David Wirtshafter, Ph.D. - US grants

Considerable evidence indicates that the median raphe nucleus (MR), located in the paramedian tegmentum of the midbrain, plays an important role in the control of behavior. This nucleus is one of the major sources of forebrain serotonin, but contains many nonserotonergic cells as well. Lesions of the MR in rats result in dramatic disturbances in locomotor activity, learning and ingestive behavior, many of which appear unrelated to serotonin depletion. Recently, it has been found that injections of the GABA agonist muscimol into the MR of behaving rats leads to hyperactivity and a large increase in food intake. The experiments proposed here are designed to investigate the functional role of GABA and several other neurotransmitters, including endogenous opiates, within the MR. The effects of acute intra-MR drug injections will be examined on a number of behaviors including locomotor activity, feeding, drinking, and gnawing and the possibility of serotonergic mediation of these effects will be examined. The effects of intra-MR injections of the metabolism of serotonin, dopamine and GABA will be investigated biochemically. Experiments will be conducted aimed at identifying the output pathways from the MR involved in the production of behavioral effects following muscimol injections. Anatomical studies will attempt to identify the projection targets of non-serotonergic MR cells, and the origin of GABAergic and other chemically defined projections to the MR. Serotonin has been implicated in a number of psychiatric and neurologic disorders and degenerative changes have been observed in the MR of patients with Alzheimer's disease. The current studies may thus provide information useful in understanding the nature of the functional disturbances in these disorders.

Considerable evidence indicates that the median raphe nucleus (MR), located in the paramedian tegmentum of the midbrain, plays an important role in the control of behavior. This nucleus is one of the major sources of forebrain serotonin, but contains many nonserotonergic cells as well. Lesions of the MR in rats result in dramatic disturbances in locomotor activity, learning and ingestive behavior, many of which appear unrelated to serotonin depletion. Recently, it has been found that injections of the GABA agonist muscimol into the MR of behaving rats leads to hyperactivity and a large increase in food intake. The experiments proposed here are designed to investigate the functional role of GABA and several other neurotransmitters, including endogenous opiates, within the MR. The effects of acute intra-MR drug injections will be examined on a number of behaviors including locomotor activity, feeding, drinking, and gnawing and the possibility of serotonergic mediation of these effects will be examined. The effects of intra-MR injections of the metabolism of serotonin, dopamine and GABA will be investigated biochemically. Experiments will be conducted aimed at identifying the output pathways from the MR involved in the production of behavioral effects following muscimol injections. Anatomical studies will attempt to identify the projection targets of non-serotonergic MR cells, and the origin of GABAergic and other chemically defined projections to the MR. Serotonin has been implicated in a number of psychiatric and neurologic disorders and degenerative changes have been observed in the MR of patients with Alzheimer's disease. The current studies may thus provide information useful in understanding the nature of the functional disturbances in these disorders.

The long term objective of the current proposal is the attainment of a greater understanding of the functional organization of the basal ganglia. Substantial evidence suggests that many neurological and psychiatric disorders, including Parkinson's disease, Huntington's Disease, Sydenham's chorea, torsion distoma, Tourette's syndrome and schizophrenia, may result from abnormal basal ganglia functioning and progress in understanding the etiology of these disorders, and in developing treatment for them, is largely dependent on advances in understanding the basic mechanisms of basal ganglia function. The proposed experiments are designed to examine basal ganglia organization using the immunocytochemical detection of the transcription factor Fos as a marker for neurons affected by various behavioral or pharmacological manipulations. The first group of experiments will study the influence of D2 dopamine receptors and muscarinic acetylcholine receptors on the induction of Fos like immunoreactivity (FLI) produced by administration of the selective, full, D1 dopamine agonist A77636 in intact animals. The possibility that D2 receptor stimulation is necessary for A77636 to elicit striatal Fos expression will be studied by examining the effect of a selective D2 antagonist of A77636-induced FLI in anatomically identified striatonigral cells. The alterations in A77636-induced FLI produced by coadministration of a selective D2 agonist will then be studied. Statistical techniques will be used to examine changes in the pattering of FLI produced by the D2 agonist and the relative effects of this compound in the striosomal and matrix compartments of the striatum will be accessed. Similar methods will be used to examine the potentiation of A77636-induced striatal FLI produced by the muscarinic antagonist scopolamine. The possibility that coadministration of a D1 and a D2 agonist, or of a D1 agonist and a cholinergic antagonist, will produce interactive effects of Fos expression in several basal ganglia output structures will also be examined. Since certain behaviors are associated with striatal dopamine release, the second group of experiments will examine the extent to which the striatal Fos expression induced by one of these behaviors, mating in male rats, resembles that produced by administration of dopamine agonists. These studies will examine the statistical patterning the regional and compartmental distribution of sex-induced striatal FLI, and the anatomical connections of the labeled cells. The next group of studies will examine the internal circuitry of the basal ganglia. Some experiments will examine the distribution of extrastriatal FLI induced by injections of the GABA agonist muscimol into the globus pallidus, the entopeduncular nucleus of the pars reticulate of the substantia nigra, while other experiments will examine the effects of lesions of the subthalamic nucleus, or systemic administration of an excitatory amino acid antagonist, on neuroleptic- induced FLI in the substantia nigra and entopeduncular nucleus. The final group of studies will attempt to characterize the circuity activated by stimulation or blockade of dopamine receptors by using retrograde tracing in combination with Fos immunocytochemistry to study the connections of immunoreactive cells in the nigra and entopeduncular nucleus following neuroleptic treatment, or in the "midbrain extrapyramidal region" following amphetamine treatment.

DESCRIPTION: (from Abstract) The long term objective of the current proposal is the attainment of a greater understanding of the functional organization of the basal ganglia. Substantial evidence suggests that many neurological and psychiatric disorders, including Parkinson's disease, Huntington's disease, Sydenham's chorea, torsion dystonia, Tourette's syndrome and schizophrenia, may result from abnormalities in the activity of these nuclei. Progress in understanding the etiology of these disorders, and in developing treatments for them, is largely dependent on advances in understanding the basic nature of basal ganglia functioning. The proposed experiments are designed to examine basal ganglia by using the immunocytochemical detection of immediate early genes (IEGs) as markers for neurons affected by various behavioral or pharmacological manipulations. The striatum is the largest nucleus within the basal ganglia and is the primary terminus of input into this system. The first set of studies will examine the pharmacological and behavioral control of IEG expression within this structure with emphasis on the patterning of IEG expression with respect to the striosome/matrix compartmentation of the striatum. The striatum contains a number of neuroactive compounds including dopamine, serotonin, adenosine, acetylcholine and substance P and the role played by these substances in controlling striatal IEG expression will be examined. The applicants will also examine the role of dopamine in IEG expression induced by shuttling behavior and characterize the cells that express IEGs under these conditions. Events occurring within the striatum can only influence behavior by affecting the activity of neurons within other parts of the brain. The second group of studies will therefore use IEG expression as a tool to investigate the basic organization of extrastriatal circuitry related to the basal ganglia. Experiments will examine the ability drugs microinjected directly into the striatum, or other basal ganglia nuclei, to influence IEG expression at extrastriatal sites. Other studies will examine the effects of lesions within the basal ganglia on the IEG expression induced by systemic administration of dopaminergic drugs.

[unreadable] DESCRIPTION (provided by applicant): A large body of evidence indicates that cells in the lateral hypothalamus (LH) and dopamine cells in the ventral midbrain both play an important role in the control of food and water intake. Damage to either of these systems, in fact, results in remarkably similar sets of deficits in both food and water intake. Although these similarities could be coincidental, it seems more likely that they reflect a functional interaction between these two groups of cells. Anatomical data suggest a number of ways in which the hypothalamus and tegmental dopamine cells could be interconnected, and a number of workers have speculated on the presence of various relationships, but the available functional data are extremely limited. We here propose five sets of experiments aimed at investigating the relation between the LH and ascending dopamine systems with respect to the control of ingestive behavior. The first study will attempt to provide direct evidence for a functional relation between the LH and the ascending dopamine system by comparing the effects on feeding and drinking produced by combined unilateral excitotoxic lesions of the LH and .unilateral 6-OHDA lesions of the dopamine cell bodies made on either the same, or the opposite sides of the brain. If the LH and the dopamine cells form parts of a functionally interconnected circuit, one would expect that larger effects would be produced with "crossed" lesions, than when the lesions were made on the same side of the brain. The remaining experiments examine various possible mechanisms which might underlie LH/dopamine interactions. Experiment 2 examines whether chemical stimulation of cells in the LH is able to alter dopamine release, as measured by in vivo microdialysis, in the nucleus accumbens or the dorsal striatum, the main termini of dopamine projections arising in the ventral tegmental area (VTA) and substantia nigra (SN) respectively. Experiment 3 examines whether injections of 2-deoxyglucose a treatment which induces feeding is able to promote expression of the immediate-early gene c-fos in LH cells projecting to the VTA or SN. Experiment 4 examines whether unilateral 6-OHDA lesions alter the ability of cells in the LH to respond to injections of 2-deoxyglucose. The final .experiment examines whether excitotoxic lesions of the LH are able to attenuate the ability of low doses of amphetamine to induce feeding behavior. Relevance: These studies should help to clarify the neural mechanisms controlling ingestive behavior and the way in which these circuits may be influenced by certain drugs of abuse. Gaining an understanding of these systems is a prerequisite for the rational development of novel treatments for disturbances of ingestion, such as occur in obesity, bulemia and cahchexia. [unreadable] [unreadable] [unreadable]