Figure 2.

Hypothesized Neural Circuit of D2 Hypersensitivity in Opioid Withdrawal. We hypothesize that D2 receptor activity is during withdrawal from chronic opioid use (1), which leads to decreased activity of GABAergic MSNs within the NA (2). This leads to a reduction in GABAergic inhibitory tone from the NA to the VP (3). Through the direct projection to the VP, disinhibition of the VP from reduced NA-derived GABAergic innervation leads to enhanced excitability of cells residing in the VP. It is also possible that MSNs co-expressing D1 and D2 receptors project from the NA to the VM, and play a critical role in enhancing dopaminergic signaling from the VM to output structures. As well, enhanced enkephalin activity may enhance neuronal excitability within the VP (4). This excitation leads to enhanced acetylcholine release into the MD (5), which may enhance reward. Through the direct GABAergic projection from the VP to the mesencephalon, there is less inhibitory tone and consequently, enhanced dopaminergic activity in cells residing in the VM and projecting back to the VP or to the MD (6). The net result of these neural adaptations is enhanced excitability of thalamic nuclei including the MD (7), and, consequently, enhanced use of dopamine agonists during opioid withdrawal (8). NA, nucleus accumbens; VP, ventral pallidum; VM, ventral mesencephalon; MD, mediodorsal thalamic nucleus; D2, dopamine receptor D2; D1, dopamine receptor D1; MSN, medium spiny neuron.