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Browsing by Author "Hupalo, Sofiya"

Now showing 1 - 5 of 5
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    Differential morphine withdrawal profiles in high- and low-saccharin preferring rats
    (2012-01-26) Hupalo, Sofiya; Radke, Anna; Gewirtz, Jonathan
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    Dopamine in the Nucleus Accumbens Shell Mediates Acute Opiate Withdrawal
    (2012-04-18) Hupalo, Sofiya
    The onset of withdrawal after cessation of drug use is one of the defining characteristics of opiate addiction. Addiction is in part driven by negative reinforcement in an attempt to alleviate negative emotional states during withdrawal. Evidence suggests that opiate withdrawal is characterized by diminished neurotransmission in the mesolimbic dopamine system. However, it is not known where dopamine’s actions may play a role during withdrawal. We hypothesized that acute withdrawal occurs when dopamine levels diminish after the initial morphine-induced surge. We microinfused a non-specific dopamine receptor agonist into three structures downstream of the ventral tegmental area, where morphine exerts its primary effects. Using the withdrawal-potentiated startle (WPS) paradigm to measure anxiety-like symptoms of withdrawal, we found that apomorphine, a dopamine receptor agonist, attenuates withdrawal symptoms when administered into the nucleus accumbens (NAc) shell. Our results demonstrate the involvement of dopamine receptor activity in morphine withdrawal, and suggest that withdrawal is brought on by declining levels of dopamine in the NAc. This finding is one of the first to show that dopamine modulates the rewarding as well as aversive properties of morphine, implicating a possible mechanism for the transition from early opiate use to dependence.
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    Dopamine, but not noradrenaline, contributes to opiate withdrawal-induced anxiety in the VTA
    (2010-12-21) Hupalo, Sofiya
    •Research in the Gewirtz laboratory has shown that one of the brain structures involved in mediating withdrawal from opiate drugs such as morphine is the ventral tegmental area(VTA). Morphine causes the VTA to release dopamine and excite downstream targets,which maybe related to the onset of withdrawal. •In addition,increased levels of noradrenaline are also present during opiate withdrawal.3,4 •We aim to test whether both the dopaminergic and adrenergic systems engage to produce WPS when morphine is supplied to the VTA. Thus,we administer propranolol, an adrenergic receptor antagonist,to determine whether noradrenaline is recruited by the VTA during withdrawal. Apomorphine ,a dopamine agonist, is given to determine the actions of dopamine during withdrawal
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    A novel in vivo approach to study circadian rhythmicity of glucocorticoids using adeno-associated virus
    (2011-09-01) Karsten, Carley; Hupalo, Sofiya; Yoder, J. Marina; Engeland, William C.
    The hypothalamic-pituitary-adrenal (HPA) axis regulates glucocorticoid release in a circadian rhythm as well as in response to stress. The adrenal gland is made up of two distinct tissues: the cortex, which produces glucocorticoids, and the medulla. The cortex responds to hormonal cues while the medulla receives input from the splanchnic nerve. Interestingly, cutting the splanchnic nerve has been shown to affect cortical function, indicating a possible interaction between the two tissues. However, the precise mechanism of this interaction remains unknown. An experimental approach that genetically manipulates adrenal activity could potentially delineate the functional relationship between medulla and cortex. One option is to infect adrenal tissue with recombinant adeno-associated virus (AAV) capable of silencing a gene of interest in a specific tissue type. This is a novel approach in the adrenal gland, so we must first develop a protocol that will optimize methodological variables such as AAV serotype, surgical procedure, injection volume, and infection time-course. We tested various combinations of these variables and used GFP-tagged AAV to assess the degree of infection in rats. Thus far, we have determined that the serotype AAV8 yields the greatest degree of infection, and AAV2 and AAV5 seem to selectively infect the cortex. In addition, the concentration of virus injected is more important than the volume, and the injection method can have a large impact. Stress tests revealed that injection of AAV-GFP does not appear to alter adrenal function. AAVs thus appear to be promising tools in neuroendocrine studies, as they provide a means for genetically modifying the adrenal gland. Future experiments will use this new technique to analyze the functional relationship between adrenal cortex and medulla.
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    Rhythmic clock gene expression in the spinal cord may underlie sympathetic nerve control of adrenal function
    (2012-04-18) Hupalo, Sofiya
    The hypothalamic-pituitary-adrenal (HPA) axis is characterized by a circadian rhythm that entrains to the light-dark cycle via inputs from a central pacemaker in the suprachiasmatic nucleus (SCN). Similar molecular clock mechanisms have been identified in each component of the HPA axis including the adrenal cortex, which generates circadian rhythms in glucocorticoid secretion. However, the mechanisms by which the adrenal clock entrains to environmental signals have not been elucidated. Since corticosterone secretion in rodents is mediated in part by sympathetic nerve activity through the intermediolateral (IML) nucleus of the thoracic spinal cord, we tested the hypothesis that these neurons also possess an endogenous clock. Using immunohistochemistry, we detected expression of two clock gene proteins – Period 2 (PER2) and brain and muscle Arnt-like protein 1 (BMAL1) – in the dorsal horn, ventral horn, and intermediate gray within mouse thoracic and lumbar segments; double labeling for vesicular acetylcholine transporter showed cholinergic neurons immunoreactive for clock gene proteins in the IML and ventral horn. To examine whether spinal cord neurons possess clock gene rhythms, we used the reporter mPer2::Luciferase knockin mouse to monitor real-time gene expression in vitro. We found that explants of thoracic spinal segments exhibit rhythms in mPER2 bioluminescence with a 22.0 ± 0.3 h period and a peak phase of 14.8 ± 0.1 h circadian time (CT), which precedes the peak of the adrenal rhythm (CT~16). Our results demonstrate that spinal cord neurons, including those in the IML, express clock gene proteins and that explants of thoracic segments exhibit an endogenous rhythm in PER2 expression. These findings suggest that circadian expression of clock genes in the IML drives sympathetic nerve activity to synchronize adrenal glucocorticoid release with daily changes in the external environment.