PubMed · 13904632
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H F HARDMAN. 1962. Local anesthetics: some basic concepts.. https://pubmed.ncbi.nlm.nih.gov/13904632/
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In a previous study, we reported that inactivation of the medial septum or the hippocampus by muscimol, a GABA(A) receptor agonist, potentiated the effects of a general anesthetic. In this study, we further investigated whether other structures that are connected to the septohippocampal system are involved in mediating general anesthesia. In freely behaving rats, muscimol (0.25 microg) or saline was infused intracerebrally into one of four areas-the supramammillary area (SUM), nucleus accumbens (NAC), ventral pallidum (VP), and ventral tegmental area (VTA)-and righting, pain, and EEG responses were recorded following either halothane or sodium pentobarbital, representing inhalational and injectable general anesthetic, respectively. The effect of halothane (2%) or pentobarbital (20 mg/kg i.p.) in abolishing the righting, pain response, or low-voltage neocortical activity was enhanced, and the initial behavioral hyperactivity (delirium) was reduced, after muscimol as compared to after saline infusion in SUM, NAC, VP, and VTA. EEGs in the hippocampus and the sensorimotor cortex following halothane or pentobarbital showed increased delta, and decreased hippocampal theta and gamma waves after muscimol infusion as compared to saline infusion in SUM, NAC, VP, and VTA. By contrast, infusion of muscimol in the median raphe increased locomotion and did not significantly alter the behavioral or EEG effects of halothane or pentobarbital. It is suggested that structures that activate the limbic cortices (MS, SUM, and VTA but not the median raphe) or mediate the output of the hippocampus (NAC and VP) normally participate in maintaining consciousness and inactivation of these structures potentiates the response to a general anesthetic.
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Microinjection of pentobarbital and GABA(A)-receptor agonists into a brainstem region we have called the mesopontine tegmental anesthesia area (MPTA; Devor and Zalkind [2001] Pain 94:101-112) induces a general anesthesia-like state. As in systemic general anesthesia, rats show loss of the righting reflex, atonia, nonresponsiveness to noxious stimuli, and apparent loss of consciousness. GABA(A) agonist anesthetics acting on the MPTA might suppress movement by engaging endogenous motor regulatory systems previously identified in research on decerebrate rigidity and REM sleep atonia. Anterograde and retrograde tracing revealed that the MPTA has multiple descending projections to pontine and medullary areas known to be associated with motor control and atonia. Prominent among these are the dorsal pontine reticular formation and components of the rostral ventromedial medulla (RVM). The MPTA also has direct projections to the intermediate gray matter and ventral horn of the spinal cord via the lateral and anterior funiculi. These projections show a rostrocaudal topography: neurons in the rostral MPTA project to the RVM, but only minimally to the spinal cord, while those in the caudal MPTA project to both targets. Finally, the MPTA has ascending projections to motor control areas including the substantia nigra, subthalamic nucleus, and the caudate-putamen. Projections are bilateral with an ipsilateral predominance. We propose that GABA(A) agonist anesthetics induce immobility at least in part by acting on these endogenous motor control pathways via the MPTA. Analysis of MPTA connectivity has the potential for furthering our understanding of the neural circuitry responsible for the various functional components of general anesthesia.