Figure 1.

The brain reward cascade (BRC). Figure1 illustrates the interaction of at least six principal neurotransmitter pathways involved in the Brain Reward Cascade (BRC). In the hypothalamus, environmental stimulation causes the release of serotonin, which in turn via, for example, 5HT-2a receptors activate (green, equal sign) the subsequent release of opioid peptides also in the hypothalamus. Then, in turn, the opioid peptides having two distinct effects possibly via two different opioid receptors: A) inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin) and projects to the Substania Nigra to GABA_A neurons B) stimulates (green equal sign) Cannabinoid neurons (e.g., Anandamide and 2-archydonoglcerol) through Beta –Endorphin linked delta receptors, which in turn inhibits GABA_A neurons at the substania nigra. Cannabinoids primarily 2-archydonoglcerol, when activated, can also indirectly disinhibit (red hash sign) GABA_A neurons in the Substania Nigra through activation of G1/0 coupled to CB1 receptors. Similarly, Glutamate neurons located in the Dorsal Raphe Nuclei (DRN) can indirectly disinhibit GABA_A neurons in the Substania Nigra through activation of GLU M₃ receptors (red hash sign). GABA_A neurons, when stimulated, will, in turn, powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB ₃ neurons. Finally, Glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (green, equal sign) to preferentially release dopamine at the Nucleus Accumbens (ACH)shown as a bullseye indicating euphoria (a wanting response)