Addiction and the Neural Signaling Pathways of Reward

      Dopamine is a neurotransmitter that has had much research connecting its role in the reward processing of addiction.  According to an article written for Promises Behavioral Health, an addiction recovery blog, dopamine has been deemed the “feel-good chemical,” playing a major role in mood, motivational drive, desire, pleasure, and satiety (Promises Behavioral Health, 2020). In actuality, substance abuse can alter the neural signaling pathways of various neurotransmitters, particularly to the motivation and reward centers of the brain. Repeated exposure to these substances can lead to cravings of more “reward,” resulting in addiction (Promises Behavioral Health, 2020).

In this article, the authors described the effect some commonly abused substances have on the circuitry of the brain and the subsequent effects on behavior. Alcohol affects neurotransmitters GABA, glutamate, serotonin, dopamine, as well as endorphins and can cause either sedative or excitatory effects. Marijuana affects the levels of dopamine and anandamide (a neurotransmitter that plays a role in the regulation of mood, memory, pain, appetite, cognition, and emotions), and can lead to feelings of euphoria, relaxation, and heightened visual and auditory perceptions. Amphetamines increase energy and excitation by affecting dopamine and some glutamate receptors in the brain. Cocaine, a drug that is commonly implicated into many studies investigating the neural circuitry of addiction, raises dopamine levels in the brain and often leads to dependency and continued cravings for the drug. It also affects serotonin and norepinephrine levels, resulting in increased energy and confidence (Promises Behavioral Health, 2020.

The ventral tegmental area (VTA) of the midbrain, a major structure in the reward circuit in the brain, is a hub of dopaminergic pathways innervating other limbic and cortical structures in the brain. The VTA receives inputs from the laterodorsal tegmental nucleus (LDTg), which has differing populations of cholinergic, glutamatergic, and GABAergic neurons (Woolf &Butcher, 1986; Oakman et al., 1995; Geisler & Zahm, 2005; Lammel et al., 2012; Watabe-Uchida et al., 2012). Some of these LDTg neurons that input into the VTA form synapses with neurons that project to the nucleus accumbens (NAc), another important structure in the reward circuit (Omelchenko & Sesack, 2005). In the study conducted by Steidl and colleagues, “Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward,” the researchers focused on LDTg-cholinergic and glutamatergic neurons to investigate their role in regulating VTA dopaminergic neurons and how their activation effects behavior. In order to induce excitatory input into the VTA, they performed optogenetics in Cre-transgenic mice to stimulate either LDTg-cholinergic or glutamatergic neurons and evaluated the motivational and reward effects this had on mice in two versions of a chamber preference paradigm. They found that selective excitation of both LDTg-cholinergic and glutamatergic neurons play roles in the reward system, although these roles differ. VTA stimulation of LDTg-glutamatergic neurons resulted in increased entry into the light-paired chamber, but only for short periods of time, while VTA stimulation of LDTg-cholinergic neurons also resulted in increased entry into the light-paired chamber (though not as significantly often as LDTg-glutamatergic stimulation) in addition to longer stay in the chamber, showing place preference for the light-paired chamber. This indicates that LDTg-glutamatergic activity might be more important for simply reinforcing initial entry into the chamber whereas LDTg-cholinergic activity might be more important for the actual rewarding effects of staying in the chamber (Steidl et al., 2016). With future directions in mind, the researchers speculated that excitation of LDTg-glutamatergic neurons to the VTA might induce short and rapid increased dopamine levels in the NAc, leading to the behavioral inclinations seen in the increased entry into the light-paired chamber and shorter stays, while excitation of the LDTg-cholinergic neurons to the VTA might have more enduring effects on increasing NAc dopamine levels that led to longer stays in the light-paired chamber (Steidel et al., 2016).

 One could speculate that LDTg-glutamatergic activity may have a role in ‘wanting’ effects towards a reward, while LDTg-cholinergic activity may have a role in the actual ‘pleasure’ of having the reward. These neural pathways may be of use to incorporate into more research for treatments of addiction. Having insight into how these neural inputs regulate dopamine levels in the reward circuits in the brain may bring rise to new ways to help recovering addicts deal with cravings, even possibly curbing the rewarding effects they receive from their drug of choice.

 

 

References

Addiction and Dopamine Neurotransmitters: How Addiction Works. Promises Behavioral Health. (2020, February 25). https://www.promisesbehavioralhealth.com/addiction-recovery-blog/addiction-lights-brain-dopamine-neurotransmitters-101/.

Geisler, S. & Zahm, D.S. (2005). Afferents of the ventral tegmental area in the rat – anatomical substratum for integrative functions. J. Comp. Neurol., 490, 270–294.

Lammel, S., Lim, B.K., Ran, C., Huang, K.W., Betley, M.J., Tye, K.M.,Deisseroth, K. & Malenka, R.C. (2012). Input-specific control of reward and aversion in the ventral tegmental area. Nature, 491, 212–217.

Oakman, S.A., Faris, P.L., Kerr, P.E., Cozzari, C. & Hartman, B.K. (1995). Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differs significantly from those projecting to ventral tegmental area. J. Neurosci., 15, 5859–5869.

Omelchenko, N. & Sesack, S.R. (2005). Laterodorsal tegmental projections toidentified cell populations in the rat ventral tegmental area. J. Comp. Neurol., 483, 217–235.

Steidl, S., Wang, H., Ordonez, M., Zhang, S., & Morales, M. (2016). Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward. European Journal of Neuroscience, 45(4), 559–571. https://doi.org/10.1111/ejn.13436.

 Watabe-Uchida, M., Zhu, L., Ogawa, S.K., Vamanaro, A. & Uchida, N. (2012). Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron, 74, 858–873.

Woolf, N.J & Butcher, L.L. (1986). Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain. Brain Res. Bull., 16, 603-637