Ventral Tegmental Area Brain-derived Neurotrophic Factor Research Articles

7,8-Dihydroxyflavone Attenuates Alcohol-Related Behavior in Rat Models of Alcohol Consumption via TrkB in the Ventral Tegmental Area.

Alcohol use disorder (AUD) is a ubiquitous substance use disorder in the world, of which neural mechanisms remain unclear. Alcohol consumption induces neuro-adaptations in the dopaminergic system originating from the ventral tegmental area (VTA), an important brain region for the reward function in AUD. Endogenous brain-derived neurotrophic factor (BDNF)-TrkB implicated in the development of neuroplasticity, including long-term potentiation of GABAergic synapses (LTPGABA). We previously found that ethanol blocks LTPGABA in the VTA, either in vivo or in vitro. 7,8-dihydroflavone (7,8-DHF), a BDNF-mimicking small compound, was recently found to penetrate the blood–brain barrier to mimic the biological role of BDNF-TrkB. In this study, we demonstrate that repeated ethanol consumption (including intermittent and continuous ethanol exposure) results in low expression of BDNF in rat VTA. The amount of ethanol intake enhances significantly in rats with intermittent ethanol exposure after 72 h abstinence. Withdrawal signs emerge in rats with continuous ethanol exposure within 3 days after abstinence. Using behavioral tests, intraperitoneal injection of 7,8-DHF can reduce excessive ethanol consumption and preference as well as withdrawal signs in rats with repeated ethanol exposure. Interestingly, microinjection of K252a, an antagonist of TrkB, into the VTA blocks the effects of 7,8-DHF on ethanol-related behaviors. Furthermore, direct microinjection of BDNF into the VTA mimics the effect of 7,8-DHF on ethanol related behaviors. Taken together, 7,8-DHF attenuates alcohol-related behaviors in rats undergoing alcohol consumption via TrkB in the VTA. Our findings suggest BDNF-TrkB in VTA is a part of regulating signals for opposing neural adaptations in AUD, and 7,8-DHF may serve as a potential candidate for treating alcoholism.

Paternal preconception alcohol exposure imparts intergenerational alcohol-related behaviors to male offspring on a pure C57BL/6J background.

While alcohol use disorder (AUD) is a highly heritable condition, the basis of AUD in families with a history of alcoholism is difficult to explain by genetic variation alone. Emerging evidence suggests that parental experience prior to conception can affect inheritance of complex behaviors in offspring via non-genomic (epigenetic) mechanisms. For instance, male C57BL/6J (B6) mice exposed to chronic intermittent vapor ethanol (CIE) prior to mating with Strain 129S1/SvImJ ethanol-naïve females produce male offspring with reduced ethanol-drinking preference, increased ethanol sensitivity, and increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). In the present study, we tested the hypothesis that these intergenerational effects of paternal CIE are reproducible in male offspring on an inbred B6 background. To this end, B6 males were exposed to 6 weeks of CIE (or room air as a control) before mating with ethanol-naïve B6 females to produce ethanol (E)-sired and control (C)-sired male and female offspring. We observed a sex-specific effect, as E-sired males exhibited decreased two-bottle free-choice ethanol-drinking preference, increased sensitivity to the anxiolytic effects of ethanol, and increased VTA BDNF expression; no differences were observed in female offspring. These findings confirm and extend our previous results by demonstrating that the effects of paternal preconception ethanol are reproducible using genetically identical, inbred B6 animals.

Overexpression of BDNF in the ventral tegmental area enhances binge cocaine self-administration in rats exposed to repeated social defeat

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access “binge” cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.

Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress–Induced Depressive Behaviors

BackgroundPrevious work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical, as increased DA signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress is unknown. MethodsWe used CSDS with repeated optogenetic activation and pharmacologic manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. We measured BDNF protein expression and DA release in this model. ResultsPharmacologic blockade of BDNF–tyrosine receptor kinase B (TrkB) signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were blocked as well by local knockdown of BDNF in VTA. ConclusionsThese findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS and they establish BDNF-TrkB signaling as a pathologic mechanism during periods of chronic stress.

Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse.

BDNF Overexpression in the Ventral Tegmental Area Prolongs Social Defeat Stress-induced Cross-Sensitization to Amphetamine and Increases ΔFosB Expression in Mesocorticolimbic Regions of Rats

Social defeat stress induces persistent cross-sensitization to psychostimulants, but the molecular mechanisms underlying the development of cross-sensitization remain unclear. One candidate is brain-derived neurotrophic factor (BDNF). The present research examined whether ventral tegmental area (VTA) BDNF overexpression would prolong the time course of cross-sensitization after a single social defeat stress, which normally produces transient cross-sensitization lasting <1 week. ΔFosB, a classic molecular marker of addiction, was also measured in mesocorticolimbic terminal regions. Separate groups of intact male Sprague-Dawley rats underwent a single episode of social defeat stress or control handling, followed by amphetamine (AMPH) challenge 3 or 14 days later. AMPH cross-sensitization was apparent 3, but not 14, days after stress. Intra-VTA infusion of adeno-associated viral (AAV-BDNF) vector resulted in a twofold increase of BDNF level in comparison to the group receiving the control virus (AAV-GFP), which lasted at least 45 days. Additionally, overexpression of BDNF in the VTA alone increased ΔFosB in the nucleus accumbens (NAc) and prefrontal cortex. Fourteen days after viral infusions, a separate group of rats underwent a single social defeat stress or control handling and were challenged with AMPH 14 and 24 days after stress. AAV-BDNF rats exposed to stress showed prolonged cross-sensitization and facilitated sensitization to the second drug challenge. Immunohistochemistry showed that the combination of virally enhanced VTA BDNF, stress, and AMPH resulted in increased ΔFosB in the NAc shell compared with the other groups. Thus, elevation of VTA BDNF prolongs cross-sensitization, facilitates sensitization, and increases ΔFosB in mesocorticolimbic terminal regions. As such, elevated VTA BDNF may be a risk factor for drug sensitivity.

Altered Brain-Derived Neurotrophic Factor Expression in the Ventral Tegmental Area, but not in the Hippocampus, Is Essential for Antidepressant-Like Effects of Electroconvulsive Therapy

Impaired neuronal plasticity and, specifically, altered expression of brain-derived neurotrophic factor (BDNF) were shown to play a critical role in depressive behavior and the mechanism of various antidepressant treatments including electroconvulsive therapy (ECT). Interestingly, opposing roles were suggested for BDNF in the hippocampus and the ventral tegmental area (VTA), while interactions between these regions were shown on various levels. Here, we evaluated whether BDNF plays an essential role in the antidepressant-like effects of ECT and performed a direct comparison between BDNF manipulations in the VTA and the hippocampus. Knockdown or overexpression of BDNF was induced in hippocampus or VTA of rats by microinjection of specific lentiviral vectors. The effects of these manipulations on antidepressant outcomes of ECT were evaluated by the forced swim test and by sucrose preference measurements, and BDNF expression levels were assessed in other reward-related brain regions. Here, we show that whereas ECT increased hippocampal BDNF expression, induction of hippocampal BDNF knockdown did not block its antidepressant-like effect. Importantly, we found that ECT caused a robust reduction in VTA BDNF levels. Moreover, VTA BDNF knockdown alone was sufficient to induce an antidepressant-like effect, and VTA BDNF overexpression blocked the antidepressant-like effect of ECT. While neuroplastic alterations, as expressed by changes in BDNF expression within different brain regions, are induced by ECT, the antidepressant-like effect of ECT in an animal model depends on reduction of VTA BDNF expression but not on the elevation of hippocampal BDNF expression.

Increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area during cocaine abstinence is associated with increased histone acetylation at BDNF exon I-containing promoters.

Recent evidence suggests that the persistence of cocaine seeking during periods of protracted drug abstinence following chronic cocaine exposure is mediated, in part, by neuroadaptations in the mesolimbic dopamine system. Specifically, incubation of cocaine-seeking behavior coincides with increased brain-derived neurotrophic factor (BDNF) protein expression in the ventral tegmental area (VTA). However, the molecular mechanisms that regulate time-dependent changes in VTA BDNF protein expression during cocaine abstinence are unclear. The goal of these experiments was to determine whether VTA BDNF transcript levels are altered following cocaine abstinence and identify the molecular mechanisms regulating cocaine-induced changes in VTA BDNF transcription. Rats were allowed to self-administer cocaine (0.25 mg/infusion, i.v.) for 14 days on a fixed-ratio schedule of reinforcement followed by 7 days of forced drug abstinence. BDNF protein and exon I-containing transcripts were significantly increased in the VTA of cocaine-experienced rats following 7 days of forced drug abstinence compared to yoked saline controls. Cocaine-induced changes in BDNF mRNA were associated with increased acetylation of histone 3 and binding of CREB-binding protein to exon I-containing promoters in the VTA. Taken together, these results suggest that drug abstinence following cocaine self-administration remodels chromatin in the VTA resulting in increased expression of BDNF, which may contribute to neuroadaptations underlying cocaine craving and relapse.

Role of brain‐derived neurotrophic factor in the ventral tegmental area in social stress‐induced psychomotor sensitization using virus‐mediated gene‐transfer

Brain‐derived neurotrophic factor (BDNF) is a known mediator of brain plasticity and is produced by dopamine neurons in the ventral tegmental area (VTA). The VTA is involved in the reinforcing effects of abused drugs, and manipulation of VTA BDNF modulates drug‐directed behavior. Sensitization, a progressive increase of locomotor response to successive drug exposures, results from neuroadaptive changes in brain thought to parallel those involved in addiction. Intermittent social stress augments locomotor response to psychostimulants, known as cross‐sensitization. Recently, we found that intermittent social stress increases VTA BDNF, which may be important for adaptations leading to cross‐sensitization. Here we use adeno‐associated virus (AAV)‐mediated gene transfer to alter VTA BDNF in male rats. We show intra‐VTA infusion of AAV‐BDNF or AAV‐siRNA(bdnf) effectively increases or decreases VTA BDNF, respectively, and increases or decreases locomotor response to amphetamine, respectively. In addition, over‐expression of VTA BDNF augmented sensitization after a single stress, and knockdown of VTA BDNF attenuated sensitization after intermittent stress. Taken together, these data indicate that VTA BDNF plays a significant role in persistent sensitization after stress, and may be important for understanding the relationship between stress and addiction