Neuronal Mechanisms Underlying Addiction

Addiction, whether it be to drugs of abuse or cigarettes, is a very complex and often misunderstood disease. It is not uncommon for people to think that cigarette and drug abusers simply lack the willpower to forgo the addictive substance. However, nicotine and drugs of abuse, such as opioids, act on the brain's reward and reinforcement systems resulting in a strong neurological hold over the individual. In order to develop treatments and interventions, it is essentially to understand what is happening mechanistically at the neuronal level when these addictive substances are introduced to the brain.

Recently, Dr. Daniel McGehee shed an important light on the nature of addiction in his talk to Loyola University Chicago neuroscience students during which he spoke of nicotine, the addictive substance in tobacco. Specifically, McGehee focused on the dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), the brain's reward and reinforcement system. McGehee and his colleagues have previously established that nicotine increases glutamate release by activating acetylcholine receptors on the glutamate terminals. This indicates that nicotine facilitates induction of long-term potentiation (LTP) in VTA dopamine (DA) neurons (Mao et al.). LTP is a persistent strengthening of synapses due to recent patterns of synaptic activity, such as repeated exposure to nicotine. As a result, this repeated nicotine exposure produces long-lasting increases in the firing of VTA DA, thus indicating that nicotine addiction is much more than a lack of willpower to quit. The post nicotine exposure LTP was supported by an increase of the AMPA/NMDAR ratio following exposure of nicotine to brain slices from drug-naive adults (Mao et al.).

In a paper titled, "Nicotine Potentiation of Excitatory Inputs to Ventral Tegmantal Area Dopamine Neurons", McGehee and his colleagues expanded upon the relationship between nicotine and the VTA DA through in vitro exposure. In order to express rewarding effects of nicotine, activation of nAChR in the VTA must occur. In essence, the activation of these receptors depolarizes dopamine neurons resulting in an influx of ions leading to a action potential excitation resulting in elevation of dopamine levels in the VTA. The pedunoculopontine tegmental nucleus (PPTg) and the laterodorsal tegmental nucleus (LDTg) serve as the only acetylcholine inputs into the VTA (Oakman, 1995). McGehee focused specifically on the LDTg and its role in nicotine's ability to stimulate the brains reward system, thus fostering addictive behavior. 

Similarly, I currently serve as a research assistant in Dr. Stephan Steidl's lab at Loyola University Chicago studying the relationship between opiates and the LDTg and PPTg cholinergic inputs to the VTA. Experiments have shown that lesions destroying the functionality of the PPTg and LDTg reduce the opiate induced dopamine response (Forster et al., 2002). Similarly, pharmacological blockage of cholinergic receptors in the VTA does not yield drug-induced elevated dopamine levels   (Steidl et al., 2011). Therefore, it can be reasonably concluded that cholinergic input to the VTA via the PPTg and the LDTg are critical to the ability of opiates to increase dopaminergic signaling. It is clear that these cholinergic pathways to the VTA play a large role in both opiate and nicotine addiction and efforts to decipher the nature of these mechanisms will serve as an essential step in the development of treatment and intervention options. 
 
According the Dr. McGehee's talk, over 400,000 deaths per year in the US are from smoking relates causes. According to the American Society of Addiction Medicine, in 2014 drug overdose took the lives of 47,055 Americans with 18,893 (~ 40%) of those lives lost as a result of an opioid overdose. With rates growing exponentially, it is clear that drug and tobacco use and addiction are widespread epidemics that deserve and necessitate attention. It is through the intense study of these mechanisms utilized by addictive substances such as opiates and nicotine that treatment and intervention options can be developed and countless lives can be saved. 

Resources 

Mao, D., Gallagher, K., & McGegee, D. S. (2011). Nicotine Potentiation of Excitatory Inputs to Ventral Tegmental Area Dopamine Neurons. The Journal of Neuroscience.

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. The Journal of Neuroscience. Retrieved from http://www.jneurosci.org/content/15/9/5859.long

Steidl, S., Miller, A. D., Blaha, C. D., & Yeomans, J. S. (2011). M5 Muscarinic Receptors Mediate Striatal Dopamine Activation by Ventral Tegmental Morphine and Pedunculopontine Stimulation in Mice. PLoS ONE, 6(11), e27538. http://doi.org/10.1371/journal.pone.0027538