Key brain circuits

Simplified schematic of the circuitry of the mesolimbic dopamine system in the rat brain highlighting the major inputs to the nucleus accumbens (NAc) and ventral tegmental area (VTA) (glutamatergic projections, blue; dopaminergic projections, red; GABAergic projections, orange; orexinergic projections, green). Glutamatergic synapses excite postsynaptic neurons and GABAergic synapses inhibit postsynaptic neurons. Dopamine release exerts more complex modulatory effects. The release of dopamine from VTA neurons increases in response to administration of all drugs of abuse

The mesolimbic dopaminergic system, consisting of midbrain dopaminergic (DA) neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc) and prefrontal cortex, plays a key role in reward and motivation and is a major target of abused drugs.

First of all, the VTA, which is the origin of the mesolimbic DA system, has been implicated in both the signaling of natural rewards and in the formation of drug addiction. Neurons of the VTA release DA in target regions including the nucleus accumbens (NAc) and the prefrontal cortex as well as locally. On the other hand, the NAc has two major populations of neurons which together comprise >95% NAc neurons (Lobo et al., 2010): medium spiny neurons (MSN) divided into two subtypes based on their distinct projections through cortical-basal ganglia circuits and their differential gene expression, including enrichment of dopamine D1 vs. D2 receptors. They project to the dorsal striatum. In a sophisticated set of experiments, Lobo et al., 2010 demonstrated that activation of D2+ neurons suppresses cocaine reward, while D1+ neurons induces cocaine reward. The relevance of this finding to the addicted brain lies in the possibility of a potential imbalance of these two MSN: overactive D1 MSN while a hypoactive D2 MSNs; which may contribute to the persistence of addiction.

Another key area of the reward circuit is the the lateral nucleus of the amygdala (LA). Specifically, the LA has been implicated in the process by which an initially neutral cue acquired conditioned rewarding properties by virtue of being paired with rewarding stimuli, such as food or cocaine. For example, Heldt et al., 2014 demonstrated that disrupting synaptic plasticity in the LA/BLA amygdala in rodents impairs the acquisition of cocaine conditioning, in which an initially neutral environmental cue is paired with cocaine administration. Furthermore, presentation of cues previously associated with a history of cocaine use induces craving and increase activation in brain regions such as the amygdala, as measured by functional magnetic resonance imaging studies.

References: 

Heldt SA, Zimmermann K, Parker K, Gaval M, Weinshenker D, Ressler KJ. (2014). BDNF deletion or TrkB impairment in amygdala inhibits both appetitive and aversive learning. J Neurosci 34(7): 2444-50.   

Lobo MK, Covington HE, Chaudhury D., Friedman AK, et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science; 2010;330:385-390.