Biology subjects

Kallupi, M.

Publications and source records attributed to Kallupi, M..

4 recordsLinked to original sources

bioRxiv2018

Deep brain stimulation of the nucleus accumbens shell does not decrease cocaine self-administration in cocaine-dependent rats but increases GluR1/GluA1 in the central nucleus of the amygdala

BackgroundCocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies of drug addiction strongly suggest that the nucleus accumbens (NAcc) is a viable target for deep brain stimulation (DBS).\n\nObjectiveAlthough previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated.\n\nMethodsRats were made cocaine-dependent by allowing them to self-administer cocaine in long-access sessions (6 h, 0.5 mg/kg/infusion). The effects of high-frequency DBS of the NAcc shell on cocaine intake was then studied. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence and the levels of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.\n\nResultsContrary to our expectations, DBS of the NAcc shell induced a slight increase in both cocaine self-administration and cocaine-induced locomotor activity. In addition, 18 h into cocaine withdrawal, we found that DBS decreased irritability-like behavior. We also found that DBS-induced a robust increase in both cytosolic and synaptosomal levels of GluR1, but not GluR2, specifically in the central nucleus of the amygdala but not in other brain regions.\n\nConclusionsThese preclinical results with cocaine-dependent animals do not support high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of cocaine addiction in active cocaine users. However, the decrease in irritability-like behavior during cocaine abstinence, together with previous findings showing that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, warrants future investigations of DBS as a treatment for negative emotional states and craving during abstinence.\n\nHighlightsO_LIHigh-frequency DBS of the NAcc shell for the treatment of cocaine addiction is proposed\nC_LIO_LIDBS of the NAcc shell does not decrease cocaine intake in cocaine-dependent rats\nC_LIO_LIDBS increases the level of GluR1 specifically in the central nucleus of the amygdala\nC_LI

neuroscience↗

bioRxiv2017

Dynorphin counteracts orexin in the paraventricular nucleus of the thalamus: cellular and behavioral evidence

The orexin (Orx) system is known to play a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system, conversely, promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orexin and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Earlier studies showed that microinjections of OrxA in the posterior paraventricular nucleus of the thalamus (pPVT) exerted priming-like effects and reinstated cocaine-seeking behavior, suggesting that Orx transmission in the pPVT participates in cocaine-seeking behavior. The present study sought to determine whether Orx and Dyn interact in the pPVT. Using a cellular approach, brain slices were prepared for whole-cell recordings and to study excitatory transmission in pPVT neurons. The superfusion of OrxA increased spontaneous glutamatergic transmission by increasing glutamate release onto pPVT neurons, whereas DynA decreased glutamate release. Furthermore, the augmentation of OrxA-induced glutamate release was reversed by DynA. To corroborate the electrophysiological data, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After self-administration training, the rats underwent extinction training and were tested with intra-pPVT administration of OrxA{+/-}DynA under extinction conditions. OrxA reinstated cocaine-and SCM-seeking behavior, with a greater effect in cocaine animals. DynA selectively blocked OrxA-induced cocaine seeking vs. SCM seeking. The data indicate that DynA in the pPVT prevents OrxA-induced cocaine seeking, perhaps by reversing the OrxA-induced increase in glutamate release, identifying a novel therapeutic target to prevent cocaine relapse.

neuroscience↗

bioRxiv2017

CRF1 receptor-dependent increases in irritability-like behavior during abstinence from chronic intermittent ethanol vapor exposure

BackgroundIn humans, emotional and physical signs of withdrawal from ethanol are commonly seen. Many of these symptoms, including anxiety-like and depression-like behavior, have been characterized in animal models of ethanol dependence. One issue with several current behavioral tests measuring withdrawal in animal models is they are often not repeatable within subjects over time. Additionally, irritability, one of the most common symptoms of ethanol withdrawal in humans, has not been well characterized in animal models. The corticotropinreleasing factor (CRF)-CRF1 receptor system has been suggested to be critical for the emergence of anxiety-like behavior in ethanol dependence, but the role of this system in irritability-like behavior has not been characterized.\n\nMethodsThe present study compared the effects of chronic intermittent ethanol vapor exposure (CIE)-induced ethanol dependence on irritabilitylike behavior in rats using the bottle-brush test during acute withdrawal and protracted abstinence. Rats were trained to self-administer ethanol in operant chambers and then either left in a nondependent state or made dependent via CIE. Naive, nondependent, and dependent rats were tested for irritability-like behavior in the bottle-brush test 8 h and 2 weeks into abstinence from ethanol. A separate cohort of dependent rats was used to examine the effect of the specific CRF1 receptor antagonist R121919 on irritability-like behavior.\n\nResultsDependent rats exhibited escalated ethanol intake compared with their own pre-CIE baseline and nondependent rats. At both time-points of abstinence, ethanol-dependent rats exhibited increased aggressive-like responses compared with naive and nondependent rats. R121919 blocked the increased irritability-like behavior in dependent rats.\n\nConclusionsThe effect of R121919 to block increased irritability-like behavior suggests that CRF plays an important role in this behavior, similar to other negative emotional withdrawal symptoms. Quantifying and understanding the molecular basis of irritability-like behavior may yield new insights into withdrawal from ethanol and other drugs of abuse.

neuroscience↗

bioRxiv2017

Optogenetic Characterization Of CeA CRF Pathways In Alcohol Dependence

Alcohol withdrawal activates a neuronal ensemble in the central nucleus of the amygdala (CeA) that is responsible for high levels of uncontrolled alcohol drinking. However, the neuronal phenotypes and circuits controlled by these neurons are unknown. We investigated the cellular identity of this CeA neuronal ensemble and found that most neurons expressed corticotropin-releasing factor (CRF). Using Crh-Cre transgenic rats combined with in vivo optogenetics, we tested the role of CeA CRF neurons and their projections in excessive alcohol self-administration during withdrawal. Rats were injected with AAV-DIO-NpHR-eYFP or AAV-DIO-eYFP and implanted with optical fibers over the CeA. Animals were then exposed to chronic intermittent ethanol vapor to induce alcohol dependence. Inactivation of CeA CRF neurons decreased alcohol drinking in dependent rats to non-dependent levels and completely suppressed activation of the CeA neuronal ensemble (Fos+ neurons) during withdrawal. No effects were observed on water or saccharin self-administration. In a second experiment, CeA CRF neurons were infected with AAV-DIO-NpHR-eYFP and optical fibers were implanted into downstream projection regions, including the bed nucleus of the stria terminalis (BNST), lateral hypothalamus (LH), parasubthalamic nucleus (pSTN), substantia innominata (SI), and parabrachial nuclei (PBN). Optogenetic inactivation of CRF terminals in the BNST reduced alcohol drinking and withdrawal signs, whereas inactivation of all other projections had no effect. These results demonstrate that CeA CRF neurons and their projections to the BNST drive excessive alcohol drinking and withdrawal in dependent rats.

neuroscience↗