1985 |
Rech, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Central Actions of Abused Drugs: Hallucinogens @ Michigan State University
Evidence will be sought for the site(s) and neurotransmitter mechanism(s) of action of indoleamine- and phenethylamine-type hallucinogenic drugs. LSD, DOM, mescaline, and DMT will be examined on FR-40 operant behavior for the pause-type pattern, extending previous studies. Lesions of regional 5-HT neurons will be accomplished by infusing the neurotoxin 5,7-DHT into portions of the limbic system and these rats will be tested for changes in the dose-response for the pause effect produced by the hallucinogenic drugs. Brain DA, NE, 5HT and their metabolites will be measured to determine the extent and specificity of the lesions. The influence of 5HT agonists, 5-HT antagonists and the non-hallucinogenic LSD analogue lisuride on the hallucinogenic pause, as well as for their effects alone on FR40 responding, will be explored in other animals. Interactions with other non-hallucinogenic psychoactive agents (e.g., depressants, stimulants) will be done as controls. Tolerance development with various repeated doses of the hallucinogens, as well as cross-tolerance, for the FR-40 pause will be characterized. Effects of pretreatments with 5,7-DHT, PCPA and 5HT antagonists will be studied to determine any alterations in the pattern of tolerance development. Since the FR-40 program cannot distinguish hallucinogens from other 5-HT agonists, other behavioral tests will be included: orienting motor activity, accommodated motor activity, "rage" response of Long-Evans hooded rats, discriminated instrumental avoidance examining late responses, and a variable interval schedule of two-lever choice behavior for food reinforcement based on discrimination of visual or auditory stimulus patterns. Rectal temperatures of rats and rabbits in response to the drugs will also be determined. These additional tests may allow us to select out the hallucinogenic 5-HT agonists. Also they may afford a better opportunity to examine the hypothesis that 5-HT agonistic activity of the hallucinogenic drugs exerted at certain brain sites causes an imbalance in activities of various forebrain 5-HT systems that is of paramount importance for the expression of their major pharmacological effects.
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1987 — 1989 |
Rech, Richard H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Drug Tolerance: Behavioral Vs. Cellular Mechanisms @ Michigan State University
The phenomenon of tolerance to CNS depressant drug effects has been extensively studied, but the mechanisms underlying it are poorly understood. Is there a "behavioral tolerance" (learned adaptation) resembling other conditioning phenomena, but different from the cellular tolerance", generally associated with physical dependence, on long-term chronic drug treatment? This study will address the hypothesis that the two tolerances are distinct phenomena. We propose that behavioral tolerance (as a learned behavior) requires repeated, concurrent (but not necessarily continuous chronic) exposure to the drug effect and behavior. Cellular tolerance (especially with the general CNS depressant class of drugs) would require chronic drug exposure, but not necessarily experience with a behavior under the drugged state, for response patterns to eventually exhibit less sensitivity to the effects of the drug. Rats will be treated acutely, intermittently, or chronically with ethanol, pentobarbital or oxazepam. Tests of rotarod performance and measurements of body temperature will be done under the drugged state in some rats but temporally separated from drug experiences in other animals. The various treatment groups are calculated to develop subjects that manifest only behavioral tolerance, those showing only metabolic/cellular tolerance, and others showing the combination. Some rats will be killed just after behavioral testing for analysis of serum and brain levels of the drug. The serum half-life of the drug from chronically-treated rats should be shorter than that in controls if metabolic tolerance is induced. Correlating brain levels of drug with the extent of behavioral impairment after a test dose in those groups which have not practiced behavior in the drugged state should define the degree of cellular tolerance that has developed. On stopping chronic drug, this tolerance should fade rather rapidly (within 10 days) even without behavioral extinction trials. Rats that have had extensive behavioral experience in the drugged state, but have not received chronic drug, should demonstrate only behavioral tolerance. This should be maintained for longer periods unless extinction trails are performed. The experimental design should effectively test the hypothesis that behavioral (learned) tolerance is separable from the classical cellular (pharmacodynamic) tolerance obtained with chronic administration of this class of drugs. The solution to this issue would have both theoretical and practical implications for important problems that relate to issues of drug dependence.
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