| 2005 — 2006 |
Wellman, Paul Jefferson |
R21Activity Code Description:
To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Psychostimulants and Alpha-1 Adrenoceptor Subtypes @ Texas a&M University System
DESCRIPTION (provided by applicant): Psychostimulant-induced changes in locomotion involve activation of the 1B subtype of the a 1 -adrenoceptor (a 1B-AR). A key gap in our knowledge base is the functional characterization of the a 1A-AR subtype for the behavioral actions of cocaine and other psychostimulants. This R21 application seeks to characterize the involvement of brain alpha1 -AR subtypes in the behavioral actions of cocaine and amphetamine in rats using a novel apparatus/procedure to concurrently assess feeding and locomotion. Adult male rats will receive systemic injections of cocaine hydrochloride (0, 2.5, 5.0,10.0, and 20.0 mg/kg, IP) or D-amphetamine sulfate (0, 0.25, 0.5,1.0, and 2.0 mg/kg, IP) five minutes after bilateral ICV injections (0, 3 or 30 nMol/rat) of either an alpha1A antagonist [5-methyl-urapadil] or an alpha1B antagonist [L-765,314]. Aim 1 will characterize the effects of systemic cocaine (Exp 1) or amphetamine (Exp 2) on eating and locomotion in rats pretreated (ICV) with either vehicle, 5-methyl-urapadil or L-765,314. Activation of alpha1-ARs within the hypothalamic paraventricular nucleus (PVN) evokes hypophagia. Aim 2 will characterize the role(s) of PVN alpha1-AR subtypes in cocaine-induced changes in feeding and locomotion. Dose-effect curves for changes in hypophagia and locomotion will be compared in rats receiving bilateral intra-PVN infusions of vehicle or 5-methyl-urapadil or L-765,314 (1 or 3 nMol/rat) followed by systemic doses of either cocaine (Exp 3), amphetamine (Exp 4). Insofar as dopamine neurons within the mesolimbic system modulate locomotion and are modulated by .1-ARs, the focus of Aim 3 is to characterize the differential involvement of alpha1 -AR subtypes within the core and shell regions of the nucleus accumbens (NAcc) for the hypophagic and locomotor actions of psychostimulants. In Experiments 5 and 6, systemic injections of cocaine or amphetamine will be preceded by bilateral injections of vehicle or of 5-methyl-urapadil or L-765,314 (1 or 3 nMol/rat) into one of three NAcc regions (rostral shell, caudal shell or core). These studies will advance our understanding of the behavioral functions of brain a l-AR subtypes and may lead to the identification of new drugs that inhibit eating without activating brain reinforcement systems.
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| 2007 — 2010 |
Wellman, Paul Jefferson |
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. |
Heavy Metal and Drug Self-Administration: Mechanisms @ Texas a&M University System
[unreadable] DESCRIPTION (provided by applicant): The scientific community is increasingly aware that environmental toxicants interact with psychoactive drugs, and affect drug selection and use. Of particular concern are the effects of metals such as lead that shift patterns of drug self-administration, and occasion synergistic as well as antagonistic effects on illicit drugs such as cocaine. It is established at a phenomenological level that patterns of drug intake and behavioral responsiveness to commonly abused drugs may be influenced by metal exposure. And this is especially true for developmental exposure to lead, where the effects are long-lasting and persist into the adult life cycle long after the exposure regimen has been discontinued. Of particular interest to this renewal application is the finding that when lead is redistributed from the dams to the pups during gestation and lactation (perinatal exposure), cocaine self-administration is maintained at drug doses too low to sustain responding among nonexposed controls. Moreover, relapse to drug seeking is more likely in animals perinatally exposed to lead. What is not understood is the mechanism of action for increased selection and use of cocaine in lead-exposed animals. In this application it is proposed that the issue of lead/cocaine interactions be explored in male and female animals employing three approaches; 1) examine the effects of perinatal lead exposure on the levels of key neurotranmitters involved in cocaine reward [dopamine (DA) and glutamate (Glu) within the nucleus accumben (NAc)] using microdialysis techniques within a framework of drug challenges, 2) using standard radiobinding assays, binding of DA and Glu in the NAc and prefrontal cortex (RFC) will be examined for animals developmentally exposed to lead, 3) and, employing in situ hybridization techniques, animals will be processed for DA D1-like, DA D2-like, and DA transporter (DAT) mRNA espression. Similarly, Glu receptor expression will be assessed in lead-exposed animals. These endpoints will be examined in animals that have received response contingent cocaine, noncontingent saline, or , noncontingent cocaine i.v. deliveries. The relevance of this proposal to public health is that it aims to link two major events that pose significant health risks, i.e., lead contamination and cocaine use. Based on the available literature, there is reason to believe that environmental pollutants may increase vulnerability to drug addiction. [unreadable] [unreadable] [unreadable]
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