Guy Mittleman - US grants

APPLICANT'S ABSTRACT: Because drug abuse continues to be a major public health problem in the United States and throughout the world, it is important that research be performed to identify the factors that may predispose an individual to abuse drugs so that effective preventative or protective strategies can be developed. It is recognized that both animals and humans display striking individual differences in their addictive liability. In order to understand the factors that influence vulnerability to addiction it is necessary to develop animal models that relate biological as well as behavioral characteristics to this phenomenon. Although traditional approaches have expanded our knowledge about the addictive properties of drugs, these studies have, by their very nature, precluded the investigation of vulnerability to addiction. The proposed research is aimed at identifying neurochemical and behavioral components that are related to an individual's propensity to self-administer drugs of abuse. Specifically, three series of experiments are proposed. Because an individual's locomotor response to novelty is predictive of high rates of drug self-administration in rats (Piazza et al., 1989), experiments in Series 1 will examine this relationship using a novel self-administration choice paradigm and in vivo neurochemical measurement techniques to provide information about individual differences in the acquisition of self-administration during exposure to a range of doses of abused drugs. Experiments in Series 2 will address the generality of individual differences in predisposition toward self-administration and specifically investigate whether differences in addictive liability are simply one facet of a more general behavioral profile. These experiments will relate an animal's performance on a serial reversal task, and a sustained attention task to a subject's sensitivity to drug-self-administration. The experiments in Series 3 are aimed at investigating prenatal factors which alter dopamine receptor populations and their subsequent effects on drug self-administration. Thus, subjects will be exposed in utero to haloperidol and nicotine, and tested for their sensitivity to self-administer drugs in adulthood.

DESCRIPTION (provided by applicant): This exploratory grant application represents the effort of a researcher that is new to the ethanol field. The 3 proposed experiments provide an opportunity to explore in mice, excessive ethanol consumption elicited in the schedule-induced polydipsia (SIP) paradigm. As the SIP paradigm has rarely been used to elicit excessive ethanol drinking in mice, experiment I will provide task validation by systematically testing male mice from the BxD, RI strains along with their parental strains. Once excessive ethanol consumption develops in some of these BXD RJ strains, additional ethanol concentrations will be tested in order to establish dose response relationships in these mice. Variability in the amount of ethanol drinking in the BxD RI lines will permit an initial QTL analysis of potential genetic loci involved in this behavior. Experiment 2 will use mice obtained from an NIH supported neuromutagenesis program (UOI: Targeted Mutagenesis of the Mouse Genome and Neural Phenotypes). In this experiment, mutant pedigrees that respond extremely in the ethanol 2-bottle choice test will be rebred and then tested in the SIP ethanol paradigm. Results of this experiment will provide convergent evidence of genetic loci associated with susceptibility to excessive ethanol drinking. In experiment 3, microarray technology will be used to more precisely identify candidate genes whose expression is correlated with excessive, voluntary ethanol drinking in the SIP paradigm. The specific aims are: (1) to establish the SIP paradigm as a reasonable way of inducing consistent and excessive ethanol consumption in mice and (2) to characterize using QTL, mutant mice and microarray analyses the genetic differences correlated with excessive and heritable ethanol drinking in this paradigm.

DESCRIPTION (provided by applicant): The developmental loss of cerebellar Purkinje cells that occurs in autism spectrum disorders has been associated with a heterogeneous pattern of cognitive deficits that cannot be explained by a unitary cognitive impairment. It is very unlikely that the simple loss of cerebellar Purkinje cells can directly account for these myriad cognitive deficits. Rather, it is likely that autism is, at its essence, a disconnection syndrome that results, at least in part, from a disruption of cerebellar modulation of the prefrontal cortex (PFC). We have exciting new data suggesting that the cerebellum modulates PFC dopamine levels. Here we propose to investigate the disconnection hypothesis that cerebellar pathology results in dopaminergic abnormalities in the prefrontal cortex (PFC) and underlies some of the core neuropsychiatric symptomatology of autism. In Aim 1 we will determine the pathway(s) whereby the cerebellum modulates dopamine release in the PFC and glutamate release in subnuclei comprising the cerebellum to PFC pathways and the neurochemical, electrophysiological, anatomical, and behavioral consequences of a disconnection between these two structures. Aim 1 will compare wildtype (control) and Lurcher mice that loose all Purkinje cells, to determine the consequences of complete loss of Purkinje cells on cerebellar-PFC communication. Aim 2 will investigate the behavioral and physiological consequences of partial loss of Purkinje cells - as typically found in autistic brains. Using Lurcher-wildtype chimeras with varying developmental loss in Purkinje cell numbers we will determine how neurochemical, electrophysiological, anatomical and behavioral indicators of PFC function depend on Purkinje cell number. Given the well documented reductions in cerebellar neuron number that are found in autism spectrum disorders, the neurochemical, electrophysiological, anatomical and behavioral analyses of chimeric mice presents a unique opportunity to model both the developmental and cerebellar aspects of these syndromes. PUBLIC HEALTH RELEVANCE Cerebellar and frontal cortical pathologies have been commonly reported in autism and other developmental disorders. The relationship between these two abnormalities is unknown. This proposal presents a framework for understanding how these seemingly disparate pathologies are related, and provides a unique opportunity for discovery of the neurochemical, electrophysiological and anatomical mechanisms whereby the cerebellum may modulate frontal cortical function, with particular focus on dopamine and Purkinje cell numbers. As the details of the functional interactions and adaptations within this neural circuitry become known, these neural substrates and associated receptor mechanisms should become new candidates for treatment of the cognitive deficits related to autism.