Stanley D. Glick - US grants

The long-term goal of this research is a better understanding of what factors determine the addictive liabilities of drugs. Using prototypical agents, experiments are planned to analyze further the neuropsychological mechanisms of opiate (e.g., morphine, meperidine), stimulant (e.g., d-amphetamine, cocaine), and hallucinogen (e.g., phencyclidine, LSD) addiction in rats. A major focus will be the determination of neuroanatomical site(s) of drug action(s) with particular reference to differential involvement of the two sides of the brain. Specific experimental problems will include the following: (1) The effects of drugs on electrical self-stimulation of the brain will continue to be studied and characterized in terms of their differential actions in the two sides of the brain. Ongoing studies with lateral hypothalamic and hippocampal placements will be completed, and striatum and frontal cortex will be studied next. (2) Mechanisms that differentiate cocaine from d-amphetamine will be investigated with respect to the hypothesis that cocaine selectively activates dopaminergic mesocortical pathways that can also be activated by stress. (3) The mechanism of asymmetry in the dopaminergic nigrostriatal system will be investigated with respect to the hypothesis that there are dual excitatory and inhibitory inputs and that rats can be distinguished on the basis of which input predominates. (4) Individual differences in brain lateralization that underlie behavioral differences in sensitivity to opiates, stimulants, and hallucinogens will be investigated. Left-, right- and non-sided rats of both sexes will be compared for their responsiveness to behavioral effects (e.g., drug self-administration, locomotor activity) of these drugs. If possible, similar comparisons will be made between rats distinguished as in (3) above. These studies should provide an animal model for understanding different drug preferences and patterns of abuse among humans.

The long-term goal of this project is to understand the mechanisms subserving and/or predisposing to addiction to alcohol and the ways in which such mechanisms are altered by prenatal exposure to alcohol. Using a model of ethanol intake and preference in rats, the effects of administering ethanol (17.5% or 35% ethanol derived calories) in utero (from Day 6 to Day 15 or 20 of gestation) will be investigated pair-fed yoked animals will be included to control for potential nutritional effects. Ethanol intake and preference of rats will be determined at three different postnatal ages. The possibility that endogenous sex steroids may modulate the effects of prenatal ethanol exposure on postnatal ethanol intake will be examined by considering the role of fetal position and in utero contiguity to siblings of the same or opposite sex. The effects of prenatal ethanol exposure on neurotransmitter release in discrete brain regions of developing rats will be determined with the use of in vivo microdialysis. Dopamine, norepinephrine and serotonin release will be measured in nucleus accumbens, striatum and medial prefrontal cortex of awake and freely moving animals; motor behavior will be measured concomitantly and the effects of acute doses of ethanol will also be determined. Lastly, the temporal relationship between ethanol consumption and neurotransmitter release in brain will be studied; in vivo microdialysis will be conducted concurrently with measurement of ethanol intake. An important goal will be to distinguish which neurochemical events precede or elicit ethanol intake and which neurochemical events are the result or consequence of ethanol intake; subsequent studies will examine how these relationships are altered by prenatal ethanol exposure. The results of the work proposed in this project should elucidate the determinants of alcohol intake, the mechanisms involved, and by doing so,, lead to the development of appropriate interventions that could be used to prevent and/or treat alcohol addiction.

DESCRIPTION: (Applicant's Abstract) The long-term goals of this research are an understanding of neurobehavioral mechanisms determining the addictive liabilities of drugs and the rational development of pharmacotherapies that will act on these mechanisms to reduce or eliminate addictive behavior. Recent research in this laboratory has focused on the neuropharmacology of iboga alkaloids (e.g., ibogaine) and congeners (e.g., 18-methoxycoronaridine) and their interactions with opioid and stimulant drugs of abuse. The methodology uses rats and involves measurement of intravenous drug self-administration and of drug effects on brain chemistry. In vivo microdialysis combined with HPLC (high performance liquid chromatography) is used to assay extracellular levels of biogenic amines (dopamine, serotonin) and their metabolites in discrete brain regions. Specific aims include the following: (1) The effects of ibogaine, its metabolite noribogaine and two iboga alkaloid congeners [18-methoxycoronaridine and 18-(N,N-dimethylaminoethyl)-coronaridine] on morphine and cocaine self-administration will continue to be investigated; it should be possible to develop agents that are at least as potent as ibogaine in suppressing drug self-administration but are much safer; iboga agents will be assessed on acquisition and on ongoing rates of drug self-administration behavior, in two models of relapse, and in a new oral model of nicotine preference. (2) Neurochemical mechanisms that might mediate putative anti-addictive effects of the same four iboga agents will be studied. In vivo microdialysis will be used to characterize the neurochemical actions of iboga agents and to define the receptor mechanisms mediating these effects; microdialysis will also be performed in rats self-administering morphine or cocaine in order to correlate neurochemical and behavioral effects of specific treatments. It is hypothesized that the unique pharmacology of these agents derives from a combination of actions at kappa opioid and NMDA receptors and at serotonin uptake sites. (3) Using GCMS (gas chromatography-mass spectrometry), the distribution and metabolism of the iboga agents will be studied. It is hypothesized that long-term effects of these agents are mediated by persistent low levels of the parent compounds and/or by active metabolites in discrete brain regions. This research may result in novel treatments for addictive disorders in humans.

This is a single year application to fund the Archer Conference on Drug Abuse: New Medications. The conference, named in honor of Sydney Archer, will focus on the development of new pharmacotherapies for drug abuse. The conference will run for two and one-half days, from September 29, 1999 to October 1, 1999, ending at approximately 12:00 p.m. on the third day. We are planning to hold speaker sessions that will focus on new approaches to treating abuse of stimulants, opioids, nicotine (smoking) and alcohol, and on the development of new analgesics. We anticipate limiting participation in the conference to approximately 100-120 people. The participants will consist of the speakers, scientists and graduate students from the northeast, several physicians and drug, counselors, and representatives from minority organizations, industry and NIDA. These individuals will be selected based upon the organizing committee's recommendations of those persons who will most directly benefit from participation in the conference.

DESCRIPTION (provided by applicant): Continuation of the currently funded predoctoral and postdoctoral training program in the pharmacology and neuroscience of drug abuse is proposed. This five-year program will consist of funding for 3 predoctoral and 3 postdoctoral trainees per year. The program has already completed training 2 predoctoral students, and two are currently supported by this grant. Four postdoctoral trainees have been supported by this grant so far; one received an individual NRSA after one year of training, one completed the planned two years of training, and two are currently in training. Faculty participation is comprised of a) 15 training faculty who serve as mentors and who are either currently funded by NIDA or whose research programs can provide training relevant to drug abuse issues, and b) 5 resource faculty who contribute to the program via teaching and laboratory training. Approximately 27,500 square feet of laboratory space, a wide array of state-of-the art chemical, physiological and behavioral testing equipment, and approximately $3.5 million (direct) of federally sponsored research funds are designated annually for the research of the training faculty. The program for predoctoral trainees consists of a comprehensive neuropharmacology/neuroscience didactic curriculum which includes a course on the biology of addiction as well as related topics (e.g., effects of prenatal drug exposure, treatment of addiction) integrated into broader-based courses. Predoctoral trainees must complete research projects in three laboratories prior to choosing a mentor and developing a thesis project. Both predoctoral and postdoctoral trainees are required to attend an annual seminar program consisting of presentations by 20 invited speakers and all trainees must present a one hour research seminar annually as well. All trainees also are required to participate in a journal club course designed to teach them how to present effectively written research for publication and how to critique published literature. Training in ethical conduct of research is required of all trainees. The current and proposed program provides a multifaceted approach to understanding mechanisms of drug abuse and treatment through an integrated program of didactic work and an outstanding in-depth research experience. It is designed to train participants to become independent, ethical and skilled scientists able to make significant contributions in drug abuse research. Predoctoral training is expected to last 4-5 years; postdoctoral training duration is 2-3 years. All aspects of the program are administered by the director and an executive committee of administrative and training faculty.

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop new and effective treatments for drug addiction. We recently discovered that several agents blocking cholinergic alpha3beta4 nicotinic receptors reduce morphine, methamphetamine and nicotine self-administration in rats. In the brain alpha3beta4 nicotinic receptors are preferentially localized in the medial habenula and interpeduncular nucleus. Since the 1980's it has been known that the habenulo-interpeduncular pathway functions as a reward system that is separate from the mesolimbic pathway. Although it has long been known that the habenulo-interpeduncular pathway and the mesolimbic pathway interact and probably modulate each other, few studies have explored how this occurs and how manipulations of one can affect the other. The goal of this proposal is to examine the role of cholinergic mechanisms in the habenulo-interpeduncular pathway as a potential substrate for new treatments. The central hypothesis is that blocking cholinergic transmission in the habenulo-interpeduncular pathway will attenuate drug self-administration. Research will be organized into three specific aims: (1) We will establish that habenulo-interpeduncular cholinergic transmission influences drug self-administration. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the intravenous self-administration of prototypicai drugs of abuse (morphine, methamphetamine, and nicotine). (2) We will establish that drugs of abuse enhance cholinergic transmission in the habenulo-interpeduncular pathway. Activation of the cholinergic habenulo-interpeduncular pathway may be an alternate or supplementary mechanism mediating or modulating the rewarding effects of drugs of abuse. Our working hypothesis is that drugs of abuse will raise extracellular levels of acetylcholine in the medial habenula and/or interpeduncular nucleus. (3) We will establish that the cholinergic habenulo-interpeduncular pathway modulates the dopaminergic mesolimbic pathway. Our working hypothesis is that nicotinic antagonists, locally administered into the medial habenula or interpeduncular nucleus, will attenuate the effects of abused drugs on extracellular levels of dopamine in the nucleus accumbens. The work proposed here may ultimately result in new kinds of treatments for drug abuse.