As reviewed by Gardner (2011), the primary reward circuitry consists of an ‘in-series’ circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. The mesolimbic dopamine (DA) circuits include DAergic projections from the ventral tegmental area and substantia nigra to the ventral striatum (which contains the nucleus accumbens), limbic structures (amygdala, hippocampus, cingulate), and frontal cortex. The nucleus accumbens receives inputs from the prefrontal cortex, amygdala and hippocampus. In addition, the ventral striatum projects to the ventral pallidum and to the ventral tegmental area and substantia nigra, which, project back to the prefrontal cortex, via the medial dorsal nucleus of the thalamus (Haber and Knutson, 2010). Activation of mu opioid receptors in the ventral tegmental area, or activation of mu opioid and delta opioid receptors via release of beta-endorphin and enkephalin in the nucleus accumbens increases extracellular DA in the nucleus accumbens (Gianoulakis, 2009). DAergic neurotransmission in the ventral striatum is also modulated via opioid peptide inputs in the hypothalamus. These interactions between opioid peptides and DA in the mesocorticolimbic circuit are thought to
