that opioids and THC's rewarding effects are mediated by way of similar processes. Research is proposed which will delineate which neurochemical systems are critical to both opioid and THC's rewarding features.

Recently collected data indicate that naltrindole (NTI), a specific delta opioid receptor antagonist, has features of a useful medicine for treating people abusing cocaine. Although the results from preliminary research are very encouraging, those results are limited by the small numbers of subjects used, and the fact that only a limited range of acute doses of NTI were used. Given both the promise of the initial results and their limitations, the aims are straightforward. The aim is to assess the effects of NTI, thereby, laying a basis for the further development of pharmacological agents that safely modify cocaine's positive affective, positively reinforcing potential. More specifically, research is planned, with respect to cocaine's effects, to (a) observe the effects of a range of doses of NTI, (b) determine if NTI is orally effective, and (c) see if NTI's effects change with repeated daily dosing. Additionally, other experiments are planned, for example, to assess NTI's ability to modify responses conditioned to cocaine's effects. Also, NTI's effects will be assessed by testing it with respect to amphetamine's reinforcement. Because NTI may have limiting side-effects, other specific delta opioid receptor antagonists' ability to modify cocaine's effects will be examined.