Cocaine abstinence induces emotional impairment and brain region-specific upregulation of the oxytocin receptor binding.

The key problem in treating cocaine addiction is the maintenance of a drug-free state since negative emotional symptoms during abstinence often trigger relapse. The mechanisms underpinning the emotional dysregulation during abstinence are currently not well-understood. There is evidence suggesting a role of the neuropeptide oxytocin in the modulation of drug addiction processes. However, its involvement during long-term abstinence from cocaine use remains unclear. In this study, we aimed to behaviourally characterize a mouse model of long-term cocaine withdrawal and assess the effect of chronic cocaine administration and long-term cocaine abstinence on the central oxytocinergic system and the Hypothalamic-Pituitary-Adrenal-axis. Fourteen-day escalating-dose cocaine administration (3 x 15-30 mg/kg/day) and 14-day withdrawal increased plasma corticosterone levels and oxytocin receptor (OTR) binding in piriform cortex, lateral septum and amygdala. A specific cocaine withdrawal-induced increase in OTR binding was observed in the medial septum. These biochemical alterations occurred concomitantly with the emergence of memory impairment, contextual psychomotor sensitization and an anhedonic and anxiogenic phenotype during withdrawal. Our study established a clear relationship between cocaine abstinence and emotional impairment in a novel translationally-relevant model of cocaine withdrawal and demonstrated for the first time brain region-specific neuroadaptations of the oxytocin system, which may contribute to abstinence-induced negative emotional state. This article is protected by copyright. All rights reserved

Local field potentials reflect multiple spatial scales in V4

Local field potentials (LFP) reflect the properties of neuronal circuits or columns recorded in a volume around a microelectrode (Buzsáki et al., 2012). The extent of this integration volume has been a subject of some debate, with estimates ranging from a few hundred microns (Katzner et al., 2009; Xing et al., 2009) to several millimeters (Kreiman et al., 2006). We estimated receptive fields (RFs) of multi-unit activity (MUA) and LFPs at an intermediate level of visual processing, in area V4 of two macaques. The spatial structure of LFP receptive fields varied greatly as a function of time lag following stimulus onset, with the retinotopy of LFPs matching that of MUAs at a restricted set of time lags. A model-based analysis of the LFPs allowed us to recover two distinct stimulus-triggered components: an MUA-like retinotopic component that originated in a small volume around the microelectrodes (~350 μm), and a second component that was shared across the entire V4 region; this second component had tuning properties unrelated to those of the MUAs. Our results suggest that the LFP reflects neural activity across multiple spatial scales, which both complicates its interpretation and offers new opportunities for investigating the large-scale structure of network processing

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

© 2020 The Author(s) Background: Cervical vagus nerve stimulation (VNS) is an emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used in place of eCAP measurements. Methods: In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (ΔHR) and breathing interval (ΔBI). Quantitative models were established to capture the relationship between A-, B- and C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results: In bivariate analyses, we found that EMG correlates with A-fiber, ΔHR with B-fiber and ΔBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS

ECoG Beta Suppression and Modulation During Finger Extension and Flexion

Neural oscillations originate predominantly from interacting cortical neurons and consequently reflect aspects of cortical information processing. However, their functional role is not yet fully understood and their interpretation is debatable. Amplitude modulations (AMs) in alpha (8–12 Hz), beta (13–30 Hz), and high gamma (70–150 Hz) band in invasive electrocorticogram (ECoG) and non-invasive electroencephalogram (EEG) signals change with behavior. Alpha and beta band AMs are typically suppressed (desynchronized) during motor behavior, while high gamma AMs highly correlate with the behavior. These two phenomena are successfully used for functional brain mapping and brain-computer interface (BCI) applications. Recent research found movement-phase related AMs (MPA) also in high beta/low gamma (24–40 Hz) EEG rhythms. These MPAs were found by separating the suppressed AMs into sustained and dynamic components. Sustained AM components are those with frequencies that are lower than the motor behavior. Dynamic components those with frequencies higher than the behavior. In this paper, we study ECoG beta/low gamma band (12–30 Hz/30–42 Hz) AM during repetitive finger movements addressing the question whether or not MPAs can be found in ECoG beta band. Indeed, MPA in the 12–18 Hz and 18–24 Hz band were found. This additional information may lead to further improvements in ECoG-based prediction and reconstruction of motor behavior by combining high gamma AM and beta band MPA

Anodal block permits directional vagus nerve stimulation

© 2020, The Author(s). Vagus nerve stimulation (VNS) is a bioelectronic therapy for disorders of the brain and peripheral organs, and a tool to study the physiology of autonomic circuits. Selective activation of afferent or efferent vagal fibers can maximize efficacy and minimize off-target effects of VNS. Anodal block (ABL) has been used to achieve directional fiber activation in nerve stimulation. However, evidence for directional VNS with ABL has been scarce and inconsistent, and it is unknown whether ABL permits directional fiber activation with respect to functional effects of VNS. Through a series of vagotomies, we established physiological markers for afferent and efferent fiber activation by VNS: stimulus-elicited change in breathing rate (ΔBR) and heart rate (ΔHR), respectively. Bipolar VNS trains of both polarities elicited mixed ΔHR and ΔBR responses. Cathode cephalad polarity caused an afferent pattern of responses (relatively stronger ΔBR) whereas cathode caudad caused an efferent pattern (stronger ΔHR). Additionally, left VNS elicited a greater afferent and right VNS a greater efferent response. By analyzing stimulus-evoked compound nerve potentials, we confirmed that such polarity differences in functional responses to VNS can be explained by ABL of A- and B-fiber activation. We conclude that ABL is a mechanism that can be leveraged for directional VNS

Methamphetamine abstinence induces changes in μ-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype

The major challenge in treating methamphetamine addicts is the maintenance of a drug free-state since they experience negative emotional symptoms during abstinence, which may trigger relapse. The neuronal mechanisms underlying long-term withdrawal and relapse are currently not well-understood. There is evidence suggesting a role of the oxytocin (OTR), μ-opioid receptor (MOPr), dopamine D2 receptor (D2R), corticotropin-releasing factor (CRF) systems and the hypothalamic-pituitary-adrenal (HPA)-axis in the different stages of methamphetamine addiction. In this study, we aimed to characterize the behavioral effects of methamphetamine withdrawal in mice and to assess the modulation of the OTR, MOPr, D2R, CRF and HPA-axis following chronic methamphetamine administration and withdrawal. Ten-day methamphetamine administration (2 mg/kg) increased OTR binding in the amygdala, whilst 7 days of withdrawal induced an upregulation of this receptor in the lateral septum. Chronic methamphetamine treatment increased plasma OT levels that returned to control levels following withdrawal. In addition, methamphetamine administration and withdrawal increased striatal MOPr binding, as well as c-Fos+/CRF+ neuronal expression in the amygdala, whereas an increase in plasma corticosterone levels was observed following METH administration, but not withdrawal. No differences were observed in the D2R binding following METH administration and withdrawal. The alterations in the OTR, MOPr and CRF systems occurred concomitantly with the emergence of anxiety-related symptoms and the development of psychomotor sensitization during withdrawal. Collectively, our findings indicate that chronic methamphetamine use and abstinence can induce brain-region specific neuroadaptations of the OTR, MOPr and CRF systems, which may, at least, partly explain the withdrawal-related anxiogenic effects

Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration.

Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 μl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

Background Cervical vagus nerve stimulation (VNS) is a rapidly emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective /Hypothesis: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used instead of eCAP measurements. Methods In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (ΔHR) and breathing interval (ΔBI). Quantitative models were established to capture the relationship between A-, B- and C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results In bivariate analyses, we found that EMG correlates with A-fiber, ΔHR with B-fiber and ΔBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS

Chronic nicotine administration restores brain region specific upregulation of oxytocin receptor binding levels in a G72 mouse model of schizophrenia.

Nicotine dependence and schizophrenia are two mental health disorders with remarkably high comorbidity. Cigarette smoking is particularly prevalent among schizophrenic patients and it is hypothesized to comprise a form of self-medication for relieving cognitive deficits in these patients. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin in the modulation of drug addiction, as well as schizophrenia symptomology; however, the underlying mechanism remains unclear. Therefore, we sought to investigate the effects of chronic nicotine administration on oxytocin receptor (OTR) binding in the brain of a transgenic mouse model of schizophrenia that carries a bacterial artificial chromosome of the human G72/G30 locus (G72Tg). Female wild-type (WT) and heterozygous G72 transgenic CD-1 mice were treated with a chronic nicotine regimen (24 mg/kg/day, osmotic minipumps for 14 days) and quantitative autoradiographic mapping of oxytocin receptors was carried out in brains of these animals. OTR binding levels were higher in the cingulate cortex (CgCx), nucleus accumbens (Acb) and central amygdala (CeA) of saline treated G72Tg mice compared with WT control mice. Chronic nicotine administration reversed this upregulation in the CgCx and CeA. Interestingly, chronic nicotine administration induced an increase in OTR binding in the CeA of solely WT mice. These results indicate that nicotine administration normalizes the dysregulated central oxytocinergic system of this mouse model of schizophrenia and may contribute towards nicotine's ability to modulate cognitive deficits which are common symptoms of schizophrenia. This article is protected by copyright. All rights reserved

The oxytocin analogue carbetocin prevents priming-induced reinstatement of morphine-seeking: Involvement of dopaminergic, noradrenergic and MOPr systems.

Relapse to illicit drug-seeking following abstinence is a major challenge for the treatment of addiction as no effective pharmacotherapy is available. We have recently shown that activating the central oxytocinergic system prevents emotional impairment and stress-induced reinstatement associated with opioid withdrawal. Here, we investigated whether the oxytocin analogue carbetocin (CBT) is able to reverse morphine-primed reinstatement of conditioned-place preference (CPP) in mice. The mechanism underlining the behavioural effect of CBT was investigated by assessing the involvement of the striatal noradrenergic and dopaminergic systems in CBT reversal of priming- and stress-induced reinstatement of opioid CPP. In addition, given recent evidence suggesting the presence of oxytocin receptor (OTR)-μ-opioid receptor (MOPr) interactions in the brain, we further explored these interactions by carrying out OTR autoradiographic binding in brain of mice lacking MOPr. CBT administration prevented priming-induced reinstatement of morphine CPP. While an acute effect of CBT in enhancing dopamine turnover was observed following stress- and priming-induced reinstatement, CBT significantly decreased striatal noradrenaline turnover only following priming-induced reinstatement. Moreover, a significant brain region- specific increase in OTR binding was observed in MOPr knockout mice, indicating the presence of a possible OTR-MOPr interaction, which may be involved in the modulation of relapse. These results support the oxytocinergic system as a promising target for the prevention of relapse to opioid use and highlight the differential involvement of monoaminergic systems on the effects of OTR stimulation in preventing stress- and priming-induced reinstatement of opioid CPP behaviour