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Official websites use. Share sensitive information only on official, secure websites. Astrocytes have become established as an important regulator of neuronal activity in the brain. Accumulating literature demonstrates that cocaine self-administration in rodent models induces structural changes within astrocytes that may influence their interaction with the surrounding neurons. Here, we provide evidence that cocaine impacts astrocytes at the functional level and alters neuronal sensitivity to astrocyte-derived glutamate. This is accompanied by increased prevalence of slow inward currents, a physiological marker of neuronal activation by astrocytic glutamate, in a subset of medium spiny neurons. Within, but not outside, of this subset, we observe an increase in duration and frequency of NMDA receptor-mediated synaptic events. Additionally, we find that the link between synaptic NMDA receptor plasticity and neuron sensitivity to astrocytic glutamate is maintained independent of drug exposure, and is observed in both cocaine and saline control animals. Therefore, our data indicate that cocaine self-administration promotes astrocyte-specific functional changes that can be linked to increased glutamate-mediated coupling with principal neurons in the nucleus accumbens. Such coupling may be spatially restricted as it does not result in a broad impact on network structure of local neuronal circuits. Astrocytes play diverse roles in regulation of synaptic transmission and have been proposed to coordinate synaptic plasticity and organization of neuronal microcircuits 1 , 2. The mechanisms underlying astrocytic release of neuromodulators, gliotransmission, remain subjects of active debate 8 — However, considering the lack of evidence for specialized gliotransmitter release sites and the fact that only the finest of astrocytic processes penetrate into the synaptic cleft, the bulk of gliotransmitter exocytosis is thought to occur outside the synapse 15 , Accordingly, neuronal response to gliotransmitters has been linked to the pool of extrasynaptic receptors. The electrophysiological hallmark of the NMDAR-mediated response to astrocytic glutamate are slow inward currents SICs , that are prominently distinguished from synaptic NMDAR-mediated events by their large amplitudes and slow kinetics 17 , 20 , SICs arise spontaneously in subpopulations of cells, but can also be elicited or inhibited by pharmacological, optical, and mechanical stimulation of astrocytes 18 , 19 , 22 — NMDA-mediated SICs may therefore serve as a useful proxy of neuronal sensitivity to glutamate released from the surrounding astrocytes. Indeed, a number of studies have highlighted the possibility that SICs may be involved in synchronization of local neuronal microcircuits in the hippocampus, the somatosensory cortex and the NAc 17 — 19 , 27 — Multiple behavioral outputs have been reported to result from astrocyte-selective manipulations. These include locomotor effects, sleep regulation, affective processing, memory encoding, and food intake Mounting evidence indicates that substance use triggers changes within astrocytes that impact drug-evoked behavior. For example, chemogenetic activation of astrocytes has been shown to attenuate motivation for ethanol, an effect that may involve signaling through astrocytic gap-junctions Astrocyte-released adenosine has been found to depress excitatory synaptic transmission and regulate effects of amphetamine 32 and ethanol while reduced association of astrocyte processes with synapses may play a role in heroin seeking Mice with astrocytes lacking putative gliotransmitter release machinery displayed attenuated cocaine-induced reinstatement of conditioned place preference and cue-induced reinstatement of cocaine self-administration in a transgenic mouse model Despite evidence that astrocyte-specific manipulations may influence cocaine-seeking, it is not known how cocaine experience affects baseline levels of astrocyte activity and functional interactions with neuronal targets. The goal of this study was to evaluate whether a history of cocaine self-administration impacts measures of astrocyte signaling that may be linked to synaptic plasticity of medium spiny neurons MSNs in the NAc shell. Male Sprague-Dawley rats Rattus norvegicus weighing — g were obtained from Taconic Laboratories. Rats were individually housed with food and water available ad libitum in their home cages. All experimental procedures were performed during the light cycle. The experimental protocols were consistent with the guidelines issued by the U. Under isoflurane anesthesia 1. The catheter was routed subcutaneously to a mesh platform placed between the shoulder blades. Catheters were flushed daily with 0. The catheters were sealed with plastic obturators when not in use. Following catheter implantation, the rats were placed in a stereotaxic apparatus under isoflurane anesthesia. SV40, Addgene or astrocytes pZac2. At 14—20 days after virus microinjections, the rats began cocaine self-administration training. The rats were placed in operant chambers Med Associates and allowed to lever-press for intravenous cocaine infusions 0. Briefly, each cocaine infusion was followed by a s timeout period during which responses had no scheduled consequences. The rats were initially trained using a fixed ratio 1 FR1 schedule of reinforcement. When stable responding was achieved under the FR1 schedule, they were switched to an FR5 schedule. Rats self-administered cocaine for 14 days and were paired with yoked saline controls. The yoked animals received an infusion of saline every time their pair received cocaine. There were no consequences to lever pressing by the yoked saline animals. Twenty-four hours after the last behavioral session, the rats were deeply anesthetized with isoflurane and decapitated. DNQX did not have a significant effect on any of the measured SIC parameters and these recordings were pooled with DNQX-free recordings for analysis unless otherwise indicated in the text. Brain slices were viewed under an upright microscope Olympus BX51WI with infrared differential interference contrast optics and a 40x water-immersion objective. The intracellular solution contained the following in mM : potassium gluconate, 2 MgCl 2 , 2. Delayed rectifier currents were measured at current peak. The amplitude of spontaneous excitatory postsynaptic currents sEPSCs was computed from an average of 50— current traces. Mean sEPSC frequencies were analyzed from 10—20 s long trace segments. Videos were analyzed offline with ImageJ and Matlab Mathworks. Individual cells were manually isolated as regions of interests ROIs. Amplitude, half-width, and frequency of calcium transients were analyzed with custom-written Matlab scripts. An undirected adjacency matrix was then constructed for each imaged field containing values of phi coefficients between ROI pairs. Adjacency matrices were used to calculate eight measures of network structure for each imaged field ROIs are nodes in this analysis. Communities: the number of non-overlapping groups maximally connected to each other, but minimally connected to other groups. Transitivity: the probability that, if one node is connected to two others, those two nodes are also connected to each other. Assortativity: coefficient that measures the extent to which nodes of similar strength connect to each other. Density: the ratio of existing connections relative to all possible connections in a network; 6. Modularity: the tendency of a network to be segregable into communities with dense intracommunity connections and sparse intercommunity connections; 7. Characteristic path length: the average shortest path between any two nodes in a network. Global efficiency: the inverse of the characteristic path length. More details on calculation, interpretation, and applicability of these and other measures to brain networks can be found in several excellent reviews 48 , All analyses were done in Excel or GraphPad Prism 8. The color scale is in arbitrary units A. Arrows indicate time points t1—t3 represented by image frames to the left. We evaluated eight measures of network organization with graph theory tools previously used for analysis of neuronal networks. Cocaine self-administration at 24 hours of withdrawal significantly decreased modularity and increased efficiency of astrocyte networks within slices as compared to the saline-yoke population Fig. None of these significant differences were preserved at 14 days of withdrawal from cocaine self-administration Fig. Instead, 14 days of withdrawal was associated with significant decreases in network transitivity and assortativity compared to networks from the respective saline-yoke population, producing disassortative networks Fig. Further implications of these findings are presented in the Discussion. A A table of network measures for astrocytes in the NAc shell of cocaine and yoked saline rats 24 hours after the last operant session. B Graphical representations of astrocytic networks in a single slice from a yoked saline or a cocaine-experienced rat at 24 hours of withdrawal. Density is the ratio of existing connections to all possible connections. Color represents connection strength phi-coefficient. Two communities are shown in the saline condition and three communities in the cocaine condition dashed squares. Intra-community connections are inside the dashed squares and all colored slots outside of dashed squares indicate inter-community connections. C A table of network measures for astrocyte in the NAc shell of cocaine and yoked saline rats 14 days after the last operant session. D Graphical representations of astrocytic networks in a single slice from a yoked saline or a cocaine experienced rat at 14 days of withdrawal. Buffering of extracellular potassium is one of the main functions attributed to astrocytes throughout the brain. Astrocytic potassium channels are known to be involved in regulation of astrocytic calcium signaling 51 , astrocytic resting membrane potential 52 , and astrocytic glutamate release In whole-cell patch-clamp recordings, we observed weak rectification of K ir amplitude in both saline and cocaine conditions at 24 hours of withdrawal from cocaine. There was no main effect of cocaine exposure across the entire range of evoked K ir current amplitudes Fig. Similarly, we observed no main effect of cocaine exposure on the amplitude of outward delayed rectifier K dr currents Fig. Together, these results show that neither the current rectification attributed to the astrocytic voltage-gated K ir and K dr currents nor the passive indicators of astrocyte membrane excitability are affected by cocaine self-administration. A Representative traces and B current-voltage relationship of currents attributed to K ir channels in NAc shell astrocytes from saline control and cocaine-experienced rats. C Representative traces and D current-voltage relationship of currents attributed to K dr channels in NAc shell astrocytes from saline control and cocaine-experienced rats. We next examined whether a combination of changes in some functional signatures of astrocyte activity i. Increased prevalence of SICs could be driven by increased number of astrocytic glutamate release events which may be reflected as an increase in SIC frequency. However, the mean frequency of SICs was not affected by cocaine self-administration saline: 0. Increased concentration of glutamate per release event may also increase probability of detecting SICs especially in the case of small-amplitude events that are not likely to saturate the pool of available NMDA receptors. If this were the case, an increase in SIC amplitude should also be expected. However, the mean amplitude of SICs was not significantly altered by cocaine experience saline: These results indicate that short-access cocaine self-administration increases functional coupling between neurons and astrocytes in the NAc shell such that greater number of neurons within the local circuit are responsive to astrocyte-released glutamate. Greater astrocyte-neuron functional coupling is not due to cocaine-induced increase in amount of astrocyte-released glutamate or increase in frequency of astrocytic glutamate release events. C-D SIC frequency and amplitude are not affected by cocaine self-administration. Circles indicate individual MSNs. Black horizontal bars indicate distribution means and standard errors, respectively. Since astrocytic glutamate release underlying the SICs has been proposed to co-ordinate neuronal microcircuit organization in a number of brain regions 17 — 19 , 27 , we followed up with exploration of network structure using graph theory methods as we had done for astrocytic networks. Despite the intriguing relationships that we report for astrocytic networks, none of the eight measures of neuronal network interactions that we examined showed significant differences between saline and cocaine conditions Table 1. Measures of network structure calculated for MSNs in the NAc shell of rats trained to self-administer cocaine and their saline-yoke counterparts. Our data indicate that cocaine self-administration is linked to a number of novel functional adaptations at NAc shell astrocytes. Second, we identify cocaine-induced plasticity of astrocytic networks supporting the hypothesis of structured communication between astrocytes. Finally, we report that increased glutamate-mediated neuroglial coupling at 24 hours of withdrawal from cocaine is not associated with altered structure of local MSN circuits in the NAc shell. Extensive literature supports the argument that history of drug exposure is a critical determinant of the molecular and behavioral adaptations to cocaine 62 — In our experiments, we controlled for the environmental stimuli lights, syringe pump sounds, etc. This design did not allow for isolation of operant training effects since the saline animals were not given the opportunity to control action-outcome contingencies. As the NAc shell is part of a network that processes not only reward signals, but salient environmental cues, environmental changes irrespective of cocaine experience could conceivably impact cellular activity. Here we examined functional networks, that is, networks whose connections are determined on the basis of correlated activity of their constituent cells. This would be predicted to decrease the fraction of cells with correlated activity, leading to reduced network density. However, we found that network density is increased after cocaine at 24 hours of withdrawal, but is similar between cocaine and saline groups at 14 days of withdrawal. These observations suggest that functional network alterations induced by cocaine may not be solely attributable to changes in activity of single cells. We propose that cocaine-induced increase in connection density may explain the finding of reduced network modularity at 24 hours of withdrawal. Modularity measures the tendency of a network to be segregable into communities of highly connected nodes that have minimal inter-community connections. Greater connection density can contribute to the breakdown of modularity if new connections are between communities or randomly distributed between and within communities cf. This finding indicates that cocaine self-administration generates less structured more random astrocyte functional networks. Increased network density may also contribute to decreased path length, the number of connections that lie between any two cells in a network which, in turn, would increase network efficiency calculated as the inverse of the characteristic path length. Such coordinated activity would be expected to increase connection density and decrease network modularity as observed in our analyses, since higher correlations among all cells in the network would increase the number of functional connections and make segregation of the network into discrete modules less likely. We found no significant differences in network density, modularity, and efficiency between saline and cocaine groups after 14 days of withdrawal. This finding, again, suggests that cessation of daily exposure to the operant chamber and non-contingent saline infusions may alter astrocyte responses independent of cocaine. Significant differences in NAc astrocyte network assortativity and transitivity between the saline and cocaine groups were observed at 14 days of withdrawal. Networks comprised of nodes that are preferentially connected to other nodes with similar numbers of connections are referred to as assortative and have a positive assortativity value. Conversely, networks comprised of nodes that are preferentially connected to nodes with different numbers of connections either less or more are described as disassortative. Cocaine self-administration followed by withdrawal, thus, produced strongly disassortative astrocyte networks. Lower transitivity values can be related to this, as disassortative networks are likely to have reduced number of three-node interconnected loops, the basis of transitivity measurements. In neuronal networks, disassortativity has been proposed to improve network stability 71 which may indicate reduced sensitivity to weak stimuli Interestingly, disassortative neural networks have also been linked to increased synchronization of activity Network level relationships have not been previously explored among astrocytes in situ and it is too early to say whether changes that we observed here warrant similar conclusions with regard to stimulus sensitivity, synchronizability, etc. It is nevertheless notable that the absence of changes in network density at 14 days of withdrawal suggests that astrocyte network plasticity after cocaine may not be explainable solely by introduction or deletion of random connections. Network changes do not require structural remodeling 72 , however, evidence in support of structural plasticity for both neurons and astrocytes after cocaine exposure is extensive and the combined impact of structural and functional connectivity changes on astrocyte network activity is of great interest. Increased SIC prevalence could be attributed to increased probability of gliotransmitter release. However, available evidence indicates that extrasynaptic glutamate is decreased in the NAc following chronic cocaine 37 , While glutamate release events associated with SICs may not substantially contribute to ambient extracellular glutamate levels, our finding that the frequency of SICs was not altered by cocaine-experience suggests that the probability of astrocytic glutamate release also remained unchanged. SICs are mediated by NMDA receptors and those receptors located at extrasynaptic sites are ideally situated to detect glia-released glutamate 20 , We and others have previously reported that cocaine self-administration increased contribution of extrasynaptic NMDA receptors in the NAc shell 46 , 75 which is supported by cocaine-induced upregulation of non-canonical NMDA receptors often found at extrasynaptic sites 76 — Upregulation of GluN2B protein following cocaine self-administration has been previously reported although sensitivity of NMDAR-mediated currents to GluN2B antagonist, Ro 25—, remained equivalent between control and cocaine-experienced animals at short withdrawal time points 46 , 69 , 78 , indicating that increased GluN2B expression may not result in functional changes at the synapse. Irrespective of subunit composition, the presence of NMDA receptors at peri- and extra-synaptic sites may be sufficient to prolong decay time of synaptic currents as a result of synaptic glutamate spillover Altogether, our data indicate that cocaine-induced redistribution of synaptic NMDARs to extrasynaptic sites facilitates both detection of SICs and slower decay kinetics of synaptic currents in SIC-positive cells. A range of factors including cocaine dose, total cocaine intake, duration of withdrawal from cocaine and other behavioral parameters could impact neuroglial coupling. We have not evaluated synaptic NMDA receptors signaling or SICs at long withdrawal intervals, but a number of recent studies indicate that cocaine-induced increase in extrasynaptic NMDA signaling may be a transient phenomenon. For example, initial up-regulation of extrasynaptic NMDA receptors was found to dissipate by one month of withdrawal from cocaine 75 and 14 days of extinction training was not associated with differences in SIC frequency in the NAc Relative abundance of extrasynaptic NMDA receptors may also be synergistic with the effects of dendritic sprouting reported after cocaine since dendritic coverage has been shown to influence duration of synaptic transients 81 , Finally, the association between cocaine self-administration training and SIC prevalence may be amplified by changes in glutamate homeostasis. Both the cocaine-induced decrease in glial glutamate extrusion by system -xc exchangers 83 and the increase in glutamate transporter-mediated reuptake 46 may be expected to accumulate glutamate inside astrocytes and promote neuronal SICs with possible behavioral effects 64 , Cocaine exposure has been linked to activation of neuronal subpopulations in the NAc, identified via various characteristics 84 , Here, we present a novel observation that plasticity of synaptic NMDA receptor currents is associated with the presence of SICs, independent of cocaine experience. Neuroglial coupling may thus serve as a marker of synapses that display NMDA receptor plasticity. It remains unknown, however, whether changes in SIC-mediated neuroglial coupling are a precursor to or a consequence of NMDA receptor synaptic plasticity. This may have relevance to cocaine-linked behaviors, as astrocytic control over the relevant neurons may be implemented via precisely targeted, rather than non-discriminate global, interactions. The authors have no competing financial interests to disclose in relation to this work. The data that support the findings of this study are available from the corresponding author upon reasonable request. As a library, NLM provides access to scientific literature. Addict Biol. Published in final edited form as: Addict Biol. Lexington, KY. Find articles by A Neugornet. Find articles by R Neogi. Find articles by Mengfan Xia. Find articles by PI Ortinski. Issue date Nov. PMC Copyright notice. The publisher's version of this article is available at Addict Biol. Open in a new tab. Network measure Saline Cocaine Clustering global 0. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. 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How can I buy cocaine online in Koh Phi Phi

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How can I buy cocaine online in Koh Phi Phi