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. 2022 Nov 23;12(12):1946. doi: 10.3390/jpm12121946

Figure 2.

Figure 2

Illustrates the interaction of at least seven significant neurotransmitter-pathways involved in the brain reward cascade (BRC). In the hypothalamus, environmental stimulation results in the release of serotonin, which in turn, via 5HT2A receptors, activates (equal green sign) the subsequent release of opioid peptides from opioid peptide neurons, also in the hypothalamus. Then, the opioid peptides have two distinct effects, possibly via two different opioid receptors. One inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin) and projects to the substantia nigra to GABAA neurons. Another stimulates (equal green sign) cannabinoid neurons (the anandamide and 2-arachidonoylglycerol, for example) through beta–endorphin linked delta receptors, which in turn inhibit GABAA receptors in the substantia nigra. Also, when activated, cannabinoids, primarily 2-archydonoglcerol, can indirectly disinhibit (red hash sign) GABAA receptors through activation of G1/0 coupled to CB1 receptors in the substantia nigra. In the dorsal raphe nuclei, glutamate neurons can indirectly disinhibit GABAA receptors in the substantia nigra by activating group III metabotropic glutamate (GLU M3) receptors (green hash). GABAA receptors, when stimulated, will in turn powerfully (red hash signs) inhibit ventral tegmental area (VTA) glutaminergic drive via GABAB 3 receptors. It is also possible that stimulation of ACh neurons at the nucleus accumbens can stimulate both muscarinic (red hash) and nicotinic (green hash) receptors. Finally, glutamate neurons in the VTA will project to dopamine neurons stimulating NMDA receptors (equal green sign) to preferentially release dopamine at the nucleus accumbens, shown as a green bullseye that indicates a euphoria or “wanting” response. The result is that when dopamine release is low (dopamine deficiency), it results in unhappiness, while general (healthy) happiness depends on the dopamine homeostatic tonic set point. (With permission from Blum et al. With permission from Blum et al. [139].).