Figure 1.

Displays the interplay of multiple neurotransmitter pathways involved in the Brain Reward Cascade (BRC). The process commences with an environmental stimulus triggering the release of serotonin in the hypothalamus, which, in turn, activates the release of opioid peptides from opioid peptide neurons, mediated by 5HT-2a receptors (indicated by a green equal sign). Subsequently, the opioid peptides have two distinct effects through different opioid receptors. One effect involves inhibition (indicated by a red hash sign) via the mu-opioid receptor, which projects to GABAA neurons in the Substantia Nigra. The other effect involves stimulation (indicated by a green equal sign) of cannabinoid neurons, facilitated by delta receptors linked to Beta-Endorphin. The activated cannabinoid neurons inhibit GABAA neurons in the Substantia Nigra. Additionally, cannabinoids, particularly 2-archidonylglycerol, can indirectly disinhibit (indicated by a red hash sign) GABAA neurons by activating G1/0 coupled to CB1 receptors in the Substantia Nigra. In the Dorsal Raphe Nuclei (DRN), glutamate neurons indirectly disinhibit GABAA neurons in the Substantia Nigra through the activation of GLU M3 receptors (indicated by a red hash sign). When GABAA neurons are activated, they strongly inhibit (indicated by red hash signs) the glutaminergic drive from the Ventral Tegmental Area (VTA) through GABAB3 neurons. Stimulation of acetylcholine (ACH) neurons in the Nucleus Accumbens activates both muscarinic (indicated by a red hash sign) and nicotinic (indicated by a green hash sign) receptors. Finally, glutamate neurons in the VTA project to dopamine neurons via NMDA receptors (indicated by a green equal sign), leading to the predominant release of dopamine at the Nucleus Accumbens, depicted as a bullseye, representing a euphoric or motivational (“wanting”) response. The result is that low dopamine release leads to feelings of unhappiness, while maintaining a balanced dopamine homeostatic tonic set point is crucial for overall well-being and happiness.

Notes: Reprinted from Blum K, McLaughlin T, Bowirrat A, Modestino EJ, Baron D, Gomez LL, Ceccanti M, Braverman ER, Thanos PK, Cadet JL, Elman I, Badgaiyan RD, Jalali R, Green R, Simpatico TA, Gupta A, Gold MS. Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It “Blowin’ in the Wind”? J Pers Med. 2022 Feb 21;12(2):321. Creative Commons.²⁵