Fig 1. Brain Reward Cascade.

Fig 1a. Schematic represents the normal physiologic state of the neurotransmitter interaction at the mesolimbic region of the brain. Briefly in terms of the “Brain Reward Cascade” first coined by Blum and Kozlowski [90]: serotonin in the hypothalamus stimulates neuronal projections of methionine enkephalin in the hypothalamus which in turn inhibits the release of GABA in the substania nigra thereby allowing for the normal amount of DA to be released at the NAc (reward site of Brain). Fig 1b Represents hypodopaminergic function of the mesolimbic region of the brain. It is possible that the hypodopaminergic state is due to gene polymorphisms as well as environmental elements including both stress and neurotoxicity from aberrant abuse of psychoactive drugs (i.e. alcohol, heroin, cocaine etc). Genetic variables could include serotonergic genes (serotonergic receptors [5HT2a]; serotonin transporter 5HTlPR); endorphinergic genes (mu OPRM1 gene; proenkephalin (PENK) [PENK polymorphic 3′ UTR dinucleotide (CA) repeats}; GABergic gene (GABRB3) and dopaminergic genes (ANKKI Taq A; DRD2 C957T, DRD4 7R, COMT Val/met substation, MAO-A uVNTR, and SLC6A3 9 or 10R). Any of these genetic and or environmental impairments could result in reduced release of DA and or reduced number of dopaminergic receptors. (Brain reward cascade -modified with permission from IIOAB Journal, Blum et al. IIOAB, 2010, 11(2) 1–14.)