The role of VTA glutamate afferents in nicotine addiction

Nicotine is the primary addictive substance found in tobacco products and dramatically effects the electrical and chemical balance of the brain’s reward pathway. The prevention and treatment of nicotine addiction will ultimately require a better understanding of the neural circuits that control motivated behavior, and specifically, the synapses upon which nicotine exerts it’s reinforcing and habit-forming effects. It is thought that nicotine changes normal brain functions through stimulating a brain structure called the ventral tegmental area (VTA) to release dopamine in another brain area called the nucleus accumbens (Acb); indeed, the VTA-Acb pathway is often referred to as “the reward circuit of the brain”. In contrast nicotine withdrawal has been shown to decrease dopamine neuronal activity in the VTA and consequently dopamine output in the Acb.

Nicotine is thought to influence VTA neuron activity by acting on synapses from the brainstem nuclei called the peduncluopontine (PPTg) and laterodorsal (LDTg) tegmental nuclei (PP/LDTg). The PP/LDTg contain a well-established population of acetycholine-releasing (cholinergic) neurons but also a population of glutamate-releasing (glutamatergic) neurons, both of which project to the VTA and regulate dopamine neuron activity. The classical view of neurotransmission presumes that a neuron releases a single transmitter at each synapse (so-called Dale’s principle). However, there is now strong evidence for the co-release of multiple classical neurotransmitters, including glutamate and acetylcholine. However, it is unknown whether PP/LDTg neurons co-release glutamate and the relative roles of the glutamate and acetylcholine neurons in driving behavioral reinforcement and addiction remain unclear. We will therefore use sophisticated modern techniques to identify new modes of synaptic transmission, interrogate the role of novel neural circuits, and define their relevance to the initiation and progression of nicotine dependence.

I am primed to make key discoveries in the basic biology of these crucial neural circuits and expect our results to have far reaching implications to the neurobiology of nicotine-mediated reinforcement, dependence, and addiction.