Abstract
Modulatory influences on sympathetic nervous system activity are diverse and far reaching, acting at select points in the complex pathways controlling sympathetic outflow to enable subtle changes or more global effects. Changes in the degree of sympathetic neuromodulation can have serious consequences on homeostatic variables such as heart rate, blood pressure and gut motility. At the level of the spinal cord, the sympathetic preganglionic neurons (SPNs) can be modulated by activation of presynaptic GABAB heteroreceptors on glutamatergic terminals and by postsynaptic GABAB receptors. Here we show that a low concentration of the GABAB agonist baclofen (1 μM) attenuated GABAergic inhibitory postsynaptic potentials in SPNs elicited from stimulation of either the central autonomic area or descending fibers in the lateral funiculus. This low baclofen concentration also elicited three categories of postsynaptic response: a large hyperpolarization with a decrease in input resistance, a moderate hyperpolarization with no change in input resistance and no response. Using cesium-loaded, tetraethylammonium chloride containing electrodes (to block potassium conductance), baclofen elicited moderate hyperpolarizations with no change in input resistance in 50% of SPNs; the remainder were unaffected. These modest hyperpolarizations were reduced in Ca2+ free solution or cadmium. Hyperpolarizing responses were also observed in interneurons in the vicinity of SPNs. These studies provide the first evidence for GABAB autoreceptors involved in inhibitory GABAergic transmission onto SPNs and for postsynaptic GABAB receptors on interneurons. The data also indicate that there is heterogeneity in the postsynaptic responses of SPNs.
Highlights
Sympathetic outflow to the many organs controlled by the autonomic nervous system is regulated at a number of levels within the central nervous system
Postsynaptic effects of low concentrations of baclofen recorded in K-Gluconate based intracellular solution Firstly we determined how a low concentration of the GABAB receptor agonist baclofen affected postsynaptic responses of sympathetic preganglionic neurons (SPNs), using a concentration (1 μM) that has previously been shown in the nucleus of the tractus solitarius to selectively target pre- rather than postsynaptic receptors (Brooks et al, 1992)
The SPNs were grouped according to their responses into (i) a large-response group (37.5%) where both parameters were significantly altered by drug application (Figure 1A); (ii) a modest response group (34.4%) with small hyperpolarizations observed but no significant alteration in input resistance (Figure 1B); and (iii) a non-responding group (28.1%) where neither membrane potential nor input resistance of neurons were changed after bath application of baclofen (Figure 1C)
Summary
Sympathetic outflow to the many organs controlled by the autonomic nervous system is regulated at a number of levels within the central nervous system. Continuing research into the spinal cord circuitry that regulates sympathetic output has revealed a high degree of complexity of control of these SPNs which enables fine tuning of the sympathetic activity influencing end organs. One avenue for selective regulation of SPN activity would be at a presynaptic level since receptors located on specific presynaptic terminals would influence synaptic transmission exclusively from that input. Such input-specific modulation is observed in SPNs where A1 adenosine receptors are located on excitatory terminals and their activation decreases excitatory transmission (Deuchars et al, 2001a) whilst A2A adenosine receptors are confined solely to inhibitory GABAergic terminals and increase GABAergic transmission (Brooke et al, 2004)
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