Benjamin S. Bunney - US grants

The therapeutic and neurological side effects of antipsychotic drugs (ADs) are believed to be due, at least in part, to an action on central dopaminergic (DA) systems. Previously we have found, using electrophysiological techniques, that many ADs increase the activity of DA neurons, activate a subpopulation of quiescent DA neurons and when given repeatedly produce, in most DA neurons, a state of depolarization inactivation. How do the ADs produce these effects and what is the consequence of these effects for the functioning of DA neurons and the systems that they innervate? The studies proposed are devoted to increasing our understanding of normal central DA system functioning and the mechanisms underlying the way that ADs change that functioning. To accomplish this task we propose to integrate three new techniques (intra- and extracellular recording from an in vitro midbrain slice preparation, voltametric measurements of DA release in both anesthetized and freely moving animals, and single unit recording from DA cells in freely moving animals) with those already ongoing in our laboratory. Combined, these should enable us to study the DA system and the effects of Ads upon it from a membrane level to behavior. In both the slice and freely moving animal preparation DA cells with first be identified and characterized and then studied in terms of the effects of ADs upon them. In the voltammetric studies basal DA release will be carefully studied in states of both activity and inactivity and during changes in the mode of firing of DA neurons (i.e., single spiking to bursting pattern). The effects of acute and chronic AD administration on AD release will be examined concomitantly. In other studies DA sensitive postsynaptic neurons in the prefrontal and piriform cortices will be identified and characterized. The effects of AD treatment upon their activity will then be determined. Finally, follow-up studies concerning the effects of repeated AD administration on DA cell function in the anesthetized or paralyzed animal will be carried out. It is hoped that these multiple approaches to studying the effect of ADs on central DA neurons will lead to a better understanding of their mechanism of action and ultimately to a rational approach for the development of ADs with fewer side effects.

The euphoric properties of psychomotor stimulants impart a powerful reinforcing action to these agents which may underly their strong potential for abuse in humans. The rewarding properties of CNS stimulants in general and cocaine in particular appear to be due, in part, to their ability to increase neurotransmission at dopaminergic (DA) synapses. Much of what is currently known about the mechanism of action of cocaine on DA transmission is derived from pharmacological studies evaluating cocaine's actions on DA systems not directly involved in the process of stimulant self administration. Since it is now appreciated that midbrain DA systems are not homogenous and possess a number of different biochemical, physiological and pharmacological properties, the relevance of prior studies investigating the interaction of cocaine with DA systems to the larger issue of cocaine abuse is unclear. The proposed project involves a combined electrophysiological and biochemical approach to evaluate the effects of cocaine on mesotelencephalic DA neurons in rodents. In the first group of experiments, extracellular single unit recording and microiontophoretic techniques will be used to determine whether antidromically identified DA neurons differ in their response to locally or parenterally administered cocaine. Biochemical studies will be conducted in parallel to assess alterations in DA metabolism in and release from selected mesotelencephalic systems. Findings will be correlated with alterations in neuronal firing evaluated by single cell recording. In a second group of experiments, biochemical and electrophysiological techniques will be employed to study the effects of cocaine on DA target neurons in regions thought to participate in stimulant self-administration (e.g. nucleus accumbens, prefrontal cortex) and compared with the non-rewarding DA projections to the DA receptive neurons in striatum. In both groups of experiments, comparisons will be made between cocaine and other drugs exhibiting similar pharmacological properties but differing in their ability to sustain self-administration. If cocaine is observed to elicit significant and selective effects on the functioning of certain DA systems or postsynaptic follower neurons, attempts will be made to prevent or reverse these electrophysiological and neurochemical effects pharmacologically. By more clearly understanding the pharmacological actions of cocaine on specific DA neurons and their follower cells, we may gain further insight into the neural mechanisms underlying cocaine's reinforcing properties and identify strategies for reversing or preventing these actions.

The therapeutic and neurological side effects of antipsychotic drugs (ADs) are believed to be due, at least in part, to an action on central dopaminergic (DA) systems. Previously we have found, using electrophysiological techniques, that many ADs increase the activity of DA neurons, activate a subpopulation of quiescent DA neurons and when given repeatedly produce, in most DA neurons, a state of depolarization inactivation. How do the ADs produce these effects and what is the consequence of these effects for the functioning of DA neurons and the systems that they innervate? The studies proposed are devoted to increasing our understanding of normal central DA system functioning and the mechanisms underlying the way that ADs change that functioning. To accomplish this task we propose to integrate three new techniques (intra- and extracellular recording from an in vitro midbrain slice preparation, voltametric measurements of DA release in both anesthetized and freely moving animals, and single unit recording from DA cells in freely moving animals) with those already ongoing in our laboratory. Combined, these should enable us to study the DA system and the effects of Ads upon it from a membrane level to behavior. In both the slice and freely moving animal preparation DA cells with first be identified and characterized and then studied in terms of the effects of ADs upon them. In the voltammetric studies basal DA release will be carefully studied in states of both activity and inactivity and during changes in the mode of firing of DA neurons (i.e., single spiking to bursting pattern). The effects of acute and chronic AD administration on AD release will be examined concomitantly. In other studies DA sensitive postsynaptic neurons in the prefrontal and piriform cortices will be identified and characterized. The effects of AD treatment upon their activity will then be determined. Finally, follow-up studies concerning the effects of repeated AD administration on DA cell function in the anesthetized or paralyzed animal will be carried out. It is hoped that these multiple approaches to studying the effect of ADs on central DA neurons will lead to a better understanding of their mechanism of action and ultimately to a rational approach for the development of ADs with fewer side effects.

The therapeutic and neurological side effects of antipsychotic drugs (ADs) are believed to be due, at least in part, to an action on central dopaminergic (DA) systems. Previously we have found, using electrophysiological techniques, that many ADs increase the activity of DA neurons, activate a subpopulation of quiescent DA neurons and when given repeatedly produce, in most DA neurons, a state of depolarization inactivation. How do the ADs produce these effects and what is the consequence of these effects for the functioning of DA neurons and the systems that they innervate? The studies proposed are devoted to increasing our understanding of normal central DA system functioning and the mechanisms underlying the way that ADs change that functioning. To accomplish this task we propose to integrate three new techniques (intra- and extracellular recording from an in vitro midbrain slice preparation, voltametric measurements of DA release in both anesthetized and freely moving animals, and single unit recording from DA cells in freely moving animals) with those already ongoing in our laboratory. Combined, these should enable us to study the DA system and the effects of Ads upon it from a membrane level to behavior. In both the slice and freely moving animal preparation DA cells with first be identified and characterized and then studied in terms of the effects of ADs upon them. In the voltammetric studies basal DA release will be carefully studied in states of both activity and inactivity and during changes in the mode of firing of DA neurons (i.e., single spiking to bursting pattern). The effects of acute and chronic AD administration on AD release will be examined concomitantly. In other studies DA sensitive postsynaptic neurons in the prefrontal and piriform cortices will be identified and characterized. The effects of AD treatment upon their activity will then be determined. Finally, follow-up studies concerning the effects of repeated AD administration on DA cell function in the anesthetized or paralyzed animal will be carried out. It is hoped that these multiple approaches to studying the effect of ADs on central DA neurons will lead to a better understanding of their mechanism of action and ultimately to a rational approach for the development of ADs with fewer side effects.

The therapeutic and neurological side effects of antipsychotic drugs (ADs) are believed to be due, at least in part, to an action on central dopaminergic (DA) systems. Previously we have found, using electrophysiological techniques, that many ADs increase the activity of DA neurons, activate a subpopulation of quiescent DA neurons and when given repeatedly produce, in most DA neurons, a state of depolarization inactivation. How do the ADs produce these effects and what is the consequence of these effects for the functioning of DA neurons and the systems that they innervate? The studies proposed are devoted to increasing our understanding of normal central DA system functioning and the mechanisms underlying the way that ADs change that functioning. To accomplish this task we propose to integrate three new techniques (intra- and extracellular recording from an in vitro midbrain slice preparation, voltametric measurements of DA release in both anesthetized and freely moving animals, and single unit recording from DA cells in freely moving animals) with those already ongoing in our laboratory. Combined, these should enable us to study the DA system and the effects of Ads upon it from a membrane level to behavior. In both the slice and freely moving animal preparation DA cells with first be identified and characterized and then studied in terms of the effects of ADs upon them. In the voltammetric studies basal DA release will be carefully studied in states of both activity and inactivity and during changes in the mode of firing of DA neurons (i.e., single spiking to bursting pattern). The effects of acute and chronic AD administration on AD release will be examined concomitantly. In other studies DA sensitive postsynaptic neurons in the prefrontal and piriform cortices will be identified and characterized. The effects of AD treatment upon their activity will then be determined. Finally, follow-up studies concerning the effects of repeated AD administration on DA cell function in the anesthetized or paralyzed animal will be carried out. It is hoped that these multiple approaches to studying the effect of ADs on central DA neurons will lead to a better understanding of their mechanism of action and ultimately to a rational approach for the development of ADs with fewer side effects.

[unreadable] DESCRIPTION (provided by applicant): Declines in the numbers of physicians pursuing careers in clinical research have raised national concerns about an impending crisis in public health care. While numerous medical fields are affected, the problem in psychiatry is particularly acute, with projected shortages prompting a recent analysis of the problem by the Institute of Medicine. Ironically, shortages of psychiatrists pursing patient-oriented research careers occur at a time when discoveries in the fields of genetics and neuroscience are having an unprecedented impact on the basic behavioral sciences. Translating such basic science insights into discoveries in the patient-care realm will be crucial for improving our understanding and treatment of severe mental illness. The current R25 application is intended to address the current crisis in mental health research education through several specific aims, including 1) to provide a program of Intensive Mentored Patient-Oriented Research Training (IMPORT) for physicians at their earliest, formative stages of clinical residency training (PGY I & II), 2) to build upon this early exposure through continued longitudinal research training in later residency years (PGY III & IV), 3) to facilitate connections of program trainees to post-residency (PGY V) research training fellowship opportunities, and 4) to refine and optimize these experiences so as to provide a national model for training psychiatry residents across the country in patient-oriented research. Funding from the R25, in conjunction with institutional resources at Yale, will allow a total of up to 4 psychiatric residents per year to receive such specialized longitudinal research training experiences. If successful, the program will benefit the country directly, through the increased identification, recruitment and retention of a highly skilled cadre of young clinical psychiatric investigators, and indirectly, as a template for other residency training programs across the country. [unreadable] [unreadable] [unreadable]