Modulating anesthetic emergence with pathway-selective dopamine signaling

Abstract

Purpose of review: To summarize the recent preclinical findings investigating dopaminergic circuits for their involvement in reversing anesthetic-induced unconsciousness.

Recent findings: The release of dopamine from the ventral tegmental area onto dopamine D1 receptor-expressing neurons in the nucleus accumbens promotes emergence following general anesthesia. Two relevant targets of dopamine D1 receptor-expressing neurons in the nucleus accumbens include the lateral hypothalamus and ventral pallidum. Activating mesocortical dopaminergic projections from the ventral tegmental area to the prelimbic cortex has also been shown to hasten emergence from general anesthesia. In contrast, the nigrostriatal dopamine pathway is not involved in regulating anesthetic emergence. The role of the tuberoinfundibular endocrine dopamine pathway remains to be tested; however, recent studies have identified an important function of neuroendocrine signaling on modulating general anesthesia.

Summary: Potential avenues for accelerating anesthetic emergence may be found through targeting specific arousal-promoting pathways in the brain. Accumulating evidence from rodent studies manipulating cell type- and circuit-specific signaling pathways have identified dopamine as a potent modulator of general anesthesia. Specifically, dopamine signaling along the mesolimbic and mesocortical pathways plays a fundamental role in regulating consciousness.

Figure 1.

The four major dopaminergic pathways of the brain. A mid-sagittal view of the human brain with the four main dopaminergic signaling pathways outlined. Mesolimbic (pink): ventral tegmental area (VTA) dopaminergic projections to the nucleus accumbens (NAc) and olfactory tubercle (OT). Mesocortical (green): VTA projections to the cortex, and predominantly the prefrontal cortex (PFC). Nigrostriatal (yellow): substantia nigra pars compacta (SNc) to the dorsal striatum (dStr). Tuberoinfundibular (purple): arcuate nucleus (AN) of the hypothalamus to the median eminence (ME).

Figure 2.

Dopaminergic circuits involved in anesthetic emergence. (Top) A mid-sagittal view of a rodent brain is depicted with dopaminergic (blue), GABAergic (red), and glutamatergic (green) projections depicted summarizing the dopamine signaling pathways involved in regulating anesthetic emergence and detailed in the bottom panel. Activation of dopaminergic neurons in the VTA induce arousal under general anesthesia (33). Activation of the RMTg, a structure with dense inhibitory projections to VTA dopamine and glutamate neurons, enhances general anesthesia (60). Dopamine release from the VTA onto D1R-expressing neurons in the NAc (40, 42, 43) and OT (48) (Mesolimbic pathway) or the Prl (mesocortical pathway)(49) has been shown to induce emergence from general anesthesia in rodent studies. Recently, D1R NAc neurons projecting to the VP and LH have been shown to both induce emergence in rodents under general anesthesia(44). The target in the VP and LH are thought to be inhibitory interneurons. GABAergic VP projections have been shown to disinhibit VTA neurons, increasing arousal(45). VTA GABAergic neurons projection to the LH has been shown to induce emergence following anesthesia(61), and glutamatergic VTA projections to the LH enhance arousal(46). VTA = ventral tegmental nucleus, RMTg = rostromedial tegmental nucleus, NAc = nucleus accumbens, Prl = prelimbic cortex, VP = ventral pallidum, LH = lateral hypothalamus, OT = olfactory tubercle. Blue projections are dopaminergic, red are GABAergic, green are glutamatergic. Inhibitory interneurons are in black.