An Investigation into the Role of the VTA in Reward Seeking Behavior and Addiction
Given the current opioid and substance abuse epidemics ravaging the country and its multifaceted nature, it is imperative to investigate the neurological foundations of addiction and potential treatments to remedy the affliction. Addiction has several components that contribute to its emergence in an individual. Ranging from genetic to cognitive behavioral disposition, what makes a person susceptible to addiction varies. However, by investigating the neurological basis for addiction and how it progresses, effective treatments designed to work at a neurobiological level can be used alongside the current rehab and cognitive behavioral treatments to ensure success.
In the article, “Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward”, Dr. Steidl and his team investigated the link between the ventral tegmental area and cholinergic and glutamatergic inputs from the laterodorsal tegmental nucleus. This link was tested by driving two sources of excitatory LDTg input into the VTA and testing mice in 3 chamber apparatus with one chamber being light paired and resulting in VTA light stimulation. It was found that ChAT-ChR2 mice spent significantly more time in the light paired chamber and also showed a conditioned preference for said chamber in the absence of light. VGluT2-ChR2 mice entered the light paired chamber significantly more times than the light unpaired chamber but remained in the light paired chamber for shorter periods of time and failed to show a conditioned place preference. The results suggest that VTA excitation of LDTg-glutamergic potentially has a role in reinforcement of initial chamber entry in comparison to VTA excitation of LDTg-cholinergic inputs which may have an influence on the reward effects of chamber stays. These findings give insight into the intersection of behavior and neurobiology in regards to addiction and paved the way for further research into the topic
Given the behavioral effects of VTA excitation, another paper, “Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs” Creed and their team investigate the activity of the VTA in the context of cocaine exposure. Utilizing injections of cocaine and in vivo single unit recordings, it was found that cocaine exposure induces potentiation of excitatory inputs on dopaminergic neurons and remodels mesocorticolimbic circuitry thus driving forth drug adaption behavior. The potentiation of dopaminergic neurons is mediated by fluctuations in NMDAR and AMPAR subunits. The team found that a single cocaine injection results in increased firing rate and activity of VTA dopaminergic neurons, a phenomenon that lasts for seven days. This increased arousal is the result of low conductance, Ca2+ impermeable NMDARs containing GluN3A as the receptors are unable to activate small conductance K+ channels resulting in an increase of the intrinsic VTA dopaminergic neuron excitability. To return to normal dopaminergic neuron firing levels, activation of group 1 mGluRs restores synaptic plasticity and small conductance Ca2+ dependent K+ channel function. The findings link synaptic changes and increased excitability of intrinsic VTA dopaminergic neurons after cocaine exposure and provides insight into how short-term cocaine exposure results in long lasting changes to the mesolimbic DA system. In regard to the potentiation of excitatory transmission on VTA dopaminergic neurons and the resulting increased activity, it was found that the absence of activation in the SK channels. However, the increase in activity can be reduced by the rescue of basal NMDAR properties which leads to normal functioning of SK channels. With the link between synaptic plasticity and VTA dopaminergic neuronal activity, the team was able to gain insight on the effects of cocaine outside the VTA. It was postulated that the alteration of synaptic plasticity in downstream regions allows for the mediation of drug adaptive behavior components. Given that plasticity in the VTA occurs within hours of cocaine exposure and downstream plasticity occurs during a withdrawal period, the excitement of VTA dopaminergic neurons via alterations in the SK channel may allow for enhanced dopaminergic tone in VTA projection regions. Thus, SK channels hold the potential to halt the remolding of the mesolimbic DA system and the formation of addiction by being exposed to positive allosteric modulation as a therapeutic tactic.
The findings presented by Steidl and his team in conjunction with the findings by Creed and their team have provided great insight into the neurological foundation of addiction and specifically the role of the VTA in the context of addiction. Steidl’s paper resulted in a profound investigation of the intersection of neurobiology and behavior and links the VTA as a major factor in the propagation of reward seeking behavior. Creed’s paper further explores the VTA’s role in reward seeking in the context of cocaine exposure and found links between potentiation of excitatory inputs on dopaminergic neurons results in the reconstruction of the mesocorticolimbic circuitry which drives addiction. Creed’s team also found a potential treatment to stop the progression of cocaine exposure into addiction in the form of a positive allosteric modulation of SK channels which would halt the reconstructions of the mesolimbic circuitry. The information gleaned from these papers allow for a more complete view of addiction and provides possible treatment routes to help abate the current epidemics ravaging communities.
Citations
Creed, M., Kaufling, J., Fois, G., Jalabert, M., Yuan, T., Lüscher, C., . . . Bellone, C. (2016, October 19). Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs. Retrieved December 07, 2020, from https://www.jneurosci.org/content/36/42/10759
Steidl, S., Wang, H., Ordonez, M., Zhang, S. and Morales, M. (2017), Optogenetic excitation in
the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward. Eur J Neurosci, 45: 559-571. https://doi.org/10.1111/ejn.13436
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