PubMed · 13585169
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F HUDON, A JACQUES, P A BOIVIN. 1958. Fluothane-ether: an azeotropic mixture.. https://doi.org/10.1007/bf03021140
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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.
Neuronal plasticity is achieved by regulation of the expression of genes for neurotransmitter receptors such as the type A receptor (GABA(A)R) for gamma-aminobutyric acid. We now show that two different rat neuronal populations in culture manifest distinct patterns of GABA(A)R plasticity in response to identical stimuli. Whereas prolonged exposure to ethanol had no effect on expression of the delta subunit of GABA(A)Rs at the mRNA or protein level in cerebellar granule neurons, it increased the abundance of delta subunit mRNA and protein in hippocampal neurons. Subsequent ethanol withdrawal transiently down-regulated delta subunit expression in cerebellar granule neurons and gradually normalized that in hippocampal neurons. These effects of ethanol exposure and withdrawal were accompanied by corresponding functional changes in GABA(A)Rs. GABA(A)Rs containing the delta subunit were also distributed differentially in the cerebellar and hippocampal neurons. These findings reveal complex and distinct mechanisms of regulation of the expression of GABA(A)Rs that contain the delta subunit in different neuronal types.
General anesthetics have been a mainstay of surgical practice for more than 150 years, but the mechanisms by which they mediate their important clinical actions remain unclear. Ion channels represent important anesthetic targets, and, although GABA(A) receptors have emerged as major contributors to sedative, immobilizing, and hypnotic effects of intravenous anesthetics, a role for those receptors is less certain in the case of inhalational anesthetics. The neuronal hyperpolarization-activated pacemaker current (Ih) is essential for oscillatory and integrative properties in numerous cell types. Here, we show that clinically relevant concentrations of inhalational anesthetics modulate neuronal Ih and the corresponding HCN channels in a subunit-specific and cAMP-dependent manner. Anesthetic inhibition of Ih involves a hyperpolarizing shift in voltage dependence of activation and a decrease in maximal current amplitude; these effects can be ascribed to HCN1 and HCN2 subunits, respectively, and both actions are recapitulated in heteromeric HCN1-HCN2 channels. Mutagenesis and simulations suggest that apparently distinct actions of anesthetics on V(1/2) and amplitude represent different manifestations of a single underlying mechanism (i.e., stabilization of channel closed state), with the predominant action determined by basal inhibition imposed by individual subunit C-terminal domains and relieved by cAMP. These data reveal a molecular basis for multiple actions of anesthetics on neuronal HCN channels, highlight the importance of proximal C terminus in modulation of HCN channel gating by diverse agents, and advance neuronal pacemaker channels as potentially relevant targets for clinical actions of inhaled anesthetics.