1986 |
Peris, Joanna |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Inhibitory Neuromodulation and Anxiety @ University of Colorado Denver |
0.957 |
1989 — 1994 |
Peris, Joanna |
K02Activity Code Description: Undocumented code - click on the grant title for more information. 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. |
Nigrotectal Gaba Neurons in Alcohol and Kindled Seizures
The GABAergic striatonigral and nigrotectal pathways appear to play a major role in the control of seizure activity. It is possible that similar changes in inhibitory GABAergic transmission in these pathways occur with different proconvulsant treatments such as kindling or ethanol withdrawal. However, the pattern of changes that occur in pre- or postsynaptic GABA function may be complex because the inhibitory GABAergic circuits are connected in series from striatum to substantia nigra (SN) to superior colliculus (SC) and possibly beyond. GABAergic transmission in the inferior colliculus (IC) has been shown to decrease in animals susceptible to audiogenic seizures, however it is not clear whether these changes are the basis for the seizure susceptibility or are caused by seizure activity transmitted through the auditory pathways including IC. This proposal will measure changes in GABAergic transmission, including GABA release, GABA, receptor binding and GABA, receptor-mediated Cl- flux, in the terminal regions of the striatonigral and nigotectal pathways and in the inferior colliculus in three proconvulsant models that have opposite initial effects on GABAA receptor function. The first model of increased seizure susceptibility will use rats chemically kindled with the benzodiazepine inverse agonist, FG7142, which suppresses withdrawn rats with increased susceptibility receptor function. The second model will use alcohol-withdrawn rats with increased susceptibility to handling-induced seizures. Ethanol enhances GABAA receptor function. The third model will use rats kindled via repeated electrical stimulation of the amygdala. This procedure does not directly affect GABA systems. It is proposed that after each of these proconvulsant treatments, GABA function will decrease in the striatonigral pathway and increase in the nigrotectal pathway and that these changes are not dependent on the occurance of a seizure. This pattern of changes would greatly increase inhibitory output to the SC, thereby decreasing SC output to reticular formation and spinal cord which and increasing seizure susceptibility. If a similar pattern of changes occurs in GABAergic transmission in the striatonigral and nigrotectal pathways in each of these three models, than a more general role of these GABAergic pathways is indicated. It has been proposed that these pathways may be implicated as a final common pathway for seizure propagation such that increased nigral output determines long-term increases in sensitivity to seizures. For this to be true, the time course of GABAergic changes in each of these models should be correlated with the time course of increased seizure sensitivity but not seizure occurance. It is expected that these studies will have important implications in the characterization and potential treatment of seizures.
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1 |
1995 |
Peris, Joanna |
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. |
Chronic Ethanol Neurotoxicity and Longterm Potentiation |
1 |
2005 — 2007 |
Peris, Joanna |
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. |
Time Resolution of Ethanol-Induced Neurotransmission
DESCRIPTION (provided by applicant): Ethanol is able to increase neuronal firing in the mesolimbic dopamine pathways associated with drug addiction. Repeated ethanol treatment can change the activity of these neurons and that of other related pathways such that stimuli associated with alcohol use can induce cravings and increase the probability of relapse to drinking. Acamprosate, a calcium homologue of taurine, has been shown to decrease craving and relapse in abstinent alcoholics, suggesting an action on neurotransmitter signaling in these areas. Preliminary data for the proposed experiments indicates that both injected and self-administered ethanol increase dopamine and taurine levels in the nucleus accumbens (Nac), the terminal area of the mesolimbic pathway. Interestingly, only self-administered ethanol (not injected ethanol) consistently results in an increase in glutamate release in Nac. We hypothesize that alterations in ethanol-induced increases in taurine levels in Nac may be a media in ism for inducing persistent alcohol cravings via an interaction with dopamine and glutamate efflux. This proposal describes a series of experiments that will characterize the mechanism for the ethanol-induced efflux of glutamate, taurine and dopamine in Nac and other limbic regions as well as determine the relationship between these neurotransmitters and changes in the "non-transmitter" amino acid environment caused by ethanol. Comparing the effect of a low dose of injected ethanol in na'ive and ethanoltrained rats will allow distinction of alterations in these relationships by the induction of self-administration (the first step in the process of alcohol addiction) as well as progression to more alcoholic-like behaviors. Using capillary electrophoresis coupled with laser-induced fluorescence detection, the effects of low doses of ethanol on the levels of at least 10 amino acids plus dopamine in brain regions important for mediating ethanol self-administration (Nac, central nucleus of the amygdala) and striatum as a control region, will be measured. The very high time resolution (in seconds) provided by this methodology will allow us to distinguish changes in neurotransmitter levels during anticipation of ethanol versus that caused pharmacologically by consuming ethanol. Since the anticipation of ethanol is a likely component of craving and relapse to alcohol, this approach will provide new information about the involvement of changes in neurotransmitter release in alcohol relapse so that more effective strategies can be developed for the successful treatment of ethanol abuse.
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1 |
2018 — 2019 |
Krause, Eric Gerald (co-PI) [⬀] Peris, Joanna |
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.) |
Ethanol Dysregulation of Oxytocin-Mediated Reward
Project Summary Intranasal oxytocin (OT) decreases alcohol craving and affective dysfunction in abstinent alcoholics, providing a potential pharmacotherapy for alcoholism. Excessive habitual ethanol use dysregulates mesocorticolimbic reward circuitry which may include decreased OT activation of neurons in the ventral tegmental area (VTA). Here, we propose that ethanol dysregulation of OT signaling specifically alters oxytocinergic innervation and OT receptor (OTR) expression within the VTA, which in turn, facilitates ethanol-seeking in an effort to maintain VTA activation. Recently, we discovered that VTA neurons that synthesize glutamate (GLU) and dopamine (DA) express OTRs indicating the complexity of OT regulation of VTA function and reward. Our use of advanced neuroanatomical techniques combined with in vivo optogenetics provides a unique opportunity to quantify ethanol-induced plasticity in OT signaling in the VTA as well as the consequences of this plasticity on reward seeking behavior. Specifically, we will use genetically altered mice, directed viral gene transfer, and in vivo optogenetics to identify and manipulate pre- and post-synaptic OT signaling in the VTA after daily binge ethanol intoxication. These studies will test the overall hypothesis that manipulations of pre- and post-synaptic OT signaling in the VTA alters reward states and that OT regulation of VTA circuitry and positive reinforcement is impaired by daily binge ethanol intoxication. Aim 1 will quantify the impact of daily binge ethanol intoxication on the number and phenotype of OTR-expressing neurons in the VTA by delivering Cre- inducible adenoassociated virus to mice that have Cre recombinase directed to the OTR gene (OTR-Cre). The effects of daily binge ethanol on hypothalamic OT mRNA and oxytocinergic innervation of the VTA will be quantified using amplified in situ hybridization and mice with Cre recombinase directed to the OT gene. Aim 2, will reveal functional consequences of ethanol-induced structural plasticity by evaluating how daily ethanol intoxication affects operant responding for stimulation of presynaptic or post-synaptic OT signaling within the VTA, which will be recapitulated using in vivo optogenetics. These experiments will determine whether daily binge ethanol decreases OT reward signaling by altering OT fibers and/or OTR expression by DA and GLU neurons in the VTA. Elucidating the impact of daily binge ethanol intake on endogenous OT regulation of VTA neurons will inform pathophysiologic mechanisms of alcohol use disorder and guide the development of novel therapeutic interventions for alcohol use disorders, particularly as they might differ according to sex.
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