Ventral Tegmental Area Dopamine System Research Articles

The Formation and Function of the VTA Dopamine System.

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well as maternal and reproductive behaviors. Dopamine is a neurotransmitter that binds to G-protein-coupled receptors. Dopamine also works together with other neurotransmitters and various neuropeptides to maintain the balance of synaptic functions. The dysfunction of the dopamine system leads to several conditions, including Parkinson's disease, Huntington's disease, major depression, schizophrenia, and drug addiction. The ventral tegmental area (VTA) has been identified as an important relay nucleus that modulates homeostatic plasticity in the midbrain dopamine system. Due to the complexity of synaptic transmissions and input-output connections in the VTA, the structure and function of this crucial brain region are still not fully understood. In this review article, we mainly focus on the cell types, neurotransmitters, neuropeptides, ion channels, receptors, and neural circuits of the VTA dopamine system, with the hope of obtaining new insight into the formation and function of this vital brain region.

Sex- and exposure age-dependent effects of adolescent stress on ventral tegmental area dopamine system and its afferent regulators.

Adolescent stress is a risk factor for schizophrenia. Emerging evidence suggests that age-dependent sensitive windows for childhood trauma are associated more strongly with adult psychosis, but the neurobiological basis and potential sex differences are unknown.Using in vivo electrophysiology and immunohistology in rats, we systematically compared the effects of two age-defined adolescent stress paradigms, prepubertal (postnatal day [PD] 21-30; PreP-S) and postpubertal (PD41-50; PostP-S) foot-shock and restraint combined stress, on ventral tegmental area (VTA) dopaminergic activity, pyramidal neuron activity in the ventral hippocampus (vHipp) and the basolateral amygdala (BLA), corticoamygdalar functional inhibitory control, and vHipp and BLA parvalbumin interneuron (PVI) impairments. These endpoints were selected based on their well-documented roles in the pathophysiology of psychosis.Overall, we found distinct sex- and exposure age-dependent stress vulnerability. Specifically, while males were selectively vulnerable to PreP-S-induced adult VTA dopamine neuron and vHipp hyperactivities, females were selectively vulnerable to PostP-S. These male selective PreP-S effects were correlated with stress-induced aberrant persistent BLA hyperactivity, dysfunctional prefrontal inhibitory control of BLA neurons, and vHipp/BLA PVI impairments. In contrast, female PostP-S only produced vHipp PVI impairments in adults, with the BLA structure and functions largely unaffected.Our results indicated distinct adolescent-sensitive periods during which stress can sex-dependently confer maximal risks to corticolimbic systems to drive dopamine hyperactivity, which provide critical insights into the neurobiological basis for sex-biased stress-related psychopathologies emphasizing but not limited to schizophrenia. Furthermore, our work also provides a framework for future translational research on age-sensitive targeted interventions.

Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats.

Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

Nucleus reuniens inactivation reverses stress-induced hypodopaminergic state and altered hippocampal-accumbens synaptic plasticity.

The nucleus reuniens of the thalamus (RE) is a pivotal area responsible for the connectivity of the prefrontal-hippocampus pathway that regulates cognitive, executive, and fear learning processes. Recently, it was proposed that the RE participates in the pathophysiological states related to affective dysregulation. We investigated the role of RE in motivational behavioral and electrophysiological dysregulation induced by stress. Adult Sprague-Dawley rats were exposed to a combination of stressors (restraint stress+footshock) for 10 days and tested one to twoweeks later in the forced swim test (FST), ventral tegmental area (VTA)dopamine (DA) neuron electrophysiological activity, and hippocampal-nucleus accumbens plasticity. The RE was inactivated by injecting TTX prior to the procedures. The stress exposure increased the immobility in the FST and decreased VTA DA neuron population activity. Whereas an early long-term potentiation (e-LTP) in the ventral hippocampus-nucleus accumbens pathway was found after fimbria high-frequency stimulation in naïve animals, stressed animals showed an early long-term depression (e-LTD). Inactivation of the RE reversed the stress-induced changes in the FST and restored dopaminergic activity. RE inactivation partially recovered the stress-induced abnormal hippocampal-accumbens plasticity observed in controls. Our findings support the role of the RE in regulating affective dysregulation and blunted VTA DA system function induced by stress. Also, it points to the hippocampal-accumbens pathway as a potential neural circuit through which RE could modulate activity. Therefore, RE may represent a key brain region involved in the neurobiology of amotivational states and may provide insights into circuit dysfunction and markers of the maladaptive stress response.

Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia.

BackgroundThe hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity.MethodsHere we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats).ResultsAberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats.ConclusionTaken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.

Maternal deprivation induces persistent adaptations in putative dopamine neurons in rat ventral tegmental area: in vivo electrophysiological study.

Early life aversive experiences can trigger persistent deficits in neuronal signaling within the mesolimbic pathway, most notably in the dopamine (DA) neurons of the ventral tegmental area (VTA). The identity of such cellular mechanisms currently appears as an important issue. To address this concern, we investigated whether early life maternal deprivation (MD) would affect the electrical activity of VTA DA neurons, via in vivo extracellular single-unit recording. Male Wistar rats were deprived of their dams for 3h per day from postnatal days (PND) 1-14. Thereafter, the adult animals (PND 70-80) were tested for the discharge activity of putative VTA DA neurons. The VTA DA neurons displayed a decrease in firing rate and an increase in the variability of baseline discharge activity in deprived animals. MD also caused a decrease in burst firing of VTA DA neurons compared to control subjects. In summary, early life MD induces a hypoactive VTA DA system, which may contribute to lifespan psychopathologies.

Distribution of VTA Glutamate and Dopamine Terminals, and their Significance in CA1 Neural Network Activity

Reciprocal connection between the ventral tegmental area (VTA) and the hippocampus forms a loop that controls information entry into long-term memory. Compared with the widely studied VTA dopamine system, VTA glutamate terminals are anatomically dominant in the hippocampus and less understood. The current study employs anterograde and retrograde labeling of VTA dopamine and glutamate neurons to map the distribution of their terminals within the layers of the hippocampus. Also, functional tracing of VTA dopamine and glutamate projections to the hippocampus was performed by photostimulation of VTA cell bodies during CA1 extracellular voltage sampling in vivo. VTA dopamine terminals predominantly innervate the CA1 basal dendrite layer and modulate the firing rate of active putative neurons. In contrast, anatomical dominance of VTA glutamate terminals in the CA1 pyramidal cell and apical dendrite layers suggests the possible involvement of these terminals in excitability regulation. In support of these outcomes, photostimulation of VTA dopamine neurons increased the firing rate but not intrinsic excitability parameters for putative pyramidal units. Conversely, activation of VTA glutamate neurons increased CA1 network firing rate and burst rate. In addition, VTA glutamate inputs reduced the interspike and interburst intervals for putative CA1 neurons. Taken together, we deduced that layer-specific distribution of presynaptic dopamine and glutamate terminals in the hippocampus determinines VTA modulation (dopamine) or regulation (glutamate) of excitability in the CA1 neural network.

Prelimbic medial prefrontal cortex disruption during adolescence increases susceptibility to helpless behavior in adult rats

Major depressive disorder (MDD) is a disabling mental disorder worldwide. Several animal models have been used to study the neurobiology of this disorder, including the learned helplessness (LH) paradigm, in which susceptible animals show helpless behavior indicated by fails to escape a controllable footshock. This behavior has been associated with a downregulation of ventral tegmental area (VTA) dopamine (DA) system activity. The prelimbic portion of the prefrontal cortex (plPFC) plays an important role in the modulation of helpless behavior, but so far there is no evidence indicating that its developmental disruption alters susceptibility to helpless behavior. We investigated the impact of plPFC lesion performed at adolescence (postnatal day 31–33) or adulthood (postnatal day 70–72) on anxiety responses (elevated plus-maze), susceptibility to helpless behavior, and the VTA DA system activity in adult Sprague-Dawley rats. Whereas adult plPFC lesions induced neither anxiety responses nor increased susceptibility to helpless behavior (plPFC lesion: 33.3% of helplessness; controls: 30.8% of helplessness rats), adolescent plPFC lesions induced anxiety responses and increased the proportion of rats showing helpless at adulthood (plPFC lesion: 92.3% helplessness; controls: 42.1% helplessness rats). Moreover, only helpless rats in the groups showed a decreased VTA DA system population activity that was confined to the medial portion of the VTA. These findings suggest that the impairment of plPFC activity during adolescence occurs during a critical window for the development of helpless behavior in adult rats, indicating that predisposition or early life adverse events that impair plPFC activity may enhance susceptibility to depression in adulthood.

Female rats are resistant to the long-lasting neurobehavioral changes induced by adolescent stress exposure

Stress during adolescence is a risk factor for neuropsychiatric diseases, including schizophrenia. We recently observed that peripubertal male rats exposed to a combination of daily footshock plus restraint stress exhibited schizophrenia-like changes. However, numerous studies have shown sex differences in neuropsychiatric diseases as well as on the impact of coping with stress. Thus, we decided to evaluate, in adolescent female rats, the impact of different stressors (restraint stress [RS], footshock [FS], or the combination of FS and RS [FS+RS]) on social interaction (3-chamber social approach test/SAT), anxiety responses (elevated plus-maze/EPM), cognitive function (novel object recognition test/NOR), and dopamine (DA) system responsivity by evaluating locomotor response to amphetamine and in vivo extracellular single unit recordings of DA neurons in the ventral tegmental area (VTA) in adulthood. The impact of FS+RS during early adulthood was also investigated. Adolescent stress had no impact on social behavior, anxiety, cognition and locomotor response to amphetamine. In addition, adolescent stress did not induce long-lasting changes in VTA DA system activity. However, a decrease in the firing rate of VTA DA neurons was found 1–2 weeks post-adolescent stress. Similar to adolescent stress, adult stress did not induce long-lasting behavioral deficits and changes in VTA DA system activity, but FS+RS decreased VTA DA neuron population activity 1–2 weeks post-adult stress. Our results are consistent with previous studies showing that female rodents appear to be more resilient to developmental stress-induced persistent changes than males and may contribute to the delayed onset and lesser severity of schizophrenia in females.

Sex differences and effects of prenatal exposure to excess testosterone on ventral tegmental area dopamine neurons in adult sheep.

Prenatal testosterone (T) excess in sheep results in a wide array of reproductive neuroendocrine deficits and alterations in motivated behavior. The ventral tegmental area (VTA) plays a critical role in reward and motivated behaviors and is hypothesised to be targeted by prenatal T. Here we report a sex difference in the number VTA dopamine cells in the adult sheep, with higher numbers of tyrosine hydroxylase (TH)-immunoreactive (-ir) cells in males than females. Moreover, prenatal exposure to excess T during either gestational days 30-90 or 60-90 resulted in increased numbers of VTA TH-ir cells in adult ewes compared to control females. Stereological analysis confirmed significantly greater numbers of neurons in the VTA of males and prenatal T-treated ewes, which was primarily accounted for by greater numbers of TH-ir cells. In addition, immunoreactivity for TH in the cells was denser in males and prenatal T-treated females, suggesting that sex differences and prenatal exposure to excess T affects both numbers of cells expressing TH and the protein levels within dopamine cells. Sex differences were also noted in numbers of TH-ir cells in the substantia nigra, with more cells in males than females. However, prenatal exposure to excess T did not affect numbers of TH-ir cells in the substantia nigra, suggesting that this sex difference is organised independently of prenatal actions of T. Together, these results demonstrate sex differences in the sheep VTA dopamine system which are mimicked by prenatal treatment with excess T.

The Role of Clock in Ethanol-Related Behaviors

Mice with a mutation in the Clock gene (ClockΔ19) exhibit increased preference for stimulant rewards and sucrose. They also have an increase in dopaminergic activity in the ventral tegmental area (VTA) and a general increase in glutamatergic tone that might underlie these behaviors. However, it is unclear if their phenotype would extend to a very different class of drug (ethanol), and if so, whether these systems might be involved in their response. Continuous access voluntary ethanol intake was evaluated in ClockΔ19 mutants and wild-type (WT) mice. We found that ClockΔ19 mice exhibited significantly increased ethanol intake in a two-bottle choice paradigm. Interestingly, this effect was more robust in female mice. Moreover, chronic ethanol experience resulted in a long-lasting decrease in VTA Clock expression. To determine the importance of VTA Clock expression in ethanol intake, we knocked down Clock expression in the VTA of WT mice via RNA interference. We found that reducing Clock expression in the VTA resulted in significantly increased ethanol intake similar to the ClockΔ19 mice. Interestingly, we also discovered that ClockΔ19 mice exhibit significantly augmented responses to the sedative effects of ethanol and ketamine, but not pentobarbital. However, their drinking behavior was not affected by acamprosate, an FDA-approved drug for the treatment of alcoholism, suggesting that their increased glutamatergic tone might underlie the increased sensitivity to the sedative/hypnotic properties of ethanol but not the rewarding properties of ethanol. Taken together, we have identified a significant role for Clock in the VTA as a negative regulator of ethanol intake and implicate the VTA dopamine system in this response.

A novel mechanism linking corticotrophin‐releasing factor to ventral tegmental area dopamine neuron firing

A novel mechanism linking corticotrophin‐releasing factor to ventral tegmental area dopamine neuron firing