Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

IntroductionUsing yoked animals as the control when monitoring operant drug-self-administration is considered the golden standard. However, instrumental learning per se recruits several neurocircuits that may produce distinct or overlapping neuroadaptations with drugs of abuse. The aim of this project was to assess if contingent responding for nicotine or saline in the presence of a light stimulus as a conditioned reinforcer is associated with sustained neurophysiological adaptations in the nucleus accumbens shell (nAcS), a brain region repeatedly associated with reward related behaviors.MethodsTo this end, nicotine-or saline-administrating rats and yoked-saline stimulus-unpaired training conditions were assessed in operant boxes over four consecutive weeks. After four additional weeks of home cage forced abstinence and subsequent cue reinforced responding under extinction conditions, ex vivo electrophysiology was performed in the nAcS medium spiny neurons (MSNs).ResultsWhole cell recordings conducted in voltage and current-clamp mode showed that excitatory synapses in the nAcS were altered after prolonged forced abstinence from nicotine self-administration. We observed an increase in sEPSC amplitude in animals with a history of contingent nicotine SA potentially indicating higher excitability of accumbal MSNs, which was further supported by current clamp recordings. Interestingly no sustained neuroadaptations were elicited in saline exposed rats from nicotine associated visual cues compared to the yoked controls.ConclusionThe data presented here indicate that nicotine self-administration produces sustained neuroadaptations in the nAcS while operant responding driven by nicotine visual stimuli has no long-term effects on MSNs in nAcS

Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABAA Receptors

The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABAA and glycine receptors in regulating synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc). Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 μM), inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 μM) and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate) only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate) decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially subregion-specific manner

Abstinence-Induced Nicotine Seeking Relays on a Persistent Hypoglutamatergic State within the Amygdalo-Striatal Neurocircuitry

Nicotine robustly sustains smoking behavior by acting as a primary reinforcer and by enhancing the incentive salience of the nicotine-associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood. In here we used a contingent nicotine and saline control self-administration model to disentangle the contribution of cue-elicited seeking responding for nicotine after drug abstinence in male Wistar rats. Using ex vivo electrophysiological recordings and a network analysis approach, we defined temporal and brain-region specific amygdalo-striatal glutamatergic alterations that occur during nicotine abstinence. The results from this study provide critical evidence indicating a persistent hypoglutamatergic state within the amygdalo-striatal neurocircuitry over protracted nicotine abstinence. During abstinence-induced nicotine seeking, electrophysiological recordings showed progressive neuroadaptations in dorsal and ventral striatum already at 14-d abstinence while neuroadaptations in subregions of the amygdala emerged only after 28-d abstinence. The observed neuroadaptations pointed to a brain network involving the amygdala and the dorsolateral striatum (DLS) to be implied in cue-induced reinstatement of nicotine seeking. Together these data suggest long-lasting neuroadaptations that might reflect neuroplastic changes responsible to abstinence-induced nicotine craving. Neurophysiological transformations were detected within a time window that allows therapeutic intervention advancing clinical development of preventive strategies in nicotine addiction. </p

Ethanol-mediated effects on astroglial cells in primary culture. With a focus on acute changes in intracellular Ca2+, cell volume, actin filaments, and gap junction coupling

The astroglial cells are abundant in the central nervous system (CNS), where they control and regulate the homeostasis of the extracellular milieu. A change in astroglial cell volume, mediated through activation of neuroactive substances or changes in osmolarity, leads to changes in the size and geometry of the extracellular space volume, which could affect the diffusion and concentration of neuroactive substances. The astroglial cells are connected through gap junctions, which are small pores that allow bidirectional communication. The intercellular coupling through gap junctions has been suggested to allow the astroglial network to function as a unit, and to equalize the concentration of intracellular ions.To enable studies of signal transduction systems involved in astroglial cell swelling and volume regulation, we developed a new method for quantifying changes in cell volume at the single-cell level (Paper I). The method, which was based on optical sectioning in combination with image analysis, was used to study changes in astroglial cell volume mediated by ethanol (10 200 mM) in three dimensions (3D) over time (Papers II and IV). The method was proven to be capable of properly reconstructing and segmenting individual cells. Exposure for 5 min to 25 mM or 150 mM ethanol increased astroglial cell volume in 19% and 36% of analyzed cells, while cell shrinkage was detected in 22% and 35%, respectively (Paper IV). The ethanol-mediated volume changes were partially inhibited during incubation in low extracellular sodium ([Na+]o), during blockage of the Na+/K+/2Cl- cotransporter with furosemide, during blockage of the Na+/K+-adenosine triphosphatase (ATPase) with ouabain, or during blockage of the inward-rectifying potassium channels (K+IR) with BaCl2 (Paper IV). Exposure to ethanol-induced morphological changes and ethanol-mediated transformation in filamentous actin led to a more dispersed appearance of the filaments and an increased number of cells with actin in ring formations (Paper II). Ethanol decreased cell-to-cell communication through gap junctions in astroglial cultures from the cerebral cortex, brain stem, or hippocampus, while cultures from the olfactory bulb or hypothalamus remained unaffected (Paper III). The decrease was not seen during incubation in low [Na+]o, or during blockage with furosemide, and ethanol had no additional effect on the decrease in gap junction coupling mediated by ouabain (Paper III). The results presented in Papers II IV suggest that astroglial cells could be important targets during ethanol exposure, and that possible changes in cell volume and gap junction coupling could be of toxicological relevance

Dopaminergic Regulation of Striatal Interneurons in Reward and Addiction: Focus on Alcohol

Corticobasal ganglia networks coursing through the striatum are key structures for reward-guided behaviors. The ventral striatum (nucleus accumbens (nAc)) and its reciprocal connection with the ventral tegmental area (VTA) represent a primary component of the reward system, but reward-guided learning also involves the dorsal striatum and dopaminergic inputs from the substantia nigra. The majority of neurons in the striatum (>90%) are GABAergic medium spiny neurons (MSNs), but both the input to and the output from these neurons are dynamically controlled by striatal interneurons. Dopamine is a key neurotransmitter in reward and reward-guided learning, and the physiological activity of GABAergic and cholinergic interneurons is regulated by dopaminergic transmission in a complex manner. Here we review the role of striatal interneurons in modulating striatal output during drug reward, with special emphasis on alcohol

Ethanol acutely decreases astroglial gap junction permeability in primary cultures from defined brain regions

The acute effect of hyperosmotic ethanol on gap junction permeability was examined in astroglial cells in primary culture from five different brain regions. Gap junction permeability was analyzed by measuring dye spreading from cell to cell with the low molecular weight dye Lucifer Yellow. Ethanol concentrations 25-300 mM significantly decreased dye spreading in cultures from the cerebral cortex in a dose-dependent but time-independent manner for up to 60 min. Besides cerebral cortex, exposure to 150 mM ethanol decreased dye spreading in astroglial cultures from the hippocampus and from the brain stem, while cultures from the olfactory bulb and from the hypothalamus were not significantly affected. The ethanol-induced decrease in dye spreading in cultures from the cerebral cortex was not mediated through changes in cell volume, osmolarity, protein kinase C (PKC) phosphorylation, intracellular pH, or intracellular calcium concentration ([Ca 2+ ] i ). The decrease in dye spreading was abolished upon incubation in sodium-reduced buffer, and after blockage of the Na + /K + /2Cl - cotransporter with furosemide. The results presented here indicate that ethanol-mediated decrease in dye spreading is directly or indirectly dependent on sodium. \ua9 2004 Elsevier Ltd. All rights reserved

Neurobiology of alcohol seeking behavior

Alcohol addiction is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse consequences. A main challenge of addiction treatment is to prevent relapse, which occurs in more than &amp;gt;50% of newly abstinent patients with alcohol disorder within 3 months. In people suffering from alcohol addiction, stressful events, drug-associated cues and contexts, or re-exposure to a small amount of alcohol trigger a chain of behaviors that frequently culminates in relapse. In this review, we first present the preclinical models that were developed for the study of alcohol seeking behavior, namely the reinstatement model of alcohol relapse and compulsive alcohol seeking under a chained schedule of reinforcement. We then provide an overview of the neurobiological findings obtained using these animal models, focusing on the role of opioids systems, corticotropin-release hormone and neurokinins, followed by dopaminergic, glutamatergic, and GABAergic neurotransmissions in alcohol seeking behavior.Funding Agencies|Swedish Research Council, VR projectSwedish Research Council [2018-02320]</p