Dopaminergic Neurons in the Ventral Tegmental Area as a Target for Treatment-Resistant Depression

Prelude

This essay is intended as an intuitive examination of a reward system neural circuit which may serve as a useful target for new therapies aimed at fighting treatment-resistant depression (TRD). My purpose here is not to introduce an entirely novel concept, but rather to compile in one place a set of important explanations on how information flow in the reward system relates to TRD and how these reward system mechanisms may have clinical relevance.

Treatment Resistant Depression

Treatment resistant depression (TRD) is a widespread and debilitating condition. Patients with TRD are defined to have failed to adequately respond to two or more treatments for depression.¹  As a broader category, depression affects about 280 million people worldwide.² TRD affects roughly 30% of these patients³ (~84 million). In the USA, it has been estimated that about 2.8 million adults suffer from TRD.¹ A common symptom associated with TRD is anhedonia, the inability to feel positive emotions. It is thought that defects in the brain’s reward pathway are central to the neurobiology of TRD since this pathway contains the neural circuitry necessary to encode positive emotional experiences.

Reward Circuits

When sensory recognition of a potential reward occurs, various pathways inhibit activity of the lateral habenula (LHb), which in turn inhibits the rostromedial tegmental nucleus (RMTg). This disinhibits the ventral tegmental area (VTA).⁴ The VTA’s dopaminergic projections then spike in phasic bursts, sending dopamine to the nucleus accumbens (NAc) (mesolimbic pathway, a part of the medial forebrain bundle or MFB) and prefrontal cortex (PFC) (mesocortical pathway).⁵ NAc GABAergic medium spiny neurons (MSNs) generally express either the dopamine 1 receptor (D1R) or express the dopamine 2 receptor (D2R). D1R MSNs are excited by dopamine while D2R MSNs are inhibited by dopamine. Mesolimbic inputs bias the NAc to output from the D1R MSNs, which stimulate the direct motor pathway to respond to the reward. The GABAergic MSN activity furthermore inhibits the ventral pallidum (VP), which in turn lifts its own GABAergic inhibition on targets such as the mediodorsal thalamus, lateral hypothalamus, and VTA.⁶ This increases arousal and helps with motor processes. The mediodorsal thalamus projects to the PFC and triggers circuits that represent the value of the reward.⁷

These circuits facilitate reward learning by a comparative mechanism called reward prediction error (RPE). The pedunculopontine tegmental nucleus (PPTg) receives inputs about the actual reward from brainstem sensory signals (and other brain areas) and projects glutamatergic and cholinergic synapses into the VTA (and elsewhere) to activate the dopaminergic neurons.⁸ If the reward is less valuable than expected, the LHb activates, which triggers firing of GABAergic neurons in the RMTg onto the VTA dopamine neurons, shutting down the mesolimbic activity.⁴ If the actual reward remains valuable, then the mesolimbic activity continues. This process where the inhibitory LHb-RMTg signal is “subtracted” from the stimulatory PPTg signal determines the RPE comparison’s outcome and whether the VTA continues its dopaminergic signals.⁹ All of this facilitates reward learning, where mesolimbic long-term potentiation (LTP) occurs if the reward is as strong as expected (or stronger) and mesolimbic long-term depression (LTD) (not the same as psychiatric depression) occurs if the reward is not as strong as expected.

Dopaminergic Neurons and Treatment Resistant Depression

As a central driver within the reward system, dopaminergic VTA neurons have high potential as a target for combatting TRD. Activation of these neurons may alleviate anhedonia and increase motivation. There already exists clinical evidence that stimulation of VTA dopaminergic neurons has significant benefits. As mentioned, the mesolimbic pathway projections of VTA dopaminergic neurons make up a major part of the MFB. Multiple clinical studies on deep brain stimulation (DBS) of the MFB (specifically the supero-lateral MFB or slMFB) have shown long-term beneficial effects for patients with TRD.^10–12 Functional imaging evidence suggests this works indirectly through activation of descending glutamatergic fibers from the PFC which activate the VTA’s dopamine neurons.¹⁰ Dopamine axons themselves are small in diameter, which make them not as responsive to conventional DBS. It should be noted that the VTA is a highly heterogeneous structure with dopaminergic, GABAergic, and glutamatergic neurons,¹³ so DBS of the VTA in general might have off-target effects and/or partially mitigate the benefits of the stimulation. Activation of the VTA’s GABAergic and glutamatergic neurons can have markedly different effects compared to activation of only its dopaminergic neurons.¹⁴ In mice, GABAergic VTA neuronal activity particularly has been found to occur in response to aversive stimuli and stimuli predicting the absence of reward.^15,16 In rats, optogenetic stimulation of VTA dopamine neurons promotes motivated behavior while optogenetic stimulation of VTA GABA neurons disrupts reward and promotes aversion.¹⁷ Clinical and animal model evidence thus supports the idea that selective activation of VTA dopamine neurons might act as a potent therapy for TRD.

Conclusion

Based on the literature, raising the basal level of VTA dopaminergic neuron activity might demonstrate a strong ameliorative effect on TRD. Extensive preclinical and clinical testing will of course be crucial to establish safety. Possible addictiveness of treatments which activate this circuit will need careful examination in particular. Depending on the modality of treatment, different forms of neurological adaptation may occur, so ways of mitigating this issue should be explored. VTA dopaminergic neurons represent a promising target for next-generation therapies aimed at overcoming TRD.

References

1.        Zhdanava, M. et al. The Prevalence and National Burden of Treatment-Resistant Depression and Major  Depressive Disorder in the United States. J. Clin. Psychiatry 82, (2021).

2.        World Health Organization – Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression (2023).

3.        McIntyre, R. S. et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry 22, 394–412 (2023).

4.        Hong, S., Jhou, T. C., Smith, M., Saleem, K. S. & Hikosaka, O. Negative Reward Signals from the Lateral Habenula to Dopamine Neurons Are Mediated by Rostromedial Tegmental Nucleus in Primates. J. Neurosci. 31, 11457 LP – 11471 (2011).

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6.        Root, D. H., Melendez, R. I., Zaborszky, L. & Napier, T. C. The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors. Prog. Neurobiol. 130, 29–70 (2015).

7.        Haber, S. N. & Knutson, B. The Reward Circuit: Linking Primate Anatomy and Human Imaging. Neuropsychopharmacology 35, 4–26 (2010).

8.        Skvortsova, V. et al. A Causal Role for the Pedunculopontine Nucleus in Human Instrumental Learning. Curr. Biol. 31, 943-954.e5 (2021).

9.        Eshel, N. et al. Arithmetic and local circuitry underlying dopamine prediction errors. Nature 525, 243–246 (2015).

10.      Fenoy, A. J. et al. Deep brain stimulation of the “medial forebrain bundle”: sustained efficacy of antidepressant effect over years. Mol. Psychiatry 27, 2546–2553 (2022).

11.      Schlaepfer, T. E., Bewernick, B. H., Kayser, S., Mädler, B. & Coenen, V. A. Rapid Effects of Deep Brain Stimulation for Treatment-Resistant Major Depression. Biol. Psychiatry 73, 1204–1212 (2013).

12.      Fenoy, A. J., Quevedo, J. & Soares, J. C. Deep brain stimulation of the “medial forebrain bundle”: a strategy to modulate the reward system and manage treatment-resistant depression. Mol. Psychiatry 27, 574–592 (2022).

13.      Faget, L. et al. Afferent Inputs to Neurotransmitter-Defined Cell Types in the Ventral Tegmental Area. Cell Rep. 15, 2796–2808 (2016).

14.      Root, D. H. et al. Distinct Signaling by Ventral Tegmental Area Glutamate, GABA, and Combinatorial Glutamate-GABA Neurons in Motivated Behavior. Cell Rep. 32, (2020).

15.      van Zessen, R., Phillips, J. L., Budygin, E. A. & Stuber, G. D. Activation of VTA GABA Neurons Disrupts Reward Consumption. Neuron 73, 1184–1194 (2012).

16.      Tan, K. R. et al. GABA Neurons of the VTA Drive Conditioned Place Aversion. Neuron 73, 1173–1183 (2012).

17.      Tong, Y., Pfeiffer, L., Serchov, T., Coenen, V. A. & Döbrössy, M. D. Optogenetic stimulation of ventral tegmental area dopaminergic neurons in a female rodent model of depression: The effect of different stimulation patterns. J. Neurosci. Res. 100, 897–911 (2022).