Modulation of mGlu5 reduces rewarding associative properties of nicotine via changes in mesolimbic plasticity: Relevance to comorbid cigarette smoking in psychosis.

RATIONALE: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia. OBJECTIVE: The current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use. METHODS: Neonatal treatment of animals with the dopamine D2-like receptor agonist quinpirole (NQ) from postnatal day (P)1-21 produces a lifelong increase in D2 receptor sensitivity, showing relevance to psychosis and comorbid tobacco use disorder. Following an 8-day conditioning paradigm, brain tissue in the mesolimbic pathway was analyzed for several plasticity markers, including brain derived neurotrophic factor (BDNF), phosphorylated p70 ribosomal S6 kinase (phospho-p70S6K), and cadherin-13 (Cdh13). RESULTS: Pretreatment with CDPPB was effective to block enhanced nicotine conditioned place preference observed in NQ-treated animals. Pretreatment was additionally effective to block the nicotine-induced increase in BDNF and sex-dependent increases in cadherin-13 in the ventral tegmental area (VTA), as well as increased phospho-p70S6K in the nucleus accumbens (NAcc) shell found in NQ-treated animals. CONCLUSION: In conjunction with prior work, the current study suggests positive allosteric modulation of the mGlu5 receptor, an emerging target for schizophrenia therapeutics, may be effective for the treatment of comorbid nicotine abuse in psychosis.

Partner-seeking and limbic dopamine system are enhanced following social loss in male prairie voles (Microtus ochrogaster).

Death of a loved one is recognized as one of life's greatest stresses, and 10%-20% of bereaved individuals will experience a complicated or prolonged grieving period that is characterized by intense yearning for the deceased. The monogamous prairie vole (Microtus ochrogaster) is a rodent species that forms pair bonds between breeding partners and has been used to study the neurobiology of social behaviors and isolation. Male prairie voles do not display distress after isolation from a familiar, same-sex conspecific; however, separation from a bonded female partner increases emotional, stress-related, and proximity-seeking behaviors. Here, we tested the investigatory response of male voles to partner odor during a period of social loss. We found that males who lost their partner spent significantly more time investigating partner odor but not non-partner social odor or food odor. Bachelor males and males in intact pairings did not respond uniquely to any odor. Furthermore, we examined dopamine (DA) receptor mRNA expression in the anterior insula cortex (aIC), nucleus accumbens (NAc), and anterior cingulate (ACC), regions with higher activation in grieving humans. While we found some effects of relationship type on DRD1 and DRD2 expression in some of these regions, loss of a high-quality opposite-sex relationship had a significant effect on DA receptor expression, with pair-bonded/loss males having higher expression in the aIC and ACC compared with pair-bonded/intact and nonbonded/loss males. Together, these data suggest that both relationship type and relationship quality affect reunion-seeking behavior and motivational neurocircuits following social loss of a bonded partner.

Pain-related cortico-limbic plasticity and opioid signaling.

Neuroplasticity in cortico-limbic circuits has been implicated in pain persistence and pain modulation in clinical and preclinical studies. The amygdala has emerged as a key player in the emotional-affective dimension of pain and pain modulation. Reciprocal interactions with medial prefrontal cortical regions undergo changes in pain conditions. Other limbic and paralimbic regions have been implicated in pain modulation as well. The cortico-limbic system is rich in opioids and opioid receptors. Preclinical evidence for their pain modulatory effects in different regions of this highly interactive system, potentially opposing functions of different opioid receptors, and knowledge gaps will be described here. There is little information about cell type- and circuit-specific functions of opioid receptor subtypes related to pain processing and pain-related plasticity in the cortico-limbic system. The important role of anterior cingulate cortex (ACC) and amygdala in MOR-dependent analgesia is most well-established, and MOR actions in the mesolimbic system appear to be similar but remain to be determined in mPFC regions other than ACC. Evidence also suggests that KOR signaling generally serves opposing functions whereas DOR signaling in the ACC has similar, if not synergistic effects, to MOR. A unifying picture of pain-related neuronal mechanisms of opioid signaling in different elements of the cortico-limbic circuitry has yet to emerge. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".

Mesolimbic dopamine release conveys causal associations.

Learning to predict rewards based on environmental cues is essential for survival. It is believed that animals learn to predict rewards by updating predictions whenever the outcome deviates from expectations, and that such reward prediction errors (RPEs) are signaled by the mesolimbic dopamine system-a key controller of learning. However, instead of learning prospective predictions from RPEs, animals can infer predictions by learning the retrospective cause of rewards. Hence, whether mesolimbic dopamine instead conveys a causal associative signal that sometimes resembles RPE remains unknown. We developed an algorithm for retrospective causal learning and found that mesolimbic dopamine release conveys causal associations but not RPE, thereby challenging the dominant theory of reward learning. Our results reshape the conceptual and biological framework for associative learning.

Social Fear Affects Limbic System Neuronal Activity and Gene Expression.

Social anxiety disorder (SAD) is a highly prevalent and comorbid anxiety disorder with rather unclear underlying mechanisms. Here, we aimed to characterize neurobiological changes occurring in mice expressing symptoms of social fear and to identify possible therapeutic targets for SAD. Social fear was induced via social fear conditioning (SFC), a validated animal model of SAD. We assessed the expression levels of the immediate early genes (IEGs) cFos, Fosl2 and Arc as markers of neuronal activity and the expression levels of several genes of the GABAergic, serotoninergic, oxytocinergic, vasopressinergic and neuropeptide Y (NPY)-ergic systems in brain regions involved in social behavior or fear-related behavior in SFC+ and SFC- mice 2 h after exposure to a conspecific. SFC+ mice showed a decreased number and density of cFos-positive cells and decreased expression levels of IEGs in the dorsal hippocampus. SFC+ mice also showed alterations in the expression of NPY and serotonin system-related genes in the paraventricular nucleus of the hypothalamus, basolateral amygdala, septum and dorsal raphe nucleus, but not in the dorsal hippocampus. Our results describe neuronal alterations occurring during the expression of social fear and identify the NPY and serotonergic systems as possible targets in the treatment of SAD.

Dopamine D1-like receptors in prelimbic, but not infralimbic, medial prefrontal cortex contribute to chronic stress-induced increases in cue-induced relapse to palatable food seeking during forced abstinence.

Chronic stress exposure causes increased vulnerability to future relapse-like behavior in male, but not female, rats with a history of palatable food self-administration. These effects are mediated by dopamine D1-like receptors, but the anatomical location of chronic stress' dopaminergic mechanism is not known. Thus, male rats were trained to respond for palatable food pellets in daily sessions. During subsequent forced abstinence from food self-administration, stress was manipulated (0 or 3 h restraint/day for 7 days). Rats also received bilateral microinjections of the D1-like receptor antagonist SCH-23390 (0.25 µg/0.5 µl/side) or vehicle (0.5 µl/side) delivered to either prelimbic or infralimbic medial prefrontal cortex prior to daily treatments. Relapse tests in the presence of food-associated cues were conducted 7 days after the last treatment. Stress caused an increase and a decrease in responding during relapse tests in rats that received prelimbic vehicle and SCH-23390 infusions, respectively, relative to unstressed rats. In rats receiving IL infusions, however, stress caused an increase in responding regardless of whether the infusion was vehicle or SCH-23390. These results establish a specific role for prelimbic D1-like receptors in chronic stress-potentiated relapse.

Hippocampal neuropeptide Y2 receptor blockade improves spatial memory retrieval and modulates limbic brain metabolism.

INTRODUCTION: The neuropeptide Y (NPY) is broadly distributed in the central nervous system (CNS), and it has been related to neuroprotective functions. NPY seems to be an important component to counteract brain damage and cognitive impairment mediated by drugs of abuse and neurodegenerative diseases, and both NPY and its Y2 receptor (Y2R) are highly expressed in the hippocampus, critical for learning and memory. We have recently demonstrated its influence on cognitive functions; however, the specific mechanism and involved brain regions where NPY modulates spatial memory by acting on Y2R remain unclear. METHODS: Here, we examined the involvement of the hippocampal NPY Y2R in spatial memory and associated changes in brain metabolism by bilateral administration of the selective antagonist BIIE0246 into the rat dorsal hippocampus. To further evaluate the relationship between memory functions and neuronal activity, we analysed the regional expression of the mitochondrial enzyme cytochrome c oxidase (CCO) as an index of oxidative metabolic capacity in limbic and non-limbic brain regions. RESULTS: The acute blockade of NPY Y2R significantly improved spatial memory recall in rats trained in the Morris water maze that matched metabolic activity changes in spatial memory processing regions. Specifically, CCO activity changes were found in the dentate gyrus of the dorsal hippocampus and CA1 subfield of the ventral hippocampus, the infralimbic region of the PFC and the mammillary bodies. CONCLUSIONS: These findings suggest that the NPY hippocampal system, through its Y2R receptor, influences spatial memory recall (retrieval) and exerts control over patterns of brain activation that are relevant for associative learning, probably mediated by Y2R modulation of long-term potentiation and long-term depression.

Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

Upregulation of FosB/ΔFosB in limbic circuits after tooth exodontia-induced occlusal instability in an experimental model of unpredictable chronic stress.

Psychological stress and occlusal alterations are contributing etiologic factors for temporomandibular and muscular disorders in the orofacial area. The neural modulation recruited for this relationship, however, is not elucidated. The aim of this study was to investigate potential central mechanisms involved in the exodontia-induced occlusal instability associated with unpredictable chronic stress (UCS). Male adult Wistar rats were submitted to occlusal instability (unilateral molar teeth extraction) and/or to a UCS protocol and treated with diazepam or vehicle. The anxiety-like behavior was evaluated by elevated plus maze (EPM) and open field (OF) tests. Limbic structures such as the central nucleus of the amygdala (CeA), paraventricular nucleus of the hypothalamus (PVN), dorsal periaqueductal gray matter (dPAG) and nucleus accumbens core (NAc) were analyzed for expression of FosB/ΔFosB (immediate early genes) by immunohistochemistry. Exodontia and/or UCS decreased the time spent in the open arms at the EPM and the distance travelled at the OF, and increased the immobility time at the OF, suggesting anxiety-like behavior. In addition, exodontia induction resulted in an upregulation of FosB/ΔFosB in the CeA, PVN and dPAG, while UCS and exodontia + UCS upregulate FosB/ΔFosB immunoreactivity in the CeA, PVN, dPAG and NAc. Treatment with diazepam decreased the expression of FosB/ΔFosB in all analyzed structures of animals subject to UCS and exodontia + UCS, while promoted a reduction in the FosB/ΔFosB expression in the CeA, PVN and dPAG in animals subject to exodontia. Our findings showed an anxiogenic effect of exodontia and UCS, which is correlated with intranuclear neuron activation of limbic structures in a spatially dependent manner and that is prevented by the administration of diazepam.

Trace amine-associated receptor 1 (TAAR1): Potential application in mood disorders: A systematic review.

There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1's functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system.

Lack of limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological changes in aged macaques with memory impairment.

The neuropathological changes of limbic-predominant age-related TDP-43 encephalopathy (LATE) are frequent in the aged population and are now recognized as a cause of memory impairment. However, it remains unknown if this proteinopathy is also present in other primate species. We thus investigated the presence and distribution of TDP-43 pathology in the hippocampus and amygdala of 7 aged memory-impaired rhesus macaques (Macaca mulatta, 18-32 years old) from 2 different cohorts. While present in an FTLD-TDP case used as a positive control for immunostaining, we found no TDP-43 or phosphorylated TDP-43 immunoreactive neuronal cytoplasmic inclusion in the amygdala or the hippocampus of these aged animals (as well as in young and mature macaques used as negative controls). We concluded that LATE is probably a human-specific condition, such as many other proteinopathies, and does not participate in age-related memory impairment in non-human primates.

Chronic oral nicotine administration and withdrawal regulate the expression of neuropeptide Y and its receptors in the mesocorticolimbic system.

Neuropeptide Y (NPY) and its receptors are involved in the regulation of mood, stress, and anxiety. In parallel, NPY signaling may play a vital role in the negative affective state induced by drug withdrawal. This study examined the changes in the transcript levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system during chronic nicotine exposure and withdrawal. Rats were administered with nicotine (initial dose: 25 µg/ml, maintenance dose: 50 µg/ml, free base) in drinking water for 12 weeks. Control group received only tap water. In the final week of the study, some of the nicotine-treated animals continued to receive nicotine (0-W), whereas some were withdrawn for either 24 (24-W) or 48 (48-W) h. All animals were decapitated after the evaluation of somatic signs (frequency of gasps, eye blinks, ptosis, shakes, teeth chatter) and the duration of locomotor activity and immobility. mRNA levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system were measured by quantitative real-time PCR (qRT-PCR). Results showed that nicotine withdrawal increased overall somatic signs. Moreover, chronic nicotine treatment increased the duration of locomotor activity, whereas withdrawal increased the duration of immobility. qRT-PCR analysis revealed that chronic nicotine treatment increased NPY mRNA levels in the hippocampus. On the other hand, 24- and 48-h withdrawals increased NPY mRNA levels in the amygdala and medial prefrontal cortex (mPFC), Y1 and Y2 mRNA levels in the nucleus accumbens and mPFC, and Y5 mRNA levels in the mPFC. These findings suggest that nicotine withdrawal enhances NPY signaling in the mesocorticolimbic system, which could be an important mechanism involved in regulating the negative affective state triggered during nicotine withdrawal.

Chronic intranasal oxytocin reverses stress-induced social avoidance in female prairie voles.

Social anxiety disorder (SAD) is a prevalent mental illness in both men and women, but current treatment approaches with selective serotonin reuptake inhibitors (SSRI) have limited success. The neuropeptide oxytocin (OXT) has become a therapeutic target due to its prosocial and anxiolytic effects. Nevertheless, no research has focused on the impact of chronic OXT treatment in animal models of SAD. Social defeat stress is an animal model of social conflict that reliably induces a social avoidance phenotype, reflecting symptoms observed in individuals suffering from SAD. Here, we used the socially monogamous prairie vole, which exhibits aggressive behavior in both sexes, to examine the effects of OXT and SSRI treatment following social defeat stress in males and females. Defeated voles became avoidant in unfamiliar social situations as early as one day after defeat experience, and this phenotype persisted for at least eight weeks. OXT receptor (OXTR) binding in mesocorticolimbic and paralimbic regions was reduced in defeated females during the eight-week recovery period. In males, serotonin 1A receptor binding was decreased in the basolateral amygdala and dorsal raphe nucleus starting at one week and four weeks post-defeat, respectively. Chronic intranasal treatment with OXT had a negative effect on sociability and mesolimbic OXTR binding in non-defeated females. However, chronic intranasal OXT promoted social engagement and increased mesolimbic OXTR binding in defeated females but not males. SSRI treatment led to only modest effects. This study identifies a sex-specific and stress-dependent function of intranasal OXT on mesolimbic OXTR and social behaviors.

Somatostatin and Astroglial Involvement in the Human Limbic System in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-ß peptide (Aß) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer's disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aß and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aß peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer's disease pathogenesis.

Conditional Inactivation of Limbic Neuropeptide Y-1 Receptors Increases Vulnerability to Diet-Induced Obesity in Male Mice.

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice (Npy1rrfb mice) decreased body weight growth and adipose tissue and increased anxiety. In the present study, we used the same conditional system to examine whether the targeted disruption of the Npy1r gene in limbic areas might affect susceptibility to obesity and associated disorders during adulthood in response to a 3-week high-fat diet (HFD) regimen. We demonstrated that following HFD exposure, Npy1rrfb male mice showed increased body weight, visceral adipose tissue, and blood glucose levels, hyperphagia and a dysregulation of calory intake as compared to control Npy1r2lox mice. These results suggest that low expression of Npy1r in limbic areas impairs habituation to high caloric food and causes high susceptibility to diet-induced obesity and glucose intolerance in male mice, uncovering a specific contribution of the limbic Npy1r gene in the dysregulation of the eating/satiety balance.

Limbic Expression of mRNA Coding for Chemoreceptors in Human Brain-Lessons from Brain Atlases.

Animals strongly rely on chemical senses to uncover the outside world and adjust their behaviour. Chemical signals are perceived by facial sensitive chemosensors that can be clustered into three families, namely the gustatory (TASR), olfactory (OR, TAAR) and pheromonal (VNR, FPR) receptors. Over recent decades, chemoreceptors were identified in non-facial parts of the body, including the brain. In order to map chemoreceptors within the encephalon, we performed a study based on four brain atlases. The transcript expression of selected members of the three chemoreceptor families and their canonical partners was analysed in major areas of healthy and demented human brains. Genes encoding all studied chemoreceptors are transcribed in the central nervous system, particularly in the limbic system. RNA of their canonical transduction partners (G proteins, ion channels) are also observed in all studied brain areas, reinforcing the suggestion that cerebral chemoreceptors are functional. In addition, we noticed that: (i) bitterness-associated receptors display an enriched expression, (ii) the brain is equipped to sense trace amines and pheromonal cues and (iii) chemoreceptor RNA expression varies with age, but not dementia or brain trauma. Extensive studies are now required to further understand how the brain makes sense of endogenous chemicals.

Alcohol drinking during early adolescence activates microglial cells and increases frontolimbic Interleukin-1 beta and Toll-like receptor 4 gene expression, with heightened sensitivity in male rats compared to females.

Adolescent drinking is risky because neural circuits in the frontal lobes are undergoing maturational processes important for cognitive function and behavioral control in adulthood. Previous studies have shown that myelinated axons in the medial prefrontal cortex (mPFC) are particularly sensitive to alcohol drinking, especially in males. Pro-inflammatory mediators like toll-like receptor 4 (TLR4) and interleukin-1 beta (IL1b) have been implicated in alcohol induced-inflammation and demyelination; thus, herein we test the hypothesis that voluntary alcohol drinking early in adolescence elicits a pro-inflammatory state that is more pronounced in the brain of males compared to females. Adolescent male and female Wistar rats self-administered sweetened alcohol or sweetened water from postnatal days 28-42 and separate sets of brains were processed for 1) immunolabeling for ionized calcium-binding adapter molecule 1 to analyze microglial cell morphology, or 2) qPCR analysis of gene expression of pro-inflammatory mediators. Binge drinking alcohol activated microglia in the mPFC and hippocampus of both males and females, suggesting that voluntary alcohol exposure initiates an inflammatory response. Il1b mRNA was upregulated in the mPFC of both sexes. Conversely, Tlr4 mRNA levels were elevated after drinking only in males, which could explain more robust effects of alcohol on myelin in this region in developing males compared to females. Il1b mRNA changes were not observed in the hippocampus, but alcohol elevated Tlr4 mRNA in both sexes, highlighting regional specificity in inflammatory responses to alcohol. Overall, these findings give insight into potential mechanisms by which low-to-moderate voluntary alcohol intake impacts the developing brain. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.

Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapeutic principle in Parkinson's disease, but the underlying mechanisms, particularly mediating non-motor actions, remain largely enigmatic. OBJECTIVE/HYPOTHESIS: The delayed onset of neuropsychiatric actions in conjunction with first experimental evidence that STN-DBS causes disease-modifying effects prompted our investigation on how cellular plasticity in midbrain dopaminergic systems is affected by STN-DBS. METHODS: We applied unilateral or bilateral STN-DBS in two independent cohorts of 6-hydroxydopamine hemiparkinsonian rats four to eight weeks after dopaminergic lesioning to allow for the development of a stable dopaminergic dysfunction prior to DBS electrode implantation. RESULTS: After 5 weeks of STN-DBS, stimulated animals had significantly more TH+ dopaminergic neurons and fibres in both the nigrostriatal and the mesolimbic systems compared to sham controls with large effect sizes of gHedges = 1.9-3.4. DBS of the entopeduncular nucleus as the homologue of the human Globus pallidus internus did not alter the dopaminergic systems. STN-DBS effects on mesolimbic dopaminergic neurons were largely confirmed in an independent animal cohort with unilateral STN stimulation for 6 weeks or for 3 weeks followed by a 3 weeks washout period. The latter subgroup even demonstrated persistent mesolimbic dopaminergic plasticity after washout. Pilot behavioural testing showed that augmentative dopaminergic effects on the mesolimbic system by STN-DBS might translate into improvement of sensorimotor neglect. CONCLUSIONS: Our data support sustained neurorestorative effects of STN-DBS not only in the nigrostriatal but also in the mesolimbic system as a potential factor mediating long-latency neuropsychiatric effects of STN-DBS in Parkinson's disease.

Traumatic Stress, Chronic Ethanol Exposure, or the Combination, Alter Cannabinoid System Components in Reward and Limbic Regions of the Mouse Brain.

The cannabinoid system is independently affected by stress and chronic ethanol exposure. However, the extent to which co-occurrence of traumatic stress and chronic ethanol exposure modulates the cannabinoid system remains unclear. We examined levels of cannabinoid system components, anandamide, 2-arachidonoylglycerol, fatty acid amide hydrolase, and monoacylglycerol lipase after mouse single-prolonged stress (mSPS) or non-mSPS (Control) exposure, with chronic intermittent ethanol (CIE) vapor or without CIE vapor (Air) across several brain regions using ultra-high-performance liquid chromatography tandem mass spectrometry or immunoblotting. Compared to mSPS-Air mice, anandamide and 2-arachidonoylglycerol levels in the anterior striatum were increased in mSPS-CIE mice. In the dorsal hippocampus, anandamide content was increased in Control-CIE mice compared to Control-Air, mSPS-Air, or mSPS-CIE mice. Finally, amygdalar anandamide content was increased in Control-CIE mice compared to Control-Air, or mSPS-CIE mice, but the anandamide content was decreased in mSPS-CIE compared to mSPS-Air mice. Based on these data we conclude that the effects of combined traumatic stress and chronic ethanol exposure on the cannabinoid system in reward pathway regions are driven by CIE exposure and that traumatic stress affects the cannabinoid components in limbic regions, warranting future investigation of neurotherapeutic treatment to attenuate these effects.

Voluntary binge-patterned alcohol drinking and sex-specific influences on monoamine-related neurochemical signatures in the mouse gut and brain.

BACKGROUND: Altered monoamine (i.e., serotonin, dopamine, and norepinephrine) activity following episodes of alcohol abuse plays key roles not only in the motivation to ingest ethanol, but also physiological dysfunction related to its misuse. Although monoamine activity is essential for physiological processes that require coordinated communication across the gut-brain axis (GBA), relatively little is known about how alcohol misuse may affect monoamine levels across the GBA. Therefore, we evaluated monoamine activity across the mouse gut and brain following episodes of binge-patterned ethanol drinking. METHODS: Monoamine and select metabolite neurochemical concentrations were analyzed by ultra-high-performance liquid chromatography in gut and brain regions of female and male C57BL/6J mice following "Drinking in the Dark" (DID), a binge-patterned ethanol ingestion paradigm. RESULTS: First, we found that alcohol access had an overall small effect on gut monoamine-related neurochemical concentrations, primarily influencing dopamine activity. Second, neurochemical patterns between the small intestine and the striatum were correlated, adding to recent evidence of modulatory activity between these areas. Third, although alcohol access robustly influenced activity in brain areas in the mesolimbic dopamine system, binge exposure also influenced monoaminergic activity in the hypothalamic region. Finally, sex differences were observed in the concentrations of neurochemicals within the gut, which was particularly pronounced in the small intestine. CONCLUSION: Together, these data provide insights into the influence of alcohol abuse and biological sex on monoamine-related neurochemical changes across the GBA, which could have important implications for GBA function and dysfunction.