Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use.

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

Subthalamic Nucleus Stimulation Impairs Motivation: Implication for Apathy in Parkinson's Disease.

BACKGROUND: Apathy is one of the most disabling neuropsychiatric symptoms in Parkinson's disease (PD) patients and has a higher prevalence in patients under subthalamic nucleus deep brain stimulation. Indeed, despite its effectiveness for alleviating PD motor symptoms, its neuropsychiatric repercussions have not yet been fully uncovered. Because it can be alleviated by dopaminergic therapies, especially D2 and D3 dopaminergic receptor agonists, the commonest explanation proposed for apathy after subthalamic nucleus deep brain stimulation is a too-strong reduction in dopaminergic treatments. The objective of this study was to determine whether subthalamic nucleus deep brain stimulation can induce apathetic behaviors, which remains an important matter of concern. We aimed to unambiguously address this question of the motivational effects of chronic subthalamic nucleus deep brain stimulation. METHODS: We longitudinally assessed the motivational effects of chronic subthalamic nucleus deep brain stimulation by using innovative wireless microstimulators, allowing continuous stimulation of the subthalamic nucleus in freely moving rats and a pharmacological therapeutic approach. RESULTS: We showed for the first time that subthalamic nucleus deep brain stimulation induces a motivational deficit in naive rats and intensifies those existing in a rodent model of PD neuropsychiatric symptoms. As reported from clinical studies, this loss of motivation was fully reversed by chronic treatment with pramipexole, a D2 and D3 dopaminergic receptor agonist. CONCLUSIONS: Taken together, these data provide experimental evidence that chronic subthalamic nucleus deep brain stimulation by itself can induce loss of motivation, reminiscent of apathy, independently of the dopaminergic neurodegenerative process or reduction in dopamine replacement therapy, presumably reflecting a dopaminergic-driven deficit. Therefore, our data help to clarify and reconcile conflicting clinical observations by highlighting some of the mechanisms of the neuropsychiatric side effects induced by chronic subthalamic nucleus deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

Psychostimulant effect of dopaminergic treatment and addictions in Parkinson's disease.

BACKGROUND: Dopamine replacement therapy in PD has been associated with both behavioral addictions and dopamine addiction. OBJECTIVES: To investigate potential association between l-dopa induced neuropsychiatric fluctuations and addictions in PD. METHODS: A cohort of 102 patients with PD suffering from motor complications of l-dopa treatment was prospectively analyzed. We evaluated dopamine addiction, behavioral addictions, and neuropsychiatric fluctuations using the Ardouin scale of behavior in PD. RESULTS: Patients with (n = 51) or without (n = 51) neuropsychiatric fluctuations did not differ in age, disease duration, medication, or UPDRS III motor score during on and off drug condition. Patients with neuropsychiatric fluctuations had a higher H & Y stage in off-drug condition. A multivariate model showed that dopamine addiction (odds ratio: 8.9; P = 0.02) and behavioral addictions (odds ratio: 3.76; P = 0.033) were more frequent in the presence of neuropsychiatric fluctuations. Behavioral addictions and dopamine addiction were more frequent in the presence than in the absence of on-drug euphoria (46% vs. 13.9%; P < 0.001 and 27% vs 6.2 %; P = 0.003), while conversely, no association emerged between dopamine or behavioral addictions and presence of off-drug dysphoria. Patients with neuropsychiatric fluctuations had a poorer quality of life and a more frequent history of anxiety disorder. CONCLUSIONS: The psychostimulant effects of dopamine treatment during on-drug euphoria, rather than avoidance of off-drug dysphoria, appear to drive both behavioral addictions and abuse of medication. © 2017 International Parkinson and Movement Disorder Society.

Emotional manifestations of PD: Neurobiological basis.

Neuropsychiatric symptoms are common and disabling in PD. Their neurobiological bases are complex, partly because of the disease itself and partly because of the dopaminergic treatment. The aim of this review is to focus on the emotional manifestations stemming from the neurodegenerative process itself. We focus on depression, anxiety, apathy, and fatigue, which can all be part of the clinical spectrum of premotor disease and may be improved or masked by medications targeting parkinsonian motor signs or psychiatric symptoms as the disease progresses. Findings from clinical, neuroimaging, and animal studies are reviewed, showing a major contribution of the dopaminergic system to the pathophysiology of these disabling symptoms. Degeneration of noradrenergic and serotonergic projection systems also has an impact on psychiatric symptoms of PD. The available literature is reviewed, but at present there is a lack of studies that would allow disentangling the separate contribution of each of the monoaminergic systems. The use of a pragmatic classification of all these symptoms under the umbrella of hypodopaminergic behavioral syndrome seems clinically useful, as it emphasizes the crucial, although not exclusive, nature of their dopaminergic neurobiological basis, which has important implications in the clinical management of PD. © 2016 International Parkinson and Movement Disorder Society.

Subthalamic deep brain stimulation differently alters striatal dopaminergic receptor levels in rats.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as an effective treatment for the motor symptoms of Parkinson's disease (PD), but its mechanisms, particularly as concern dopaminergic transmission, remain unclear. The aim of this study was to evaluate changes in the expression of dopaminergic receptors (D1, D2, and D3 receptors) after prolonged (4 h) unilateral STN-HFS in anesthetized intact rats and rats with total dopaminergic denervation. We used [(3)H]SCH 23390, [(125)I]iodosulpride, and [(125)I]OH-PIPAT to assess the densities of D1R, D2R, and D3R, respectively, within different areas of the striatum-a major input structure of the basal ganglia-including the nucleus accumbens. We found that STN-HFS increased D1 R levels in almost all of the striatal areas examined, in both intact and denervated rats. By contrast, STN-HFS led to a large decrease in D2 R and D3R levels, limited to the nucleus accumbens and independent of the dopaminergic state of the animals. These data suggest that the influence of STN-HFS on striatal D1 R expression may contribute to its therapeutic effects on motor symptoms, whereas its impact on D2R/D3 R levels in the nucleus accumbens may account for the neuropsychiatric side effects often observed in stimulated PD patients, such as postoperative apathy.

Pramipexole reverses Parkinson's disease-related motivational deficits in rats.

Recent evidence suggests that Parkinson's disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal-directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion-based model, with stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6-OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD-associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD.

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks.

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modeling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

The small G protein H-Ras in the mesolimbic system is a molecular gateway to alcohol-seeking and excessive drinking behaviors.

Uncontrolled consumption of alcohol is a hallmark of alcohol abuse disorders; however, the central molecular mechanisms underlying excessive alcohol consumption are still unclear. Here, we report that the GTP binding protein, H-Ras in the nucleus accumbens (NAc) plays a key role in neuroadaptations that underlie excessive alcohol-drinking behaviors. Specifically, acute (15 min) systemic administration of alcohol (2.5 g/kg) leads to the activation of H-Ras in the NAc of mice, which is observed even 24 h later. Similarly, rat operant self-administration of alcohol (20%) also results in the activation of H-Ras in the NAc. Using the same procedures, we provide evidence suggesting that the exchange factor GRF1 is upstream of H-Ras activation by alcohol. Importantly, we show that infection of mice NAc with lentivirus expressing a short hairpin RNA that targets the H-Ras gene produces a significant reduction of voluntary consumption of 20% alcohol. In contrast, knockdown of H-Ras in the NAc of mice did not alter water, quinine, and saccharin intake. Furthermore, using two-bottle choice and operant self-administration procedures, we show that inhibiting H-Ras activity by intra-NAc infusion of the farnesyltransferase inhibitor, FTI-276, produced a robust decrease of rats' alcohol drinking; however, sucrose consumption was unaltered. Finally, intra-NAc infusion of FTI-276 also resulted in an attenuation of seeking for alcohol. Together, these results position H-Ras as a central molecular mediator of alcohol's actions within the mesolimbic system and put forward the potential value of the enzyme as a novel target to treat alcohol use disorders.

Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior.

We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.

Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours.

Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinson's disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinson's disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinson's disease may be considered as new indications for subthalamic stimulation.

Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders.

Alcohol addiction is a chronically relapsing disorder that includes certain maladaptive learning and memory. The serine and threonine kinase complex, mammalian target of rapamycin complex 1 (mTORC1), has been implicated in synaptic plasticity, learning, and memory by controlling protein translation. Here we show that administration of alcohol and excessive voluntary consumption of alcohol induce the activation of the mTORC1-mediated signaling pathway in the nucleus accumbens (NAc) of rodents. We further show that the protein expression levels of GluR1 and Homer, two synaptic proteins whose translation has been shown to be modulated by mTORC1, are up-regulated in the NAc of rodents with a history of excessive alcohol consumption. In addition, our results document that the Food and Drug Administration-approved inhibitor of mTORC1, rapamycin, decreases expression of alcohol-induced locomotor sensitization and place preference, as well as excessive alcohol intake and seeking in preclinical rodent models of alcohol abuse. Together, our results suggest that mTORC1 within the NAc is a contributor to molecular mechanisms underlying alcohol-drinking behaviors. Furthermore, despite its massive health and socioeconomic impact worldwide, pharmacotherapies for alcohol abuse and addiction remain limited. Our data therefore put forward the possibility that targeting the mTORC1 signaling cascade is an innovative and valuable strategy for the treatment of alcohol use and abuse disorders.

Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson's Disease.

Parkinson's disease (PD), which is traditionally viewed as a motor disorder involving the degeneration of dopaminergic (DA) neurons, has recently been identified as a quintessential neuropsychiatric condition. Indeed, a plethora of non-motor symptoms may occur in PD, including apathy. Apathy can be defined as a lack of motivation or a deficit of goal-directed behaviors and results in a pathological decrease of self-initiated voluntary behavior. Apathy in PD appears to fluctuate with the DA state of the patients, suggesting a critical role of DA neurotransmission in the pathophysiology of this neuropsychiatric syndrome. Using a lesion-based approach, we developed a rodent model which exhibits specific alteration in the preparatory component of motivational processes, reminiscent to apathy in PD. We found a selective decrease of DA D3 receptors (D3R) expression in the dorsal striatum of lesioned rats. Next, we showed that inhibition of D3R neurotransmission in non-lesioned animals was sufficient to reproduce the motivational deficit observed in our model. Interestingly, we also found that pharmacologically targeting D3R efficiently reversed the motivational deficit induced by the lesion. Our findings, among other recent data, suggest a critical role of D3R in parkinsonian apathy and highlight this receptor as a promising target for treating motivational deficits.

Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: implications for alcohol reward and seeking.

We previously showed that infusion of glial cell line-derived neurotrophic factor (GDNF) into the ventral tegmental area (VTA) rapidly reduces alcohol intake and relapse (Carnicella et al., 2008, 2009a), and increases dopamine (DA) levels in the nucleus accumbens (NAc) of alcohol-naive rats (Wang et al., 2010). Withdrawal from excessive alcohol intake is associated with a reduction in NAc DA levels, whereas drug-induced increases in NAc DA levels are associated with reward. We therefore tested whether GDNF in the VTA reverses alcohol withdrawal-associated DA deficiency and/or possesses rewarding properties. Rats were trained for 7 weeks to consume high levels of alcohol (5.47 ± 0.37 g/kg/24 h) in intermittent access to 20% alcohol in a two-bottle choice procedure. Using in vivo microdialysis, we show that 24 h withdrawal from alcohol causes a substantial reduction in NAc DA overflow, which was reversed by intra-VTA GDNF infusion. Using conditioned place preference (CPP) paradigm, we observed that GDNF on its own does not induce CPP, suggesting that the growth factor is not rewarding. However, GDNF blocked acquisition and expression of alcohol-CPP. In addition, GDNF induced a downward shift in the dose-response curve for operant self-administration of alcohol, further suggesting that GDNF suppresses, rather than substitutes for, the reinforcing effects of alcohol. Our findings suggest that GDNF reduces alcohol-drinking behaviors by reversing an alcohol-induced allostatic DA deficiency in the mesolimbic system. In addition, as it lacks abuse liability, the study further highlights GDNF as a promising target for treatment of alcohol use/abuse disorders.

Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson's Disease.

A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson's disease (PD). Central regulators of energy production, mitochondria, are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. We investigated behavioral, cellular, and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrially related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. MSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation, and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation, and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. MSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.

A metabolic biomarker predicts Parkinson's disease at the early stages in patients and animal models.

BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.FundingFrench National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.

Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse.

A growing number of studies suggest that the development of compulsive drug seeking and taking depends on dorsostriatal mechanisms. We previously observed that ex vivo acute exposure of the dorsal striatum to, and withdrawal from, alcohol induces long-term facilitation (LTF) of the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in a mechanism that requires the Src family protein tyrosine kinase (PTK), Fyn (Wang et al., 2007). In the present study, we first compared alcohol's actions in rat dorsomedial (DMS) and the dorsolateral (DLS) subregions of the striatum, which differ in their anatomical connectivity and function. We found that alcohol-mediated induction of LTF of NR2B-NMDAR activity is centered in the DMS. Next, we tested whether in vivo exposure of rats to alcohol leads to long-term adaptations of the NMDAR system in the DMS. We observed that repeated daily administration of alcohol results in a long-lasting increase in the activity of the NR2B-NMDARs in the DMS. The same procedure leads to a prolonged activation of Fyn, increased NR2B phosphorylation, and membrane localization of the subunit. Importantly, similar electrophysiological and biochemical modifications were observed in the DMS of rats that consumed large quantities of alcohol. Finally, we show that inhibition of NR2B-NMDARs or Src family PTKs in the DMS, but not in the DLS, significantly decreases operant self-administration of alcohol and reduces alcohol-priming-induced reinstatement of alcohol seeking. Our results suggest that the upregulation of NR2B-NMDAR activity within the DMS by alcohol contributes to the maladaptive synaptic changes that lead to excessive alcohol intake and relapse.

Nucleus accumbens-derived glial cell line-derived neurotrophic factor is a retrograde enhancer of dopaminergic tone in the mesocorticolimbic system.

Spontaneous firing of ventral tegmental area (VTA) dopamine (DA) neurons provides ambient levels of DA in target areas such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC). Here we report that the glial cell line-derived neurotrophic factor (GDNF), produced in one target region, the NAc, is retrogradely transported by DA neurons to the VTA where the growth factor positively regulates the spontaneous firing activity of both NAc- and PFC-projecting DA neurons in a mechanism that requires the activation of the mitogen-activated protein kinase (MAPK) pathway. We also show that the consequence of GDNF-mediated activation of the MAPK signaling cascade in the VTA is an increase in DA overflow in the NAc. Together, these results demonstrate that NAc-produced GDNF serves as a retrograde enhancer that upregulates the activity of the mesocorticolimbic DA system.

Regulation of operant oral ethanol self-administration: a dose-response curve study in rats.

BACKGROUND: Oral ethanol self-administration procedures in rats are useful preclinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation into the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose-response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored because of the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In this study, we set out to determine whether a meaningful dose-response curve for oral ethanol self-administration can be obtained in rats. METHODS: Long-Evans rats were trained to self-administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self-administration, the concentration of the solution was varied from 2.5 to 60% (v/v), and operant and drinking behaviors, as well as blood ethanol concentration (BEC), were evaluated following the self-administration of a 20, 40, and 60% ethanol solution. RESULTS: Varying the concentration of ethanol from 2.5 to 60% after the development of excessive ethanol consumption led to a typical inverted U-shaped dose-response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. CONCLUSION: This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders.