Ventral Tegmental Area Dopaminergic Activity Research Articles

Interactions of sex and stress in modulation of ventral tegmental area dopaminergic activity

Interactions of sex and stress in modulation of ventral tegmental area dopaminergic activity

Protracted Abstinence From Extended Cocaine Self-Administration Is Associated With Hypodopaminergic Activity in the VTA but Not in the SNc.

The chronic relapsing nature of cocaine addiction suggests that chronic cocaine exposure produces persistent neuroadaptations that may be temporally and regionally dynamic in brain areas such as the dopaminergic (DA) system. We have previously shown altered metabolism of DA-target structures, the ventral and dorsal striatum, between early and late abstinence. However, specific changes within the midbrain DA system were not investigated. Here, we investigated potential time- and region-specific changes of activity in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) in rats that had extended or limited access to cocaine and later underwent a period of abstinence. We found that DA activity is decreased only in the VTA in rats with extended access to cocaine, with no changes in SNc DA activity. These changes in VTA DA activity may participate in the negative emotional state and the incubation of drug seeking that occur during abstinence from cocaine.

Effects of brief inhibition of the ventral tegmental area dopamine neurons on the cocaine seeking during abstinence.

Preclinical studies strongly suggest that cocaine seeking depends on the neuronal activity of the ventral tegmental area (VTA) and phasic dopaminergic (DA) signaling. Notably, VTA pharmacological inactivation or dopamine receptor blockade in the forebrain may induce behavioral inhibition in general and acute aversive states in particular, thus reducing cocaine seeking indirectly. Such artifacts hinder successful translation of these findings in clinical studies and practice. Here, we aimed to evaluate if dynamic VTA manipulations effectively reduce cocaine seeking. We used male tyrosine hydroxylase (TH) IRES-Cre+ rats along with optogenetic tools to inhibit directly and briefly VTA DA neurons during conditioned stimulus (CS)-induced cocaine seeking under extinction conditions. The behavioral effects of optogenetic inhibition were also assessed in the real-time dynamic place aversion, conditioned place aversion, and CS-induced food-seeking tests. We found that brief and nondysphoric/nonsedative pulses of VTA photo-inhibition (1 s every 9 s, ie, for 10% of time) attenuated CS-induced cocaine seeking under extinction conditions in rats expressing archaerhodopsin selectively on the TH+ neurons. Furthermore, direct inhibition of the VTA DA activity reduced CS-induced cocaine seeking 24 hours after photo-modulation. Importantly, such effect appears to be selective for cocaine seeking as similar inhibition of the VTA DA activity had no effect on CS-induced food seeking. Thus, briefly inhibiting VTA DA activity during CS-induced cocaine seeking drastically and selectively reduces seeking without behavioral artifacts such as sedation or dysphoria. Our results point to the therapeutic possibilities of coupling nonpharmacologic treatments with extinction training in reducing cocaine addiction.

Adolescent Nicotine Exposure Induces Molecular and Neuronal Features of Depressive Disorder in Adulthood in the Mesolimbic Dopamine System

Introduction/ObjectivesSmoking tobacco is the leading cause of preventable death world‐wide and the main psychoactive component of tobacco, nicotine, is associated with short‐ and long‐term mood‐state alterations. Adolescent nicotine exposure has been shown to induce long‐term depressive and anxiety‐related symptoms in adulthood. Nicotine exposure increases ventral tegmental area (VTA) dopaminergic (DA) inputs to the nucleus accumbens shell (NAcSh), comprising the mesolimbic DA system. Disturbances in the mesolimbic system are well‐established neuropathological correlates of mood disorders, however, the mechanisms by which adolescent nicotine exposure may cause the later development of mood and anxiety disorders is not currently understood. Mood disorders precipitate changes in activation state of intra‐cellular targets, such as glycogen synthase‐3 (GSK3) and extracellular signal‐regulated kinase (ERK). The objectives of the present study are to examine the effects of adolescent nicotine exposure on later adulthood neurobiological phenotypes associated with mood disorders.MethodsAdolescent male Sprague‐Dawley rats were either administered 0.4mg/kg nicotine or saline vehicle injections three times per day for 11 days during a critical period of rodent adolescent neurodevelopment (post‐natal day 35–45). Rats matured into early adulthood (post‐natal day 65) and the VTA and NAc were subjected to protein extraction to examine intracellular molecular protein expression and activation profiles. Separate vehicle and nicotine‐treated groups underwent electrophysiology to record VTA and NAcSh neuronal activity. The VTA and NAcSh DA and medium spiny neuron (MSN) activity was recorded in vehicle and nicotine treated groups using dual‐cell neuronal recordings. Baseline recordings were examined along with recordings following a 0.4mg/kg nicotine injection and a subthreshold dose of 0.1mg/kg.ResultsConsistent with phenotypes observed in human depression, molecular analyses of the NAc revealed significant increases in the phosphorylation states of ERK1/2 (1: p=0.0219, 2: p=0.0151), GSK3 phosphorylation state (1: p=0.0029, 2: p=0.0028), and pGSK3:tGSK3 (site1: p=0.0165, site2: p=0.0291) in nicotine vs. vehicle treated rats. Furthermore, consistent with dysregulated mesolimbic activity states present in mood disorders, preliminary electrophysiological results indicate a larger increase in VTA DA and NAcSh MSN cellular firing frequency and burst rate in the nicotine treated group compared to the control group when subjected to 0.4mg/kg and o.1mg/kg doses of nicotine in adulthood.ConclusionOur results indicate that nicotine exposure in adolescence elicits long‐term changes in neuronal activity and intracellular molecular activation states, consistent with phenotypes observed in clinical mood disorder populations. Together, these findings identify a novel molecular and neuronal mechanism directly in the mesolimbic DA system, underlying the effects of adolescent nicotine exposure on the later development of mood disorders in adulthood.Support or Funding InformationThis work was supported by the Canadian Institutes of Health Research (MOP‐123378).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

Substantial evidence indicates that the ventral tegmental area (VTA) of the mesocorticolimbic dopaminergic (DA) system has a key role in mechanisms of opiate dependence. Although DA neurons have been studied extensively, little is known about their activity and their response to acute morphine during morphine dependence. We recorded the activity of VTA DA neurons in five groups of anesthetized rats: drug-naive (naive) rats, morphine-dependent [(MD) implanted with pellets] rats, and three groups of withdrawn rats. Withdrawals either were precipitated by naltrexone or occurred spontaneously 24 h or 15 d after pellet removal. We confirmed that acute morphine in naive rats produced a marked increase in the firing of VTA DA neurons. We also found that the basal firing rate of VTA DA neurons was markedly higher in MD than in naive rats; however, in MD rats, acute morphine failed to increase DA activity. We confirmed inhibition of VTA DA activity in MD rats in response to precipitated withdrawal; however, this inhibition resulted only in a normalization of the firing rate to that of naive animals. In rats that had spontaneous withdrawal after 24 h or 15 d, the activity of VTA DA neurons was similar to that of naive rats, and an acute injection of morphine failed to alter their activity. Our results indicate that VTA DA neurons show long-lasting tolerance to the acute effect of morphine after withdrawal. These findings show that VTA DA neural activity is unlikely to be a factor in the altered behavioral responses that occur with acute morphine or naltrexone administration after chronic opiate exposure.