Mesolimbic Dopamine Transmission Research Articles

Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission.

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Ventral tegmental area dopaminergic circuits participates in stress-induced chronic postsurgical pain in male mice

BackgroundChronic postsurgical pain (CPP) markedly impairs patients’ quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS.MethodsWe conducted CSDS on C57BL/6 J wild-type male mice (n = 12–16 mice/group) and DAT-cre male mice (n = 10–12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC.ResultsThe ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC.ConclusionCSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

Interleukin-10 enhances activity of ventral tegmental area dopamine neurons resulting in increased dopamine release

Dopamine transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) regulates important aspects of motivation and is influenced by the neuroimmune system. The neuroimmune system is a complex network of leukocytes, microglia and astrocytes that detect and remove foreign threats like bacteria or viruses and communicate with each other to regulate non-immune (e.g neuronal) cell activity through cytokine signaling. Inflammation is a key regulator of motivational states, though the effects of specific cytokines on VTA circuitry and motivation are largely unknown. Therefore, electrophysiology, neurochemical, immunohistochemical and behavioral studies were performed to determine the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) on mesolimbic activity, dopamine transmission and conditioned behavior. IL-10 enhanced VTA dopamine firing and NAc dopamine levels via decreased VTA GABA currents in dopamine neurons. The IL-10 receptor was localized on VTA dopamine and non-dopamine cells. The IL-10 effects on dopamine neurons required post-synaptic phosphoinositide 3-kinase activity, and IL-10 appeared to have little-to-no efficacy on presynaptic GABA terminals. Intracranial IL-10 enhanced NAc dopamine levels in vivo and produced conditioned place aversion. Together, these studies identify the IL-10R on VTA dopamine neurons as a potential regulator of motivational states.

FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

Effects of chronic delta-opioid receptor agonist on the excitability of hippocampal glutamate and brainstem monoamine neurons, anxiety, locomotion, and habituation in rats.

Short-term treatment with non-peptide agonists of delta-opioid receptors, such as agonist SNC80, induced behavioral effects in rodents, which could be modulated via changes in central neurotransmission. The present experiments aimed at testing the hypothesis that chronic treatment with SNC80 induces anxiolytic effects associated with changes in hippocampal glutamate and brainstem monoamine pathways. Adult male Wistar rats were used in experiments. Rats were treated with SNC80 (3mg/kg/day) for fourteen days. Neuronal excitability was assessed using extracellular in vivo single-unit electrophysiology. The behavioral parameters were examined using the elevated plus maze and open field tests. Chronic SNC80 treatment increased the excitability of hippocampal glutamate and ventral tegmental area dopamine neurons and had no effect on the firing activity of dorsal raphe nucleus serotonin cells. Chronic SNC80 treatment induced anxiolytic effects, which were, however, confounded by increased locomotor activity clearly confirmed in an open field test. The ability to cope with stressful situations and habituation processes in a novel environment was not influenced by chronic treatment with SNC80. Our study suggests that the psychoactive effects of SNC80 might be explained by its ability to stimulate hippocampal glutamate and mesolimbic dopamine transmission.

The involvement of dopamine and D2 receptor-mediated transmission in effects of cotinine in male rats

Previous studies indicated that cotinine, the major metabolite of nicotine, supported intravenous self-administration and exhibited relapse-like drug-seeking behaviors in rats. Subsequent studies started to reveal an important role of the mesolimbic dopamine system in cotinine's effects. Passive administration of cotinine elevated extracellular dopamine levels in the nucleus accumbens (NAC) and the D1 receptor antagonist SCH23390 attenuated cotinine self-administration. The objective of the current study was to further investigate the role of mesolimbic dopamine system in mediating cotinine's effects in male rats. Conventional microdialysis was conducted to examine NAC dopamine changes during active self-administration. Quantitative microdialysis and Western blot were used to determine cotinine-induced neuroadaptations within the NAC. Behavioral pharmacology was performed to investigate potential involvement of D2-like receptors in cotinine self-administration and relapse-like behaviors. NAC extracellular dopamine levels increased during active self-administration of cotinine and nicotine with less robust increase during cotinine self-administration. Repeated subcutaneous injections of cotinine reduced basal extracellular dopamine concentrations without altering dopamine reuptake in the NAC. Chronic self-administration of cotinine led to reduced protein expression of D2 receptors within the core but not shell subregion of the NAC, but did not change either D1 receptors or tyrosine hydroxylase in either subregion. On the other hand, chronic nicotine self-administration had no significant effect on any of these proteins. Systemic administration of eticlopride, a D2-like receptor antagonist attenuated both cotinine self-administration and cue-induced reinstatement of cotinine seeking. These results further support the hypothesis that the mesolimbic dopamine transmission plays a critical role in mediating reinforcing effects of cotinine.

Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens.

The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc), underlies the reward properties of ethanol (EtOH) and nicotine (NIC). We have shown previously that EtOH and NIC modulation of DA release in the NAc is mediated by α6-containing nicotinic acetylcholine receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and that α6*-nAChRs may be a molecular target for low-dose EtOH. However, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. The aim of this study was to evaluate EtOH effects on GABAergic modulation of VTA GABA neurons and VTA GABAergic input to cholinergic interneurons (CINs) in the NAc. Low-dose EtOH enhanced GABAergic input to VTA GABA neurons that was blocked by knockdown of α6*-nAChRs. Knockdown was achieved either by α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice or by superfusion of the α-conotoxin MII[H9A;L15A] (MII). Superfusion of MII blocked EtOH inhibition of mIPSCs in NAc CINs. Concomitantly, EtOH enhanced CIN firing rate, which was blocked by knockdown of α6*-nAChRs with α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice. The firing rate of CINs was not enhanced by EtOH in EtOH-dependent mice, and low-frequency stimulation (LFS; 1Hz, 240 pulses) caused inhibitory long-term depression at this synapse (VTA-NAc CIN-iLTD) which was blocked by knockdown of α6*-nAChR and MII. Ethanol inhibition of CIN-mediated evoked DA release in the NAc was blocked by MII. Taken together, these findings suggest that α6*-nAChRs in the VTA-NAc pathway are sensitive to low-dose EtOH and play a role in plasticity associated with chronic EtOH.

The multitarget FAAH inhibitor/D3 partial agonist ARN15381 decreases nicotine self-administration in male rats

Tobacco use disorder is a worldwide health problem for which available medications show limited efficacy. Nicotine is the psychoactive component of tobacco responsible for its addictive liability. Similar to other addictive drugs, nicotine enhances mesolimbic dopamine transmission. Inhibition of the fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), reduces nicotine-enhanced dopamine transmission and acquisition of nicotine self-administration in rats. Down-regulation of dopamine transmission by antagonists or partial agonists of the dopamine D3 receptor (DRD3) also reduced nicotine self-administration and conditioned place preference. Based on these premises, we evaluated the effect of ARN15381, a multitarget compound showing FAAH inhibition and DRD3 partial agonist activity in the low nanomolar range, on nicotine self-administration in rats. Pretreatment with ARN15381 dose dependently decreased self-administration of a nicotine dose at the top of the nicotine dose/response (D/R) curve, while it did not affect self-administration of a nicotine dose laying on the descending limb of the D/R curve. Conversely, pretreatment with the selective FAAH inhibitor URB597 and the DRD3 partial agonist CJB090 failed to modify nicotine self-administration independent of the nicotine dose self-administered. Our data indicates that the concomitant FAAH inhibition and DRD3 partial agonism produced by ARN15381 is key to the observed reduction of nicotine self-administration, demonstrating that a multitarget approach may hold clinical importance for the treatment of tobacco use disorder.

Distinct dose-dependent effects of methamphetamine on real-time dopamine transmission in the rat nucleus accumbens and behaviors.

Methamphetamine (METH) is a potent psychostimulant that exerts many of its physiological and psychomotor effects by increasing extracellular dopamine (DA) concentrations in limbic brain regions. While several studies have focused on how potent, neurotoxic doses of METH augment or attenuate DA transmission, the acute effects of lower and behaviorally activating doses of METH on modulating DA regulation (release and clearance) through DA D2 autoreceptors and transporters remain to be elucidated. In this study, we investigated how systemic administration of escalating, subneurotoxic doses of METH (0.5-5mg/kg, IP) alter extracellular DA regulation in the nucleus accumbens (NAc), in both anesthetized and awake-behaving rats through the use of in vivo fast-scan cyclic voltammetry. Pharmacological, electrochemical, and behavioral evidence show that lower doses (≤2.0mg/kg, IP) of METH enhance extracellular phasic DA concentrations and locomotion as well as stereotypies. In contrast, higher doses (≥5.0mg/kg) further increase both phasic and baseline DA concentrations and stereotypies but decrease horizontal locomotion. Importantly, our results suggest that acute METH-induced enhancement of extracellular DA concentrations dose dependently activates D2 autoreceptors. Therefore, these different METH dose-dependent effects on mesolimbic DA transmission may distinctly impact METH-induced behavioral changes. This study provides valuable insights regarding how low METH doses alter DA transmission and paves the way for future clinical studies on the reinforcing effects of METH.

Chronic Red Bull Consumption during Adolescence: Effect on Mesocortical and Mesolimbic Dopamine Transmission and Cardiovascular System in Adult Rats

Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment.

Regulator of G protein signaling 6 (RGS6) is a critical modulator of reward behavior and dopamine signaling in the mesolimbic circuit

Spicer MM1,2, Weber MA3, Yang J1, Stewart AM6, Luo Z5, Yang J1, Narayanan NS3,4, and Fisher RA1,2,4. 1Department of Neuroscience & Pharmacology, 2Interdisciplinary Graduate Program in Molecular Medicine, 3Department of Neurology, 4Iowa Neuroscience Institute, 5Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 6Department of Biomedical Sciences, Florida Atlantic University Brain Institute, Florida Atlantic University, Boca Raton, FL 33431 Alcohol (EtOH) is the most commonly abused drug worldwide and chronic EtOH consumption often leads to development of dependence and abuse. EtOH dependence is characterized by progressive, neuroadaptive changes to the brain's reward system resulting from chronic EtOH exposure. The neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, resulting in limited therapeutics. Currently, abstinence remains the only effective way to prevent alcohol use disorders (AUDs). We previously discovered that loss of RGS6 in mice leads to reduced EtOH seeking and reward behaviors. GABAB and D2 autoreceptor (D2R) antagonism partially reduced EtOH seeking in RGS6-/- mice, whereas singular inhibition of the dopamine (DA) transporter (DAT) completely reversed this effect. Moreover, RGS6-/- mice exhibited reduced striatal DA content. These findings led us to hypothesize that RGS6 promotes mesolimbic DA neurotransmission by suppressing GPCR-Gαi/o-mediated upregulation of DAT. To investigate this possibility, we examined the effects of RGS6 loss on DAT expression in VTA cell bodies and synaptic terminals in the nucleus accumbens (NAcc). In addition, we examined the effects of RGS6 loss on mesolimbic neuronal activity and DA transmission using c-Fos staining and EtOH-induced release of DA from VTA neurons, respectively. We found robust RGS6 expression in VTA cell bodies and terminals, where its loss led to upregulated expression of DAT. Additionally, RGS6 loss reduced VTA neuronal activity as measured by c-Fos immunostaining. These findings suggest that RGS6 functions to promote EtOH seeking and reward behavior by promoting DA transmission in the mesolimbic circuit by suppressing GPCR-Gαi/o signaling, thereby promoting VTA neuronal activity and suppressing DAT upregulation.

Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage.

Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5–25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to β-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.

Mice with dopaminergic neuron-specific deletion of DTNBP-1 gene show blunted nucleus accumbens dopamine release and associated behaviors

Reduced expression of a schizophrenia-associated gene Dystrobrevin Binding Protein 1 (DTNBP1) and its protein product dysbindin-1, has been reported in the brains of schizophrenia patients. DTNBP1-null mutant Sdy (Sandy) mice exhibit several behavioral features relevant to schizophrenia. Changes in dopaminergic as well as glutamatergic and GABAergic neurotransmission in cortico-limbic regions have been reported in Sdy mice. Since dysbindin-1 is expressed in multiple brain regions, it is not known whether dopamine (DA) changes observed in Sdy null mutants are due to dysbindin-1 deficiency in DAergic neurons specifically. Here, using a mouse line with conditional knockout (cKO) of DTNBP1 in DA neurons, we studied the effects of dysbindin-1 deficiency on DA release and DA-dependent behaviors. Spontaneous locomotor activity of cKO mice in novel environment was significantly reduced initially but was comparable at later time points with littermate controls. However, the locomotion-enhancing effect of a low dose of d-amphetamine (d-AMPH; 2.5 mg/kg, ip) was significantly attenuated in the cKO mice suggesting a dampened mesolimbic DA transmission. Similarly, the prepulse inhibition disrupting effect of d-AMPH was found to be significantly reduced in the mutant mice. No significant differences between the cKO and control mice were observed in tests of anxiety, spatial learning and memory and social interaction. In- vivo microdialysis in the nucleus accumbens (NAc) showed a decrease in d-AMPH-induced extracellular DA release in the cKO mice. No significant alterations in protein levels of DA transporter, phosphorylated CaM kinase-II or Akt308 in the NAc were observed in the cKO mice. Taken together, our data suggest an important role of dysbindin-1 in maintaining mesolimbic DA tone and call for further investigations identifying mechanisms linking dysbindin-1, DA and schizophrenia.

Cerebellar Modulation of Mesolimbic Dopamine Transmission Is Functionally Asymmetrical.

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed potential amperometry with carbon fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.

Role of genetic background in the effects of adolescent nicotine exposure on mesolimbic dopamine transmission.

Smoking during adolescence may increase the likelihood to develop nicotine dependence and to abuse other drugs such as cocaine. Despite great efforts to understand underlying neurobiological mechanisms of this progression, less attention has been paid to the role of genetic factors. Here, we investigated the influence of both genetic background and age at first nicotine exposure in the long-lasting effects on mesolimbic dopamine transmission including the increased cocaine-rewarding effect. Mid-adolescent and adult rats of inbred strains Lewis (addiction prone) and Fischer 344 (addiction resistant) were administered nicotine (0.4 mg/kg) or vehicle once daily for 5 days. Changes in dopamine transmission were investigated by in vivo microdialysis and electrophysiology after 30 days of withdrawal, whereas changes in cocaine-rewarding effect were assessed via conditioned place preference paradigm. Nicotine pre-exposure differentially changed mesolimbic dopamine transmission depending on strain and age of pre-exposure. A potentiation of dopamine response to nicotine was observed in nucleus accumbens (NAc) core of both strains and age groups, whereas dopamine response in NAc shell was enhanced exclusively in Lewis rats exposed to nicotine during adolescence. A similar response was observed following cocaine challenge at adulthood. Changes in VTA dopamine cell population and activity were observed only in adolescent nicotine-pretreated Lewis rats, which also showed an increased cocaine-rewarding effect at adulthood. These results highlight the influence of genetic background in the long-lasting effects of nicotine exposure and suggest that exposure during adolescence might increase nicotine and cocaine-rewarding properties in genetically vulnerable individuals, thereby facilitating progression toward dependence.

Systemic oxytocin administration alters mesolimbic dopamine release in mice

Growing research indicates oxytocin may be involved in relieving anxiety and attenuating the rewarding effects of psychostimulants. This study investigated the effects of subchronic oxytocin treatments on mesolimbic dopamine transmission in areas associated with anxiety and addiction, the amygdala and the nucleus accumbens (NAc), respectively. Using in vivo fixed potential amperometry, stimulation-evoked dopamine release was recorded in anesthetized mice pretreated with subchronic oxytocin (four i.p. injections of 1 mg/kg oxytocin or saline with 48 h between injections). During dopamine recordings, mice received an i.p. drug challenge of either oxytocin (1 mg/kg), the dopamine reuptake blocker nomifensine (10 mg/kg), or saline. Overall, subchronic oxytocin pretreatment did alter properties of dopamine release in these limbic structures. In the amygdala, dopamine release was decreased following the oxytocin challenge but only in oxytocin pretreated mice. In the NAc, baseline dopamine release was attenuated in oxytocin pretreated mice relative to saline pretreated mice. Furthermore, oxytocin pretreated mice displayed a reduced dopaminergic response to the drug challenge of nomifensine relative to control mice. Together these results suggest that oxytocin may be useful at treating aspects of anxiety and drug abuse. Elucidating the neural effects of oxytocin is critical given the multitude of potential therapeutic uses for this drug.

Decrease in Operant Responding Under Obesogenic Diet Exposure is not Related to Deficits in Incentive or Hedonic Processes.

A growing body of evidence suggests that obesity could result from alterations in reward processing. In rodent models, chronic exposure to an obesogenic diet leads to blunted dopamine signaling and related incentive responding. This study aimed to determine which reward-related behavioral dimensions are actually impacted by obesogenic diet exposure. Mice were chronically exposed to an obesogenic diet. Incentive and hedonic processes were tested through operant conditioning and licking microstructures, respectively. In parallel, mesolimbic dopamine transmission was assessed using microdialysis. Prolonged high-fat (HF) diet exposure led to blunted mesolimbic dopamine release, paralleled by a decrease in operant responding in all schedules tested. HF-fed and control animals similarly decreased their operant responding in an effort-based choice task, and HF-fed animals displayed an overall lower calorie intake in this task. Analysis of the licking microstructures during consumption of a freely accessible reward suggested a decrease in basal hunger and a potentiation of gastrointestinal inhibition in HF-fed animals, without changes in hedonic reactivity. These results suggest that the decrease in operant responding under prolonged HF diet exposure is mainly driven by decrease in hunger as well as stronger postingestive negative feedback mechanisms, rather than by a decrease in incentive or hedonic responses.

Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol.

Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self-administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons. Whole-cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons inthe VTA of GAD67-GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure. Acute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol. These results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission.

Mesolimbic dopamine system and its modulation by vitamin D in a chronic mild stress model of depression in the rat

Depression, a common mood disorder, involves anhedonia and defects in reward circuits and mesolimbic dopamine transmission in the striatum and nucleus accumbens (NAc). Active vitamin-D, (1,25-(OH)2 vitamin-D3), exerts protective and regulatory effects on the brain dopamine system. In this study, key depression-like symptoms were induced in rats by chronic mild-stress (CMS) and the comparative effect of treatment with 1,25-(OH)2 vitamin-D3 (5, 10 μg/kg, or vehicle; i.p., twice weekly) or fluoxetine (5 mg/kg or vehicle, i.p., daily) on anhedonic behavior, locomotor activity and anxiety-like behavior was examined using sucrose preference test (SPT), open field test (OFT) and novel object exploration test (NOT), respectively. We also measured serum corticosterone levels and dopamine transporter-immunoreactivity (DAT-ir) levels in NAc shell and core. CMS exposure for 3 weeks was followed by a SPT and thereafter CMS was continued for 5 weeks, along with vitamin-D or fluoxetine treatment and further testing, which was concluded with another SPT. Vitamin-D treatment enhanced sucrose preference (P < 0.01; an hedonic effect) and increased object exploration (P < 0.01) in CMS rats. CMS significantly reduced the level of DAT-ir in NAc (P < 0.0001). Vitamin-D treatment restored/increased DAT-ir levels (P < 0.0001) in CMS rat NAc (core/ shell), compared to levels in fluoxetine treated and non-treated CMS rats. Vitamin-D did not alter locomotor activity or produce an anxiolytic effect in the OFT. These data suggest that similar to the antidepressant, fluoxetine, regular vitamin-D treatment can improve ‘anhedonia-like symptoms’ in rats subjected to CMS, probably by regulating the effect of dopamine-related actions in the NAc.