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Abstract-␥-Aminobutyric acid-B (GABA B ) receptor function and regulation in the nucleus of the solitary tract (NTS) was examined in Sprague-Dawley rats made chronically (4 to 5 weeks) hypertensive with the one-kidney, figure-8 renal wrap model of hypertension. NTS microinjection of the GABA B agonist baclofen produced a pressor response that was enhanced in hypertensive rats compared with the response observed in sham-operated normotensive rats (36Ϯ4 mm Hg increase in mean arterial pressure in 8 hypertensive rats compared with 21Ϯ2 mm Hg increase in 7 sham-operated normotensive rats, Pϭ0.03). Responses to microinjection of GABA B antagonists (CGP-55845A and SCH-90511), the GABA A agonist muscimol, the GABA A antagonist bicuculline, and the GABA reuptake inhibitor nipecotic acid were not different comparing normotensive sham-operated and hypertensive rats. Renal sympathetic nerve responses to NTS microinjection of these drugs were not different in hypertensive compared with normotensive rats. Micropunches of the NTS were homogenized and reverse transcriptase-polymerase chain reaction was performed to examine mRNA levels for the GABA B receptor. There was a 3-fold increase in GABA B receptor mRNA levels in the caudal NTS of 7 chronically hypertensive rats compared with levels measured in 8 sham-operated normotensive rats (Pϭ0.01). In conclusion, chronic hypertension is associated with an upregulation of GABA B receptor function; however, the tonic activity of the system does not appear to be different between normotensive and hypertensive rats. The upregulation of GABA B receptor function might be due to an increased number of receptors, as suggested by the elevated levels of GABA B receptor mRNA measured in the NTS of hypertensive rats. All of these alterations suggest that hypertension is associated with dynamic changes in receptor-mediated mechanisms within the NTS, and these alterations could modify baroreflex regulation of cardiovascular function in hypertension. Key Words: kidney Ⅲ tractus solitarius Ⅲ hypertension, renal Ⅲ receptors, aminobutyric acid Ⅲ baclofen Ⅲ reverse transcriptase T he nucleus of the solitary tract (NTS) is the brain stem nucleus where baroreceptor afferent fibers make their initial synapse within the central nervous system. Therefore, information regarding the physiology and pharmacology of NTS neurons is critical to our understanding of baroreflex regulation of cardiovascular function. The region of the NTS where baroreceptor afferents terminate contains a high density of both ␥-aminobutyric acid-A (GABA A ) and GABA B receptors. 1,2 A number of in vivo microinjection studies 3-6 as well as in vivo 7-9 and in vitro 10,11 single unit electrophysiological experiments have demonstrated that both GABA A and GABA B receptors play an important role in the integration of baroreceptor afferent inputs and baroreflex function. Since activation of GABA A receptors evokes postsynaptic inhibition and activation of GABA B receptors evokes both presynaptic and postsynaptic inhibition of NTS neuron...

The neuromodulatory effect of NO on glutamatergic transmission has been studied in several brain areas. Our previous single-cell studies suggested that NO facilitates glutamatergic transmission in the nucleus of the solitary tract (NTS). In this study, we examined the effect of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) on glutamatergic and reflex transmission in the NTS. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) from Inactin-anesthetized Sprague-Dawley rats. Bilateral microinjections of L-NAME (10 nmol/100 nl) into the NTS did not cause significant changes in basal MAP, HR, or RSNA. Unilateral microinjection of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 1 pmol/100 nl) into the NTS decreased MAP and RSNA. Fifteen minutes after L-NAME microinjections, AMPA-evoked cardiovascular changes were significantly reduced. N-methyl-D-aspartate (NMDA, 0.5 pmol/100 nl) microinjection into the NTS decreased MAP, HR, and RSNA. NMDA-evoked falls in MAP, HR, and RSNA were significantly reduced 30 min after L-NAME. To examine baroreceptor and cardiopulmonary reflex function, L-NAME was microinjected at multiple sites within the rostro-caudal extent of the NTS. Baroreflex function was tested with phenylephrine (PE, 25 microg iv) before and after L-NAME. Five minutes after L-NAME the decrease in RSNA caused by PE was significantly reduced. To examine cardiopulmonary reflex function, phenylbiguanide (PBG, 8 microg/kg) was injected into the right atrium. PBG-evoked hypotension, bradycardia, and RSNA reduction were significantly attenuated 5 min after L-NAME. Our results indicate that inhibition of NOS within the NTS attenuates baro- and cardiopulmonary reflexes, suggesting that NO plays a physiologically significant neuromodulatory role in cardiovascular regulation.

Abstract-The increase in mean arterial pressure evoked by injection of the ␥-aminobutyric acid (GABA) B agonist baclofen into the nucleus tractus solitarius (NTS) is greater in spontaneously hypertensive rats and renal wrap chronically hypertensive (CHT) rats compared with normotensive (NT) controls. We report here that the baclofeninduced pressor response (BIPR) is enhanced after acute hypertension (AHT) of only 30 minutes. Sprague-Dawley rats were anesthetized with Inactin, paralyzed, and artificially ventilated. As we previously reported, after unilateral electrolytic ablation of the NTS, microinjection of 40 pmol baclofen into the contralateral NTS of NT rats resulted in a BIPR of 22Ϯ1 mm Hg (nϭ12). During the infusion of phenylephrine for 30 minutes (AHT), the BIPR was 39Ϯ5 mm Hg (nϭ10), significantly greater than the response in NT rats (PϽ0.01) and no different from the response in CHT rats (39Ϯ5 mm Hg, nϭ7). Baclofen has both presynaptic and postsynaptic effects. To eliminate the presynaptic component of the baclofen response, sinoaortic denervation (SAD) was performed before the microinjections. The magnitude of the BIPR was 12Ϯ1 mm Hg in NT-SAD rats (nϭ8), 12Ϯ1 mm Hg in AHT-SAD rats (nϭ12), and 20Ϯ3 mm Hg in CHT-SAD rats (nϭ7). The BIPR is enhanced in both CHT and AHT rats. It appears that the increase in baroreceptor afferent input to NTS during phenylephrine-induced AHT provides a greater substrate for presynaptic inhibition by baclofen because the postsynaptic component of the baclofen response is the same in NT-SAD and AHT-SAD. The enhanced BIPR in CHT rats appears to be associated with an enhancement of both the presynaptic and postsynaptic components of the response. has been demonstrated to be a potent modulator of neurons within the nucleus of the solitary tract (NTS), the initial site of baroreceptor afferent integration within the central nervous system. In vivo and in vitro studies have demonstrated that the inhibition of NTS neurons and afferent evoked discharge in these neurons by the GABA B receptor agonist baclofen is mediated by both presynaptic and postsynaptic mechanisms. 1,2 The microinjection into the NTS of baclofen results in an increase in arterial pressure, heart rate, and sympathetic nerve discharge to the kidney, 3-6 which are predictable effects of inhibition of NTS neurons that integrate baroreceptor afferent inputs. This baclofen-induced pressor response (BIPR) is enhanced in chronically hypertensive rats, specifically the spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt 5 and 1-kidney, renal wrap models of hypertension. 6 The duration that arterial pressure must be elevated before an enhanced BIPR is observed is currently unknown. Furthermore, the relative contributions of presynaptic and postsynaptic inhibitory mechanisms to the BIPR are also unknown.The present study was designed to answer 2 questions. First, is the enhanced BIPR that is observed in chronic hypertension also observed in acute hypertension? Second, what are the relative contributi...

Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression.