Explain the mechanisms of action of nicotine, opiates and cocaine in the mesolimbic reward pathway. Which other brain circuitries could mediate the reinforcing effects of natural rewards and drugs of abuse?

The mesolimbic pathway, interchangeably referred to as the ‘reward’ pathway, is a network in the brain comprised of dopaminergic neurons and modulated primarily by the neurotransmitter dopamine, which can be affected by stimulation due to natural rewards such as sex or eating as well as the action of specific drugs. The role of the reward pathway is to enhance evolutionary success, promoting survival and reproduction (Kelley & Berridge 2002) as well as reinforcement (Wise, R.A. 2004) without which there would be no incentive to alter behaviour, learn or decide.

The dopaminergic receptors are g-protein coupled and exist in 2 major classes ‘D1like’ containing D1 and D5 as well as ‘D2Like’ which contain D2,3,4. Type D1like are inhibitory or excitatory whereas type D2like are inhibitory (Romanelli, R.J., Williams, J.T., Neve, K.A. 2009). Dopamine neurons can release dopamine into the synaptic cleft which diffuses out to bind with multiple postsynaptic neurons as opposed to classical neurons which transmit neurotransmitter only to the adjacent postsynaptic neuron across the synaptic cleft.

Addictive drugs such as nicotine, cocaine and opiates uniquely affect the reward pathway. With the potential to stimulate dopamine to reach synaptic concentrations surpassing that of natural reward by several orders of magnitude.

Cocaine causes an increase in the dopamine concentration in the nucleus accumbens brain region by acting on the dopamine reuptake transporters at the synaptic cleft. It effectively disables the dopamine transporters ability to re-uptake excess dopamine back into the presynaptic neuron, resulting in concentrations rapidly increasing in the extracellular spaces.

Opiates bind to specific μ-opiate receptors in the Ventral Tegmental Area (VTA), indirectly affecting the reward pathway through subsequent receptor signalling to inhibit GABA suppression in the mesolimbic dopaminergic pathway (Johnson, S.W. & North, R.A. 1992). Thus having an excitatory effect on the dopaminergic pathway, elevating concentrations in the Nucleus Accumbens. There is also a degree of direct opiate mediated response  in the reward pathway as μ-opiate receptors are also found in the Nucleus Accumbens and VTA.

Nicotine has a direct effect on dopamine neurons in the VTA which feature acetylcholine receptors. Binding to these receptors induces dopamine release downstream in the Nucleus Accumbens.

The aforementioned three drugs when used frequently for an extended period of time, cause the receptors to be downregulated, which means that the corresponding pathway induced by the natural reward is less pronounced. Thus the drug user must take more of the drug in order to merely feel natural levels of reward.

Other regions and pathways also impact reward circuits: it is by no means restricted to the mesolimbic route. The basal ganglia circuits for example plays a crucial function in reward based behavioural patterns. Neuronal activity in different regions of the basal ganglia appears to be heavily influenced by reward in particular reward anticipation (Kim, F.H., & Hikosaka, O. 2015). It is hypothesised that the direct pathway is predominantly responsible for processing prediction of reward signals thus pre-empting reward based motion. The indirect pathway is the route mainly for processes non-reward signals thus inhibiting non-rewarded movements. The interplay between these two pathways combine to result in reward and non reward motivated movement. These pathways draw on input from other pathways received from sensory stimuli, memories and emotive bases. Which rely on the hippocampus for memory retrieval input and amygdala for emotional input as a basis for assessing whether the behaviour is worth repeating.

Ketamine activates different pathways which also have a long term potentiation impact on the reward pathway through mechanisms that are not well understood. It has a binding affinity for several receptors including the μ-opiate receptor and inhibits the NMDA glutamate receptor which has indirect impacts from the hippocampus and cortex to the nucleus accumbens (NAc) and dopaminergic (DA) innervation of the NAc from the ventral tegmental area (VTA) have key roles in these motivational behaviors (Yao et al. 2017).

The role of dopamine in the reward pathway has evolved over the years, initially being considered the neurotransmitter responsible for pleasure to being viewed as a behavioural reinforcement signal molecule (Wise, R.A. 2004), inducing incentive salience rather than directly inducing hedonic effects.

 

Wise, R.A. (2004). Dopamine, learning and motivation. Nat Rev Neurosci 5: 483–494.

Kelley, A.E., and Berridge, K.C. (2002). The Neuroscience of Natural Rewards: Relevance to Addictive Drugs. The Journal of Neuroscience, May 1, 2002, 22(9):3306–3311.

Romanelli, R.J., Williams, J.T., Neve, K.A. (2009) Chapter 6: Dopamine receptor signalling: intracellular pathways to behavior. The Dopamine Receptors. Springer.

Johnson, S.W., North, R.A. (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. Journal of Neuroscience 12(2): 483–8.

Kim, F.H., and Hikosaka, O. (2015). Parallel basal ganglia circuits for voluntary and automatic behaviour to reach rewards. BRAIN 2015: 138; 1776–1800.

Yao, N., Skiteva1, O., Zhang, X., Svenningsson, P. and Chergui1, K. (2017). Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Molecular Psychiatry (2017) 00, 1–12