Area:
Addiction, Cocaine, Behavioral Sensitization, Neurochemistry
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According to our matching algorithm, Jeffery Dennis Steketee is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2001 — 2004 |
Steketee, Jeffery D |
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. |
Medial Prefrontal Cortex and Cocaine Sensitization @ University of Tennessee Health Sci Ctr
Behavioral sensitization, the enhanced motor-stimulant response that occurs with repeated, intermittent exposure to cocaine, has been proposed to play a role in drug craving and relapse. An increased understanding of the mechanisms involved in the development of sensitization may lead to improved pharmacotherapies for drug addiction. It has been suggested that cocaine-induced changes in the ventral tegmental area (VIA) and nucleus accumbens are involved in the initiation and expression of sensitization, respectively. However, recent studies do not entirely support this hypothesis. Thus, the present proposal will test the hypothesis that sensitization results from a decrease in dopamine-mediated glutamate transmission from the medial prefrontal cortex (mPFC). We have reported that depletion of dopamine in the mPFC by 6-hydroxydopamine lesions enhances the motor-stimulant response to cocaine. Follow up studies will determine whether these lesions also enhance glutamate transmission in the mPFC and dopamine and glutamate transmission in regions innervated by the mPFC such as the VTA and nucleus accumbens. A second set of studies will determine whether sensitization to cocaine is associated with changes in dopamine and glutamate transmission in the mPFC using in vivo microdialysis. The temporal relation of neurochemical changes in the mPFC, compared with those previously shown in the nucleus accumbens, will also be assessed. The role of mPFC dopamine in the development of sensitization will be further examined by determining the effects of site specific injections of dopamine receptor agonists or antagonists into the mPFC on behavioral and neurochemical responses to cocaine. Preliminary data suggest that sensitization to cocaine may result from a decrease in dopamine receptor function in the mPFC. To determine this, the effects of repeated cocaine exposure on dopamine receptor regulation of adenylyl cyclase activity in the mPFC will be examined. Results of these studies should provide a better understanding of the role the mPFC plays in the development of sensitization to cocaine.
|
0.924 |
2002 — 2004 |
Steketee, Jeffery D |
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. |
Toluene as a Gateway Drug: Role of Dopamine Systems @ University of Tennessee Health Sci Ctr
[unreadable] DESCRIPTION (provided by applicant): Inhalants are a classified as central nervous system depressants that are used, and abused, for their euphoria-inducing effects, especially by adolescents. The long-term consequences ensuing from the abuse of inhalants, including toluene have received relatively little attention in the drug abuse field. One potential concern with inhalant use is the possibility of these compounds serving as a "gateway" to the abuse of other drugs. In this regard, we recently demonstrated that animals that received repeated exposure to toluene showed an enhanced motor-stimulant response to subsequent acute cocaine treatment. This sensitized behavioral response to cocaine was paralleled by an enhancement of the cocaine-induced increase in dopamine overflow in the nucleus accumbens. These data support the hypothesis that inhalants can serve as a gateway to the use and abuse of psychostimulants. The present proposal will further examine this hypothesis. Initial studies will characterize the effects of acute and repeated toluene exposure on the mesocorticolimbic dopamine system, which has been reported to play a role in drug abuse. Additional studies will further characterize the effects of repeated toluene exposure on the development of behavioral and neurochemical cross-sensitization to cocaine. A third set of studies will then determine whether repeated toluene exposure influences the acquisition of cocaine self-administration. It is hypothesized that repeated exposure to toluene alters dopamine transmission in the animal's mesocorticolimbic dopamine system in a manner similar to repeated cocaine, thereby making them more susceptible to the reinforcing properties of cocaine. The results from these studies should provide further information on the long-term consequences of inhalant use. Future studies will examine the mechanisms by which repeated toluene exposure alters mesocorticolimbic dopamine transmission. [unreadable] [unreadable]
|
0.924 |
2008 — 2012 |
Steketee, Jeffery D |
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. |
Cortical Mechanisms of Cocaine Sensitization @ University of Tennessee Health Sci Ctr
DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) functions in an executive role to, in part, oversee activity within limbic reward regions, including the nucleus accumbens and ventral tegmental area (VTA). Research suggests that the use of drugs of abuse can produce a dysfunctional PFC leading to increased impulsivity, and thereby drug craving, which can then act as a switch from casual to compulsive drug use. Behavioral sensitization, which can serve as a model for drug-induced neuroplasticity, is the enhanced motor-stimulant response that occurs with repeated exposure to psychostimulants, such as cocaine. Previous studies have suggested that the ventromedial PFC (vmPFC) plays an important role in the development of sensitization. Specifically, recent studies demonstrated that repeated exposure to cocaine produces a transient attenuation in cocaine-induced dopamine release and a concomitant augmentation in glutamate release in the vmPFC. Furthermore, dopamine D2 receptor (D2R) function appears to be decreased in cocaine sensitized animals. These data support the hypothesis that sensitization is associated with changes in inhibitory and excitatory modulation of vmPFC pyramidal neurons that leads to an increase in excitatory transmission to the nucleus accumbens and ventral tegmental area; regions previously linked to sensitization. The present proposal will continue to study this hypothesis. Thus, Aim 1 will determine whether the apparent reduction in dopamine D2R function seen in sensitized animals is associated with a reduction in the ability of intra-vmPFC infusion of the D2 agonist quinpirole to reduce mesocorticolimbic glutamate transmission and mesoaccumbens dopamine transmission using in vivo microdialysis. Aim 2 will explore the involvement of Group I and Group II metabotropic glutamate receptors (mGluR) in sensitization. Studies in this aim will include intra-vmPFC injection of agonists or antagonists to mGluRs to determine their involvement in the initiation and expression of sensitization. Follow- up studies will determine whether the ability of the mGluRs to modulate mesocorticolimbic glutamate transmission and mesoaccumbens dopamine transmission is altered in sensitized animals. Aim 3 will determine whether repeated cocaine exposure influences the release of vesicular versus non-vesicular pools of glutamate in the vmPFC. Additional studies will determine whether D2R or mGluR regulation of glutamate release from vesicular and/or non-vesicular sources is altered in sensitized animals. Taken as a whole, the proposed studies should better define the mechanisms by which repeated cocaine alters vmPFC function, thereby leading to enhanced glutamate transmission in the VTA and nucleus accumbens that is associated with behavioral sensitization. Increased knowledge of drug-induced neuroplasticity in the vmPFC should lead to a better understanding of the mechanisms that underlie the switch from casual to compulsive drug use. Cocaine-induced behavioral sensitization has been proposed to be a useful model for drug-induced neuroplasticity. Understanding cocaine-induced neuroplasticity in the medial prefrontal cortex could help explain the mechanisms responsible for the switch from casual to compulsive drug use. Thus, the proposed studies are relevant in that an increased understanding of the mechanisms of sensitization might lead to improved treatment strategies for cocaine addiction.
|
0.924 |