Fig. 1.

The brain reward cascade.

Fig. 1 illustrates the interaction of at least seven major neurotransmitter-pathways involved in the Brain Reward Cascade (BRC). In the hypothalamus environmental stimulation results in the release of serotonin, which in turn via, for example, 5HT-2a receptors activate (green equal sign) the subsequent release of opioid peptides from opioid peptide neurons, also in the hypothalamus. Then, in turn, the opioid peptides have two distinct effects, possibly via two different opioid receptors. One that inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin) and projects to the Substania Nigra to GABAA neurons. Another stimulates (green equal sign) cannabinoid neurons (the Anandamide and 2-archydonoglcerol, for example) through Beta –Endorphin linked delta receptors, which in turn inhibit GABAA neurons at the substania nigra. Also, when activated, cannabinoids primarily 2-archydonoglcerol, can indirectly disinhibit (red hash sign) GABAA neurons through activation of G1/0 coupled to CB1 receptors in the Substania Nigra. In the Dorsal Raphe Nuclei (DRN), glutamate neurons can then indirectly disinhibit GABAA neurons in the Substania Nigra through activation of GLU M3 receptors (red hash sign). GABAA neurons, when stimulated, will, in turn, powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB 3 neurons. It is also possible that stimulation of ACH neurons that at the Nucleus Accumbens ACH can stimulate both muscarinic (red hash) or Nicotinic (green hash). 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 (NAc) shown as a bullseye indicates a euphoria, or “wanting” response. The result is that when dopamine release is low (endorphin deficiency), unhappiness is felt while general (healthy) happiness depends on the dopamine homeostatic tonic set point (see Fig. 2).