Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area.
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ABSTRACT:
SUBMITTER: Riegel AC
PROVIDER: S-EPMC4857882 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Synaptic plasticity in the ventral tegmental area (VTA) is modulated by drugs of abuse and stress and is hypothesized to contribute to specific aspects of addiction. Both excitatory and inhibitory synapses on dopamine neurons in the VTA are capable of undergoing long-term changes in synaptic strength. While the strengthening or weakening of excitatory synapses in the VTA has been widely examined, the role of inhibitory synaptic plasticity in brain reward circuitry is less established. Here, we investigated the effects of drugs of abuse, as well as acute stress, on long-term potentiation of GABAergic synapses onto VTA dopamine neurons (LTP(GABA)). Morphine (10 mg/kg i.p.) reduced the ability of inhibitory synapses in midbrain slices to express LTP(GABA) both at 2 and 24 h after drug exposure but not after 5 days. Cocaine (15 mg/kg i.p.) impaired LTP(GABA) 24 h after exposure, but not at 2 h. Nicotine (0.5 mg/kg i.p.) impaired LTP(GABA) 2 h after exposure, but not after 24 h. Furthermore, LTP(GABA) was completely blocked 24 h following brief exposure to a stressful stimulus, a forced swim task. Our data suggest that drugs of abuse and stress trigger a common modification to inhibitory plasticity, synergizing with their collective effect at excitatory synapses. Together, the net effect of addictive substances or stress is expected to increase excitability of VTA dopamine neurons, potentially contributing to the early stages of addiction.
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Project description:Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.
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Project description:The ventral tegmental area (VTA) is involved in adaptive reward and motivation processing and is composed of dopamine (DA) and GABA neurons. Defining the elements regulating activity and synaptic plasticity of these cells is critical to understanding mechanisms of reward and addiction. While endocannabinoids (eCBs) that potentially contribute to addiction are known to be involved in synaptic plasticity mechanisms in the VTA, where they are produced is poorly understood. In this study, DA and GABAergic cells were identified using electrophysiology, cellular markers, and a transgenic mouse model that specifically labels GABA cells. Using single-cell RT-qPCR and immunohistochemistry, we investigated mRNA and proteins involved in eCB signaling such as diacylglycerol lipase α, N-acyl-phosphatidylethanolamine-specific phospholipase D, and 12-lipoxygenase, as well as type I metabotropic glutamate receptors (mGluRs). Our results demonstrate the first molecular evidence of colocalization of eCB biosynthetic enzyme and type I mGluR mRNA in VTA neurons. Further, these data reveal higher expression of mGluR1 in DA neurons, suggesting potential differences in eCB synthesis between DA and GABA neurons. These data collectively suggest that VTA GABAergic and DAergic cells have the potential to produce various eCBs implicated in altering neuronal activity or plasticity in adaptive motivational reward or addiction.
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Project description:Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.
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Project description:BackgroundAlcohol excites neurons of the ventral tegmental area (VTA) and the release of dopamine from these neurons is a key event in ethanol (EtOH)-induced reward and reinforcement. Many mechanisms have been proposed to explain EtOH's actions on neurons of the VTA, but antagonists generally do not eliminate the EtOH-induced excitation of VTA neurons. We have previously demonstrated that the ion channel KCNK13 plays an important role in the EtOH-related excitation of mouse VTA neurons. Here, we elaborate on that finding and further assess the importance of KCNK13 in rats.MethodsRats (Sprague-Dawley and Fisher 344) were used in these studies. In addition to single-unit electrophysiology in brain slices, we used quantitative PCR and immunohistochemistry to discern the effects of EtOH and the brain slice preparation method on the expression levels of the Kcnk13 gene and KCNK13 protein.ResultsImmunohistochemistry demonstrated that the levels of KCNK13 were significantly reduced during procedures normally used to prepare brain slices for electrophysiology, with a reduction of about 75% in KCNK13 protein at the time that electrophysiological recordings would normally be made. Extracellular recordings demonstrated that EtOH-induced excitation of VTA neurons was reduced after knockdown of Kcnk13 using a small interfering RNA (siRNA) delivered via the recording micropipette. Real-time PCR demonstrated that the expression of Kcnk13 was altered in a time-dependent manner after alcohol withdrawal.ConclusionsKCNK13 plays an important role in EtOH-induced stimulation of rat VTA neurons and is dynamically regulated by cell damage and EtOH exposure, and during withdrawal. KCNK13 is a novel alcohol-sensitive protein, and further investigation of this channel may offer new avenues for the development of agents useful in altering the rewarding effect of alcohol.
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Project description:Previous studies have shown that homosynaptic potentiation produced by rather mild tetanic stimulation (20 Hz, 2 sec) at Aplysia sensory-motor neuron synapses in isolated cell culture involves both presynaptic and postsynaptic Ca2+ (Bao et al., 1997). We have now investigated the sources of Ca2+ and some of its downstream targets. Although the potentiation lasts >30 min, it does not require Ca2+ influx through either NMDA receptor channels or L-type Ca2+ channels. Rather, the potentiation involves metabotropic receptors and intracellular Ca2+ release from both postsynaptic IP3-sensitive and presynaptic ryanodine-sensitive stores. In addition, it involves protein kinases, including both presynaptic and postsynaptic CamKII and probably MAP kinase. Finally, it does not require transsynaptic signaling by nitric oxide but it may involve AMPA receptor insertion. The potentiation, thus, shares components of the mechanisms of post-tetanic potentiation, NMDA- and mGluR-dependent long-term potentiation, and even long-term depression, but is not identical to any of them. These results are consistent with the more general idea that there is a molecular alphabet of basic components that can be combined in various ways to create novel as well as known types of plasticity.
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Project description:Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine's motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABAA receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization.The present study investigated whether pharmacological manipulation of VTA GABAA receptor activity could directly influence the mechanisms underlying opiate motivation.Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl(-) cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine's motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABAA receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons.Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABAA receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively.
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