Active Ventral Tegmental Area Dopamine Research Articles

Role of ventral tegmental area dopamine neurons in fear memory retention in post-traumatic stress disorder model rats

Ventral tegmental area (VTA) dopamine (DA) neurons have been found to substantially associate with post-traumatic stress disorder (PTSD) pathology, however, whether and how these DA neurons affect fear memory management in PTSD individuals remains largely unknown. In this study, we utilized auditory conditioned foot-shock to evaluate the fear memory retrieval and retention characteristics in a single prolonged stress-induced PTSD rat model. We employed chemogenetic technology to specifically activate VTA DA neurons to examine the freezing behaviors responding to the conditioned stimuli. In vivo extracellular electrophysiological analyses were used to identify VTA DA neuronal firing alterations due to the chemogenetic activation. The results demonstrated that PTSD model rats showed comparable fear memory retrieval (Day 2 after the conditioned foot-shock), but significant enhancements in fear memory retention (Day 8 after the conditioned foot-shock), compared to normal control rats. Chemogenetic activation of VTA DA neurons markedly diminished the retention of fear memory in PTSD model rats, which appeared concomitantly with increases in the firing activities of the DA neurons. These findings revealed that PTSD induced the persistence of fear memory, which could be attenuated by activation of VTA DA neurons. It is presumed that VTA dopaminergic signals may serve as a prospective option for PTSD treatment.

Fecal microbiota transplantation of patients with anorexia nervosa did not alter flexible behavior in rats.

Patients with anorexia nervosa (AN) are often anxious, display inflexible behavior and disrupted reward processing. Emerging evidence suggests that gut dysbiosis in patients contributes to the disease phenotype and progression. In a preclinical study, we explored whether AN-derived microbiota impacts cognitive flexibility, anxiety, and dopamine signaling using fecal microbiota transplantation (FMT) in tyrosine hydroxylase-cre rats. We performed probabilistic reversal learning task (PRLT) at the baseline, after antibiotic treatment, and following FMT from patients with AN and controls. We assessed flexible behavior, task engagement, and ventral tegmental area (VTA) dopamine signaling during and in the absence of reward. Furthermore, anxiety-like behavior was evaluated with open field (OF) and elevated plus maze (EPM) tests. Neither antibiotic-induced dysbiosis nor AN FMT led to significant alterations in the number of reversals or lever press strategies after reinforced or nonreinforced lever presses (win and lose-stay) in the PRLT. However, the number of initiated trials decreased after antibiotic treatment while remaining unchanged after FMT. No significant differences were observed in VTA dopamine activity, anxiety measures in the OF and EPM tests. Microbiome analysis revealed limited overlap between the microbiota of the donors and recipients. No evidence was found that the microbiota of patients compared to controls, nor a depleted microbiome impacts cognitive flexibility. Nonetheless, antibiotic-induced dysbiosis resulted in reduced task engagement during the PRLT. The relatively low efficiency of the FMT is a limitation of our study and highlights the need for improved protocols to draw robust conclusions in future studies. While our study did not reveal direct impacts of AN-associated gut microbiota on cognitive flexibility or anxiety behaviors in our preclinical model, we observed a decrease in task engagement after antibiotic-induced dysbiosis, underscoring that the presence of a gut microbiome matters. Our findings underscore the need for further refinement in FMT protocols to better elucidate the complex interplay between gut microbiota and behaviors characteristic of anorexia nervosa.

GLP-1 receptor agonist semaglutide reduces appetite while increasing dopamine reward signaling

Semaglutide, a glucagon-like peptide-1 receptor agonist, is an effective drug reducing body weight and decreasing motivation for palatable food. The mechanisms underlying its effects on food reward remain unclear. We aimed to determine the impact of semaglutide on food reward collection and dopamine-neuron activity in the ventral tegmental area (VTA) upon exposure to a cue-induced sucrose delivery task.Pitx3-cre mice were injected with cre-dependent GCaMP6s virus into the VTA, to measure the activity of dopaminergic neurons in the VTA using in vivo fiber photometry. Mice were trained on a Pavlovian sucrose conditioning paradigm in which a 5-s cue signaled a 20% sucrose reward. Upon stable performance, semaglutide or vehicle was intraperitoneally injected during the task.1 mg/kg semaglutide reduced the number of collected rewards and licks during the task. Semaglutide increased VTA dopamine neuron activity during sucrose collection but not during the cue. Lower doses of semaglutide (0.1 and 0.3 mg/kg) reduced chow intake but not sucrose intake nor VTA dopamine activity in the task.Semaglutide reduces appetite but increases VTA dopamine signaling during reward collection. Semaglutide does not influence dopamine signaling during the presentation of food cues.

The amygdala-ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine.

Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]-ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. In a model of cocaine self-administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA-VP pathway using a pharmacological approach. We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short-term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA-VP pathway in cocaine-induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence.

Mesoaccumbal Dopamine Heterogeneity: What Do Dopamine Firing and Release Have to Do with It?

Ventral tegmental area (VTA) dopamine (DA) neurons are often thought to uniformly encode reward prediction errors. Conversely, DA release in the nucleus accumbens (NAc), the prominent projection target of these neurons, has been implicated in reinforcement learning, motivation, aversion, and incentive salience. This contrast between heterogeneous functions of DA release versus a homogeneous role for DA neuron activity raises numerous questions regarding how VTA DA activity translates into NAc DA release. Further complicating this issue is increasing evidence that distinct VTA DA projections into defined NAc subregions mediate diverse behavioral functions. Here, we evaluate evidence for heterogeneity within the mesoaccumbal DA system and argue that frameworks of DA function must incorporate the precise topographic organization of VTA DA neurons to clarify their contribution to health and disease.

Postpartum scarcity-adversity disrupts maternal behavior and induces a hypodopaminergic state in the rat dam and adult female offspring.

Postpartum adversity is among the strongest predictors for the emergence of postpartum depression (PPD) in humans and a translational risk factor employed in rodent models. Parental care is disturbed under conditions of environmental adversity, including low resource environments, and in PPD. Nonetheless, the neural changes associated with these adversity-induced maladaptive behavioral states remain poorly understood. Postpartum scarcity-adversity can be modeled in rats by providing the dam with limited bedding and nesting (LBN) materials, which mimics the effects of a stressful low resource environment in potentiating maltreatment/neglect in humans. Indeed, LBN exposure from postpartum days (PD) 2-9 increased adverse maternal behaviors, impaired pup retrieval, and increased passive stress coping responses. Since mesolimbic dopamine (DA) activity is an important mechanism for motivated maternal behavior and is implicated in PPD, we assessed the impact of postpartum scarcity-adversity on in vivo electrophysiological properties of ventral tegmental area (VTA) DA neurons at two timepoints. We found reduced numbers of active VTA DA neurons in LBN dams at PD 9-10 but not PD-21, suggesting a transient impact on VTA population activity in LBN dams. Finally, we assessed the impact of early life scarcity-adversity on VTA DA function by conducting VTA recordings in adult female offspring and found a long-lasting attenuation in DA activity. These findings highlight a link between adversity-induced deficits in DA function and disrupted maternal behavior, suggesting the VTA/mesolimbic DA system as a potential mechanism by which postpartum scarcity-adversity drives aberrant maternal behavior, and early postnatal programming of adult VTA function in the offspring.

Pain modulates dopamine neurons via a spinal-parabrachial-mesencephalic circuit.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.

Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats.

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.

A Comparison of Dopaminergic and Cholinergic Populations Reveals Unique Contributions of VTA Dopamine Neurons to Short-Term Memory

We systematically compare the contributions of two dopaminergic and two cholinergic ascending populations to a spatial short-term memory task in rats. In ventral tegmental area dopamine (VTA-DA) and nucleus basalis cholinergic (NB-ChAT) populations, trial-by-trial fluctuations in activity during the delay period relate to performance with an inverted-U, despite the fact that both populations have low activity during that time. Transient manipulations reveal that only VTA-DA neurons, and not the other three populations we examine, contribute causally and selectively to short-term memory. This contribution is most significant during the delay period, when both increases and decreases in VTA-DA activity impair short-term memory. Our results reveal a surprising dissociation between when VTA-DA neurons are most active and when they have the biggest causal contribution to short-term memory, and they also provide support for classic ideas about an inverted-U relationship between neuromodulation and cognition.

Medial septum activation produces opposite effects on dopamine neuron activity in the ventral tegmental area and substantia nigra in MAM vs. normal rats

The medial septum (MS) differentially impacts midbrain dopamine (DA) neuron activity via the ventral hippocampus, a region implicated in DA-related disorders. However, whether MS regulation of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is disrupted in a developmental disruption model of schizophrenia is unknown. Male Sprague-Dawley rats were exposed at gestational day 17 to methylazoxymethanol (MAM) or saline. As adults, NMDA (0.75 µg/0.2 µL) was infused into the MS, and either DA neuron activity in the VTA and SNc (7–9 anesthetized rats per group) or amphetamine-induced hyperlocomotion (AIH, 11-13 rats per group) was measured. MS activation produced a 58% increase in the number of spontaneously active DA neurons in VTA and a 37% decrease in SNc in saline rats. However, MS activation produced opposite effects on DA population activity in MAM rats, decreasing VTA DA activity by 51% and increasing SNc DA activity by 47%. MS activation also increased AIH by 113% in MAM rats, opposite of what is seen in intact rats. The effect in behavioral output may be due to disrupted GABAergic regulation of SNc as bicuculline infusion into vSub, which selectively prevented the MS activation-induced decrease in SNc DA activity in intact rats, prevented the increase in AIH and SNc DA activity in MAM rats. These findings demonstrate that the regulation of midbrain DA neurons by the MS is disrupted in this well-validated animal model, suggesting that it could be a potential locus for pharmacological intervention in disorders such as schizophrenia.

Diazepam reverses increased anxiety-like behavior, social behavior deficit, and dopamine dysregulation following withdrawal from acute amphetamine.

Psychostimulants such as amphetamine (AMPH) increase dopamine (DA) release from ventral tegmental area (VTA) neurons, which is associated with their acute reinforcing actions. This positive state is followed by a negative affective state during the withdrawal period each time the drug is taken (i.e., opponent process theory). AMPH withdrawal is accompanied by symptoms of anxiety and depression, which are associated with DA system dysfunction in humans and animal models. Most studies have focused on the negative affective state after withdrawal from chronic drug administration; yet, this negative state appears even after a drug is taken for the first time in both humans and rodents. In rats, withdrawal from a single dose of AMPH (2 mg/kg) increases forced swim test immobility and decreases the number of spontaneously active VTA DA neurons up to 48 h post-withdrawal. In the current study, acute AMPH withdrawal was found to increase anxiety-like behavior in the elevated plus maze (EPM), reduce social cage time in the three-chambered social approach test (SAT), and attenuate VTA population activity. The effects of diazepam, a drug commonly used to treat anxiety disorders, were tested on anxiety-like and social behavior as well as VTA DA neuron activity following acute AMPH withdrawal. A single (5 mg/kg) dose of diazepam circumvented the neurobehavioral effects induced by acute AMPH withdrawal, as demonstrated by increased open arm time and social cage time as well as normalized VTA DA activity comparable to controls, suggesting that these neurobehavioral effects of acute AMPH withdrawal reflect an anxiety-like state.

α7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia.

Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of α7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems rather than on a validated developmental model of schizophrenia. Furthermore, there have been only few studies on whether orthosteric and allosteric modulators have differential impacts in such models. Thus, we investigated the effects of α7 agonists and positive allosteric modulators (PAMs) on dopamine (DA) neuron activity in the ventral tegmental area (VTA) in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. Four different drugs were evaluated: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM type I) and PNU120596 (PAM type II). PNU120596 increased the number of spontaneously active VTA DA neurons in normal rats. In contrast, PNU282987 and SSR180711 reduced the hyperdopaminergic tone in MAM rats. This appeared to be due to effects on DA afferent regulation, in that PNU282987 or SSR180711 infusion into the ventral hippocampus of MAM rats replicated the decrease in the number of spontaneously active VTA DA neurons. In contrast, infusion of the same drugs into the basolateral amygdala increased the number of spontaneously active VTA DA neurons in normal rats without impacting MAM rats. These data suggest that α7 receptors may represent a promising target in the development of new pharmacological therapies for schizophrenia.

S40. MEDIAL SEPTUM ACTIVATION PRODUCES OPPOSITE EFFECTS ON DOPAMINE NEURON ACTIVITY IN THE VENTRAL TEGMENTAL AREA AND SUBSTANTIA NIGRA PARS COMPACTA IN MAM VERSUS NORMAL RATS

BackgroundDisruptions in dopamine (DA) signaling are central to the pathophysiology of several major psychiatric disorders, including schizophrenia. Thus, discovery of novel therapeutic approaches that normalize DA signaling is a major focus of research. One pathway that is critical for DA regulation originates from the ventral subiculum (vSub) of the hippocampus and controls ventral tegmental area (VTA) DA neuron activity. A potent regulator of hippocampal function is the medial septum (MS); a sub-region of the basal forebrain that widely innervates the hippocampus, including the vSub, via cholinergic, GABAergic, and glutamatergic projections, drives hippocampal theta rhythms, and affects goal-directed learning and memory. Despite this, it has never been determined if the MS is an afferent regulator of the midbrain DA system, and therefore may be a novel therapeutic treatment target for DA-related disorders.MethodsEffects of MS activation (NMDA, 0.75 µg/ 0.2 µL) were examined in intact and methylazoxymethanol acetate- treated (MAM) male Sprague-Dawley rats using anesthetized single unit DA recordings in the VTA and substantia nigra pars compacta (SNc) and locomotor behavior in an open field following systemic amphetamine (0.75 mg/kg).ResultsMS activation produced a prolonged 71% increase in the number of spontaneously active DA cells in the VTA, and an opposing 40% decrease in the number of active DA cells in the SNc, compared to vehicle infusions. These effects were mediated by the vSub and ventral pallidum as local infusion of TTX (1 µM /0.5 µL) and bicuculline (1 ng/ 0.5 µL), respectively, reversed DA population activity changes in both regions. MS activation also decreased the locomotor response to amphetamine (49% reduction in distance traveled during peak ambulation compared to vehicle). MS activation-induced changes in both DA population activity and amphetamine-induced hyperlocomotion were selectively mediated by different neurotransmitter populations from MS to vSub as infusion of scopolamine (8 µg/1.0 µL) into the vSub selectively prevented DA population activity changes in the VTA. In contrast, infusion of bicuculline (12.5 ng/0.5 µL) selectively prevented DA population activity changes in the SNc and the decrease in amphetamine-induced hyperlocomotion. In MAM rats, MS activation produced opposite effects on DA population activity versus controls as it decreased VTA DA activity by 51% and increased SNc DA activity by 47%. This was accompanied by a similar reversal in amphetamine-induced hyperlocomotion, with MS activation increasing locomotion in MAM animals (113% increase in distance traveled during peak ambulation compared to control animals). The reversal in behavioral output is likely due to disrupted GABAergic projections from MS to vSub as bicuculline infusion into vSub prevented the increase in locomotor behavior.DiscussionThese data indicate that the MS differentially regulates both VTA and SNc DA neuron activity and behavioral output, but via distinct pathways, and that this regulation is disrupted in a well-validated animal model of schizophrenia. Therefore, this suggests that in normal animals the MS might activate the VTA to increase information processing while delaying action via SNc inhibition. In contrast, the inhibition of VTA and activation of SNc in MAM rats might promote a rapid response without adequate processing of information.

Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition.

Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.

Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels, and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviours in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behaviour. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Dopamine and reward seeking: the role of ventral tegmental area.

Reward seeking is controlled by conditioned stimuli (CSs). There is a positive relation between mesocorticolimbic dopamine (DA) and the performance of learned reward-directed behavior. The mechanisms by which reward-, including drug-, associated stimuli come to acquire the capacity to activate the DA systems are not fully understood. In this review, we discuss the possible neurochemical mechanisms within the ventral tegmental area that may be involved in how CSs acquire the capacity to activate ventral tegmental area (VTA) DA neurons based on principles of long-term potentiation in the VTA and the role of mesocorticolimbic DA in reward-related learning. We propose that CSs function as such because they acquire the capacity to activate VTA DA neurons. Furthermore, CSs come to acquire this control of VTA DA cells when there is coincident N-methyl-d-aspartate receptor stimulation on VTA DA cells and strong depolarization of VTA DA cells, possibly by muscarinic acetylcholine receptor stimulation on these cells. This coincident activity leads to the strengthening of CS-associated glutamatergic synapses and the control by CSs of mesocorticolimbic DA systems and reward-directed behavior.

The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways.

The ventral tegmental area (VTA) has been implicated in a number of psychiatric disorders, including schizophrenia, depression, and bipolar disorder. One major regulator of the mesolimbic dopaminergic system is the medial prefrontal cortex (mPFC), which makes direct and indirect connections to the hippocampus and amygdala, as well as directly to the VTA. The mPFC is comprised of two subregions: the infralimbic and prelimbic cortices (ilPFC and plPFC). However, the specific roles of these subregions in regulating VTA dopamine activity have remained unclear. In this study, we aim to clarify this role and to examine the divergent neuranatomical circuits by which the mPFC regulates VTA activity. Using in vivo extracellular recordings in rats, we tested the effects of pharmacological activation (with NMDA) and inactivation (with TTX) of the ilPFC and plPFC on dopamine neuron activity, and tested the roles of the ventral subiculum (vSub) and basolateral amygdala in this process. We found that the ilPFC exerts a bidirectional control of VTA dopamine neurons, which are differentially modulated through the vSub and the basolateral amygdala. Specifically, activation or inactivation of the ilPFC attenuated or activated dopamine neuron population activity, respectively. Furthermore, dopamine activation depended on the ventral hippocampus and inactivation on the amygdala. In contrast, only inactivation of the plPFC altered dopamine neuron activity. These data indicate that the mPFC has the ability to uniquely fine-tune dopaminergic activity in the VTA. Furthermore, the data presented here suggest that the ilPFC may have a role in the pathophysiology of psychiatric disorders.

α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine in rodents, suggesting that they may be key mediators of nicotine's action in humans. However, it is unknown which nAChR subtypes are sufficient to activate these neurons. To test the hypothesis that nAChRs containing α6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-of-function α6 nAChRs (α6L9'S mice). In voltage-clamp recordings in brain slices from adult mice, 100 nM nicotine was sufficient to elicit inward currents in VTA DA neurons via α6β2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through α6β2* nAChRs to enhance the function of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors on the surface of these cells. In contrast, α6β2* activation did not enhance N-methyl-D-aspartic acid receptor function. Finally, AMPA receptor (AMPAR) function was not similarly enhanced in brain slices from α6L9'S mice lacking α4 nAChR subunits, suggesting that α4α6β2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of α4α6β2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. α4α6β2* nAChRs may be a promising target for future smoking cessation pharmacotherapy.

Salsolinol and ethanol-derived excitation of dopamine mesolimbic neurons: new insights

Salsolinol and ethanol-derived excitation of dopamine mesolimbic neurons: new insights

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

Prenatal stress exposure (PSE) is known to increase addiction risk. Dopamine (DA) neurons in the ventral tegmental area (VTA) play an important role in addiction. In order to understand the cellular mechanisms underlying PSE-induced increase in addiction risk, we examined the effects of PSE on the electrical impulse activity of VTA DA neurons using the in vivo extracellular single-unit recording technique. Amphetamine self-administration was also conducted to confirm increased addiction risk after PSE. The PSE was carried out by restraining pregnant dams from GD 11 to 20. Adult male offspring (3-6 months old) were used in the experiments. Animals with PSE showed enhanced amphetamine self-administration compared with controls when amphetamine dose was reduced after acquisition. The number of spontaneously active VTA DA neurons was also reduced in PSE rats. The reduction was reversed by acute apomorphine that normally inhibits the impulse activity of DA neurons. The reversal effect suggests that PSE-induced reduction in the number of spontaneously active VTA DA neurons is caused by overexcitation to the extent of depolarization block. Furthermore, the reduced number of spontaneously active VTA DA neurons was also reversed by acute psychostimulants (eg, amphetamine; cocaine), which in control rats inhibited the activity of VTA DA neurons. The reversal effect on VTA DA neuron in PSE animals represents an actual increase in the impulse activity. This effect might contribute to increased responding to psychostimulants and mediate increased addiction risk after PSE.