Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner.

Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling. Here we attempt to reverse this deficit by overexpression of the α5-GABAA receptor within the ventral hippocampus (vHipp). Indeed, this is sufficient to normalize vHipp activity and downstream alterations in dopamine neuron function in the MAM rodent model. This approach also attenuated behavioral deficits in cognitive flexibility. To understand the specific pathways that mediate these effects, we used chemogenetics to manipulate discrete projections from the vHipp to the nucleus accumbens (NAc) or prefrontal cortex (mPFC). We found that inhibition of the vHipp-NAc, but not the vHipp-mPFC pathway, normalized aberrant dopamine neuron activity. Conversely, inhibition of the vHipp-mPFC improved cognitive function. Taken together, these results demonstrate that restoring GABAergic signaling in the vHipp improves schizophrenia-like deficits and that distinct behavioral alterations are mediated by discrete projections from the vHipp to the NAc and mPFC.

High salt intake enhances swim stress-induced PVN vasopressin cell activation and active stress coping.

PURPOSE: Stress contributes to many psychiatric disorders; however, responsivity to stressors can vary depending on previous or current stress exposure. Relatively innocuous heterotypic (differing in type) stressors can summate to result in exaggerated neuronal and behavioral responses. Here we investigated the ability of prior high dietary sodium chloride (salt) intake, a dehydrating osmotic stressor, to enhance neuronal and behavioral responses of mice to an acute psychogenic swim stress (SS). Further, we evaluated the contribution of the osmo-regulatory stress-related neuropeptide arginine vasopressin (VP) in the hypothalamic paraventricular nucleus (PVN), one of only a few brain regions that synthesize VP. The purpose of this study was to determine the impact of high dietary salt intake on responsivity to heterotypic stress and the potential contribution of VPergic-mediated neuronal activity on high salt-induced stress modulation, thereby providing insight into how dietary (homeostatic) and environmental (psychogenic) stressors might interact to facilitate psychiatric disorder vulnerability. APPROACH: Salt loading (SL) with 4% saline for 7 days was used to dehydrate and osmotically stress mice prior to exposure to an acute SS. Fluid intake and hematological measurements were taken to quantify osmotic dehydration, and serum corticosterone levels were measured to index stress axis activation. Immunohistochemistry (IHC) was used to stain for the immediate early gene product c-Fos to quantify effects of SL on SS-induced activation of neurons in the PVN and extended amygdala - brain regions that are synaptically connected and implicated in responding to osmotic stress and in modulation of SS behavior, respectively. Lastly, the role of VPergic PVN neurons and VP type 1 receptor (V1R) activity in the amygdala in mediating effects of SL on SS behavior was evaluated by quantifying c-Fos activation of VPergic PVN neurons and, in functional experiments, by nano-injecting the V1R selective antagonist dGly[Phaa1,d-tyr(et), Lys, Arg]-VP bilaterally into the amygdala prior to the SS. FINDINGS: SL increased serum osmolality (P < 0.01), which positively correlated with time spent mobile during, and time spent grooming after a SS (P < 0.01, P < 0.01), and SL increased serum corticosterone levels (P < 0.01). SL alone increased c-Fos immunoreactivity among PVN neurons (P = .02), including VP positive neurons (P < 0.01). SL increased SS-induced c-Fos activation of PVN neurons as well (P < 0.01). In addition, SL and SS each increased the total number of PVN neurons that were immunoreactive for VP (P < 0.01). An enhancing effect of SL and SS was observed on c-Fos positive cell counts in the central (P = .02) and basolateral (P < 0.01) nuclei of the amygdala and bilateral nano-injections of V1R antagonist into the amygdala reduced time spent mobile both in salt loaded and control mice during SS (P < 0.05, P < 0.05). SUMMARY: Taken together, these data indicate that neuronal and behavioral responsivity to an acute psychogenic stressor is potentiated by prior exposure to high salt intake. This synergistic effect was associated with activation of PVN VP neurons and depended, in part, on activity of V1 receptors in the amygdala. Findings provide novel insight into neural mechanisms whereby prior exposure to a homeostatic stressor such as osmotic dehydration by excessive salt intake increases responsivity to a perceived stress. These experiments show that high dietary salt can influence stress responsivity and raise the possibility that excessive salt intake could be a contributing factor in the development of stress-related psychiatric disorders.

Mutagenicity of cyclopenta-fused isomers of benz(a)anthracene in bacterial and rodent cells and identification of the major rat liver microsomal metabolites.

The microsomal metabolites and mutagenic activity of four cyclopenta-fused benz(a)anthracenes, benz(j)aceanthrylene [B(j)A], benz(e)aceanthrylene [B(e)A], benz(l)aceanthrylene [B(l)A], and benz(k)acephenanthrylene [B(k)A], have been studied. Aroclor 1254-induced rat liver microsomes metabolized B(j)A to B(j)A-1,2-dihydrodiol, B(j)A-9,10-dihydrodiol, B(j)A-11,12-dihydrodiol, and 10-hydroxy-B(j)A; B(e)A-1,2-dihydrodiol, B(e)A-3,4-dihydrodiol, and B(e)A-5,6-dihydrodiol; B(l)A to B(l)A-1,2-dihydrodiol, B(l)A-4,5-dihydrodiol, and B(l)A-7,8-dihydrodiol; and B(k)A to B(k)A-4,5-dihydrodiol and B(k)A-8,9-dihydrodiol. With each polycyclic aromatic hydrocarbon, metabolism occurred on the cyclopenta ring. All four isomers were active as gene mutagens in Salmonella typhimurium and in Chinese hamster V79 cells. In the S. typhimurium mutation studies, using Aroclor 1254-induced rat liver S9, B(j)A, B(e)A, and B(l)A required significantly less microsomal protein for maximal mutation response than B(k)A and B(a)P, suggesting a one-step activation mechanism, presumably on the cyclopenta-fused ring. B(j)A, B(e)A, and B(l)A were significantly more mutagenic than B(k)A and B(a)P in S. typhimurium. In the Aroclor 1254-induced rat liver S9-mediated V79 mutagenesis system, all four isomers were active, with B(l)A the most active. When Syrian hamster embryo cells were used as the metabolic activation component for V79 cells, only B(l)A produced a significant response and was equivalent in activity to B(a)P. A helical configuration for B(l)A is inferred from the identification of two trans-B(l)A-1,2-dihydrodiols, syn and anti, which have been synthesized, separated, and characterized. The metabolically formed dihydrodiol is anti-trans-B(l)A-1,2-dihydrodiol, and experimental evidence suggests that the metabolically formed B(l)A-1,2-oxide is the anti-isomer. Synthetic B(l)A-1,2-oxide was found to be a direct-acting mutagen in S. typhimurium and Chinese hamster V79 cells and is estimated to account for up to 40% of the mutagenic activity of the parent hydrocarbon. Therefore, certain cyclopenta-ring fusions on benz(a)anthracene appear to markedly increase its genotoxic and carcinogenic activities.

Effects of blockade of AT1 and AT2 receptors in brain on the central angiotensin II pressor response in conscious spontaneously hypertensive rats.

Intracerebroventricular (i.c.v.) administration of angiotensin II (ANG II) increases vascular resistance and arterial pressure by increasing the activity in the sympathetic nervous system (SNS-component) and secretion of vasopressin (VP-component). This study examined the role of AT1 and AT2 receptors in brain in mediating the exaggerated central cardiovascular effects of ANG II in conscious, adult (10 weeks) spontaneously hypertensive rats (SHR). Mean arterial pressure, heart rate and renal blood flow responses to intraventricular injection of ANG II (100 ng in 5 microliters) were determined 10 min after intraventricular administration of the AT1 receptor antagonist losartan alone (1.0, 2.5, 5.0, 10.0 micrograms), the AT2 receptor ligand PD 123319 alone (3.5 x [10(-6), 10(-4), 10(-2), 10(0)] micrograms), or both ligands in combination. In control rats, intraventricular administration of losartan prevented the pressor and renal vascular resistance responses to intraventricular injection of ANG II, in a dose-dependent manner (P < 0.05), while intraventricular injection of PD 123319 was ineffective. Likewise, when the SNS- and VP-components were studied individually by preventing the VP-component with a V1 receptor antagonist (i.v.) or the SNS-component with chlorisondamine (i.v.), losartan (i.c.v.) prevented both components, while PD 123319 (i.c.v.) was without affect. In addition, doses of losartan, combined with 3.5 micrograms PD 123319, were no more effective in preventing the pressor or renal vascular resistance responses than losartan, administered alone, suggesting that the VP- and SNS-components of the pressor response to ANG II (i.c.v.) are mediated primarily by AT1 receptors in brain in conscious spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependent inhibition of hindlimb somatic afferent transmission within nucleus tractus solitarius: an in vivo intracellular recording study.

In a previous study we demonstrated that hindlimb somatic afferent stimulation evokes excitatory responses from neurons in nucleus tractus solitarius. When paired electrical stimuli were delivered to hindlimb somatic afferents, the unit response to the second stimulus was significantly reduced compared with responses to the first. This temporal response pattern has been termed time-dependent inhibition since responses to the second stimulus recover as the interval separating the first and second stimuli is increased. To examine possible synaptic mechanisms for somatic afferent-evoked time-dependent inhibition, intracellular recordings were made from nucleus tractus solitarius neurons in anesthetized, paralysed rats. Skeletal muscle afferent fibers were activated by electrically stimulating the right tibial nerve in the hindlimb and neuronal responses recorded in the contralateral nucleus of the solitary tract. Time-dependent inhibition of tibial nerve-evoked unit discharge was studied using a conditioning-test stimulation procedure, with the first (conditioning) and second (test) stimuli separated by intervals of 50, 150 and 250 ms. In 49 units that responded to tibial nerve stimulation, 46 were excited and three were inhibited. Among units excited, 25 displayed a unimodal response that had an onset latency of 21.3 +/- 5.9 ms. The remaining 21 units responded with a bimodal discharge pattern characterized by both a short-latency and a long-latency response. The onset latency of the early response was 23.7 +/- 5.3 ms and was not statistically different from the unimodal response onset latency. The onset latency of the late response was 143 +/- 23.9 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification and characterization of two functionally distinct groups of spinal cord-projecting paraventricular nucleus neurons with sympathetic-related activity.

Activation of spinal cord-projecting neurons of the hypothalamic paraventricular nucleus (PVN) has been implicated in a host of sympathetic nervous system functions. Here, we report two distinct activity patterns among electrophysiologically identified PVN spinal neurons that may contribute to the varied functional responses elicited by PVN activation. Extracellular single-unit recording was performed in anesthetized rats, and PVN neurons were antidromically identified by electrical stimulation of the spinal cord (T1-3 or T10-12). Axonal conduction velocity was determined for each identified neuron and revealed two distinct groups of cells, designated Group I (n=19) and Group II (n=34). Conduction velocity was significantly (P<0.01) different between Group I (3.67+/-0.29 m/s) and Group II (0.45+/-0.01 m/s) cells and indicates that axons of Group I cells are larger and/or more heavily myelinated than those of Group II, which appear to be unmyelinated. The majority of Group I (15/19: 79%) and Group II (23/34: 68%) cells discharged spontaneously. Basal firing rates were significantly different between groups (Group I: 2.7+/-0.85 versus Group II: 1.8+/-0.64 spikes s(-1); P<0.05). Spike-triggered averaging of renal sympathetic nerve activity revealed sympathetic-related discharge among a majority of Group I (11/15:73%) and Group II (17/23: 74%) neurons. In addition, seven of 11 Group I cells showed cardiac-related discharge. Pulse-rhythmic discharge was not detectable in any Group II cells tested (n=17). Among 11 Group I cells tested for barosensitivity, discharge in eight (73%) was graded by changes in mean arterial pressure. None of the 16 Group II cells tested for arterial pressure sensitivity responded.We conclude that the PVN spinal pathway is comprised of at least two functionally distinct cell types. The response profile and activity patterns of Group I cells suggest involvement in regulating vasomotor components of sympathetic outflow. By comparison, the activity of Groups II cells suggests a possible role in non-vasomotor sympathetic control.

Branded versus generic clozapine: bioavailability comparison and interchangeability issues.

Clozapine has been the treatment of choice for patients with refractory schizophrenia. Generic clozapine has recently become available, because of a waiver of the usual criteria for establishing bioequivalence. However, there are biopharmaceutical, bioavailability, and clinical concerns related to the generic formulation raised by both clinicians and academic researchers. We conducted a prospective, randomized, crossover study to evaluate steady-state pharmacokinetics, pharmacodynamics, and tolerability of generic clozapine (Zenith Goldline Pharmaceuticals) versus Clozaril (Novartis Pharmaceuticals) in schizophrenic patients. A preliminary report of the pertinent bioavailability results is presented here. Despite comparable mean plasma concentration-time curves, significant differences were found in the primary pharmacokinetic parameters of the 2 formulations in almost 40% of patients. Such intraindividual differences raise the issue of average bioequivalence versus individual bioequivalence and the implication for interchangeability of different clozapine formulations. The decision to switch a patient from branded to generic clozapine should be made on an individual basis with special emphasis on clinical outcome, and patients should be monitored closely during the transition.

Acute and subacute physiological and histological studies of the central nervous system after intrathecal gadolinium injection in the anesthetized rat.

RATIONALE AND OBJECTIVES: To determine the acute physiological and subacute neurohistological effects of gadopentetate dimeglumine (GdD) administered intrathecally. METHODS: Twenty-four rats were separated into two study groups. In the first group, the acute effects of intrathecal GdD on cortical electroencephalographic activity, renal sympathetic nerve activity, arterial blood pressure, and heart rate were determined. In the second group, histological evaluation of the neural tissues was performed 10 days after treatment. In both the physiological and histological studies, a single GdD dose of 2.5 micromol/g brain (10 microL) was administered intrathecally. Control animals were injected intrathecally with the same volume of a sucrose solution that had the same osmolality as GdD. RESULTS: In the physiological study, GdD and sucrose injections elicited no significant change in any of the parameters recorded. In the histologic study, examination revealed two cases of pre-existing chronic spinal cord gliosis; one of these rats also exhibited signs of pre-existing chronic choroid plexus inflammation. No acute or subacute alterations observed could be specifically linked to the intrathecal administration of GdD. CONCLUSIONS: Intrathecally administered GdD was accompanied by no significant change in any of the physiologic or histologic parameters examined. Based on the relatively short time interval between GdD treatment and histologic examination, the neural tissue abnormalities (gliosis/inflammation) observed in two animals were judged to be incidental and likely due to prior chronic pre-existing processes such as viral infection. Although additional studies are required to verify the safety and effectiveness of intrathecal GdD in humans, data from the present study in animals provide evidence that when intrathecal GdD is used in doses sufficient to improve MRI of the cerebrospinal fluid compartment, it is likely to be accompanied by a low incidence of acute changes in neural function or structure.

Mediators of contraction-evoked skeletal muscle depressor response in anesthetized rats.

In the present study, mediators of muscle contraction-evoked cardiovascular responses were examined in anesthetized rats. Rhythmic contractions of the hindlimb triceps surae muscle were produced by stimulating the tibial nerve (motor threshold 22.7 +/- 2.3 microA; n = 10) by using a 1 s on-1 s off pattern. Mean arterial pressure (MAP) and heart rate (HR) responses were recorded before and after 1) muscarinic receptor blockade (atropine sulfate; 2.0 mg/kg i.v., n = 5); 2) nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME; 300 microM/kg i.v., n = 7); 3) beta-adrenoceptor blockade (propranolol; 2.0 mg/kg i.v., n = 10); and 4) bilateral adrenalectomy (n = 4). Rhythmic stimulation (10-s) significantly reduced MAP (P < 0.05) and elicited small decreases in HR that were abolished by neuromuscular blockade (n = 4). Atropine had no effect on MAP or HR responses to contraction. L-NAME increased baseline MAP (112.2 +/- 2.2 to 137.1 +/- 4.6 mmHg, P < 0.05) and attenuated contraction-evoked reductions of MAP (P < 0.05) without affecting HR. L-NAME-induced response deficits were mimicked in four separate rats by elevating MAP with phenylephrine (7-10 micrograms.kg-1.h-1 iv) to a level not different from that produced by L-NAME. Bilateral adrenalectomy and propranolol did not significantly affect HR responses but reduced contraction-evoked decreases in MAP from 14.3 +/- 2.9 to 7.7 +/- 2.2 mmHg and from 13.4 +/- 1.3 to 6.3 +/- 3.1 mmHg, respectively (P < 0.05). Baseline MAP was unchanged. We conclude that adrenal catecholamines, acting at beta-adrenoceptors, contribute significantly to the contraction-evoked depressor response in rats. No role for muscarinic receptors is evident in this response. Furthermore, attenuation of depressor responses to contraction after nitric oxide inhibition could result from an indirect effect of the pressor actions of L-NAME.

Sensory modalities conveyed in the hindlimb somatic afferent input to nucleus tractus solitarius.

To determine the somatic sensory modalities conveyed by hindlimb somatic afferent inputs, the discharge of neurons in the nucleus tractus solitarius was recorded in anesthetized rats after electrical stimulation of either the contralateral sciatic nerve or L(6) spinal nerve, which innervates the hindlimb. The discharge of seven of eight cells was increased (P < 0.05) by capsaicin injected into the arterial supply of the hindlimb. Discharge was unaltered in 19 neurons tested for sensitivity to nonnoxious (40 degrees C) and noxious (47 degrees C) heating of the hindlimb skin. In contrast, lightly stroking the skin elicited discharge in 2 of 14 cells, whereas noxious pinching increased activity in 4 other cells. Rhythmic (1- to 3-s) muscle contraction (MC) increased (P < 0.05) discharge in >60% of neurons tested (11 of 18). Static (10- to 30-s) MC significantly (P < 0.05) increased discharge in four cells, two of which were also responsive to rhythmic MC. Rhythmic and sustained muscle stretch increased discharge (P < 0.05) in three of eight neurons tested. These data indicate that nucleus tractus solitarius neurons receive input from low- and high-threshold cutaneous mechanoreceptors, respond to capsaicin delivered into the hindlimb arterial supply, lack thermal sensitivity, and respond to activation of mechanosensitive as well as metabosensitive endings in skeletal muscle.

In vivo chronoamperometric measurements of the clearance of exogenously applied serotonin in the rat dentate gyrus.

The present study evaluated high-speed chronoamperometry as a method for measuring the clearance of serotonin (5-HT) from extracellular space in vivo. Male Sprague-Dawley rats were anaesthetized and a Nafion-coated, carbon fiber electrode, attached to a multibarrel pipette, was lowered into the subgranular layer of the dentate gyrus, a region which receives dense serotonergic innervation, or the corpus callosum, a fiber tract relatively devoid of the 5-HT transporter (SERT). Serotonin, pressure ejected into these regions, produced replicable electrochemical signals. The amplitude and time course of the signals were significantly prolonged in the corpus callosum compared to the dentate gyrus. Similarly, signals produced by locally applied 5-HT in the dentate gyrus of rats following destruction of hippocampal serotonergic innervation with 5,7-dihydroxytryptamine (5,7-DHT), were significantly enhanced compared to those observed in control animals. The time course of the 5-HT signal was significantly prolonged by local application of the selective 5-HT reuptake inhibitor, fluvoxamine, into the dentate gyrus. By contrast, fluvoxamine did not modify the clearance of 5-HT when locally applied into the dentate gyrus of 5,7-DHT lesioned rats or into the corpus callosum of intact rats. Taken together, these data demonstrate that in intact rats, the SERT contributes to the clearance of exogenously applied 5-HT from the extracellular space. Under the experimental conditions used in this study, high-speed chronoamperometry proved to be a reliable method for directly measuring extracellular 5-HT and appears to be a valuable tool for the study of 5-HT clearance by the SERT in vivo.

Functional role of brain AT1 and AT2 receptors in the central angiotensin II pressor response.

Intracerebroventricular (i.c.v.) angiotensin II (ANG II) increases vascular resistance and elicits a pressor response characterized by sympathetic nervous system activation (SNS component) and increased vasopressin (VP) secretion (VP component). This study examines the role of brain AT1 and AT2 ANG II receptors in mediating the pressor and renal hemodynamic effects of i.c.v. ANG II in conscious Sprague-Dawley rats. Mean arterial pressure, heart rate and renal vascular resistance responses to i.c.v. ANG II (100 ng in 5 microliters) were determined 10 min after i.c.v. injection of either the AT1 receptor antagonist, DuP 753 (1.0, 2.5, 5.0, 10.0 micrograms), the AT2 receptor ligand, PD 123319 (3.5 x [10(-6), 10(-4), 10(-2), 10(0)] micrograms), or both. In control rats, i.c.v. DuP 753 prevented the pressor response and the increase in renal vascular resistance that occurred following i.c.v. ANG II in a dose-dependent manner (P < 0.05), while i.c.v. PD 123319 was without affect. When the VP- and SNS components were studied individually, by preventing the SNS component with intravenous (i.v.) chlorisondamine or the VP component with a V1 receptor antagonist (i.v.) similar results were obtained; DuP 753 prevented the SNS component and significantly reduced the VP component. These results indicate that both central ANG II pressor components are mediated primarily by brain AT1 receptors. However, doses of DuP 753 were more effective when combined with 3.5 micrograms of PD 123319 than when given alone (P < 0.05), suggesting that the pressor effects of i.c.v. ANG II may involve activation of multiple ANG II receptor subtypes.

Functional roles of brain AT1 and AT2 receptors in the central angiotensin II pressor response in conscious young spontaneously hypertensive rats.

Areas of adult rat brain that mediate the cardiovascular effects of central angiotensin II (ANG II) predominantly express AT1 ANG II receptors. In contrast, AT2 receptor expression in young rats is transiently increased, reaching a maximum during the first few weeks of life. This study was designed to determine the roles of brain AT1 and AT2 receptors in mediating the central pressor effects of ANG II in young (4-week-old) conscious spontaneously hypertensive rats (SHR). Mean arterial pressure responses to intracerebroventricular (i.c.v.) ANG II (100 ng in 5 microliters) were determined 10 minutes after i.c.v. injection of either the AT1 receptor antagonist Losartan (1.0, 2.5, 5.0, and 10.0 micrograms), the AT2 receptor ligand PD 123319 (3.5 x [10(-6), 10(-4), 10(-2), 10(0)] micrograms), or both. In control rats, i.c.v. Losartan prevented the pressor response to i.c.v. ANG II in a dose-dependent manner (P < 0.05), while i.c.v. PD 123319 alone was without effect. In other animals, pressor responses caused by i.c.v. ANG II-induced vasopressin secretion (VP-component) and sympathetic nervous system activation (SNS-component) were studied individually, with similar result; Losartan prevented the SNS-component, but reduced the VP-component by only 45%, indicating that both pressor components involve AT1 receptor activation. However, doses of Losartan were more effective when combined with 3.5 micrograms of PD 123319 than when given alone (P < 0.05); nearly eliminating the VP-component. These results suggest that i.c.v. ANG-II-induced pressor effects may involve activation of multiple receptor subtypes.

Magnetic resonance imaging studies of the brains of anesthetized rats treated with manganese chloride.

An understanding of the distribution of manganese ions in the brain is of interest in connection with the development of an understanding of the neurotoxicity of this element. Information about the time dependent biodistribution of manganese ions in the brains of intact rats subsequent to single IP injections of MnCl2 has been obtained from magnetic resonance imaging (MRI) studies. The enhanced MRI contrast is based on the reduction in the spin lattice relaxation time (T1) of water protons which exchange into the coordination sphere of the manganese ions. These studies indicate rapid and significant accumulations of water accessible manganese in the ventricles, the pineal gland, and the pituitary gland. The rapid appearance of high levels of manganese in the ventricular cerebrospinal fluid indicates that manganese readily crosses the filtration barrier of the choroid plexus and is thereafter apparently absorbed by the ependymal surfaces of the ventricles and transported to the subarachnoid space.

Benz[j]aceanthrylene: a novel polycyclic aromatic hydrocarbon with bacterial mutagenic activity.

Initial studies on the mutagenicity and metabolism of a novel cyclopenta-PAH, benz[j]aceanthrylene, are reported in the Salmonella bacterial system. The spectrum of activity of benz[j]aceanthrylene over the 5 Ames tester strains is similar to that of benzo[a]pyrene, and the dose-response curves for strain TA98 are comparable. Like other biologically active PAH, benz[j]aceanthrylene is a frame-shift mutagen requiring metabolic activation. An interesting feature of the S9 dependence of activity is the low concentration (congruent to 10-fold smaller than for benzo[a]pyrene) at which optimal activity is observed. The 1,2-dihydro-1,2-diol (product of metabolism of the cyclopenta-ring) appears to be the predominant metabolite, and implicates the 1,2-oxide as the ultimate mutagenic species.

Sleep disorders: assisting patients to a good night's sleep.

Sleep is an active process consisting of macro- and microarchitectural rhythms, chronobiology, and neurochemical changes. Disruptions in sleep chronobiology, which may occur in shift workers and the elderly or due to jet lag, often respond to exogenous melatonin. Insomnia requires careful evaluation to determine contributions of comorbid medical conditions and drug effects. Treatment options include sleep hygiene principles and sedative hypnotic therapy. Zaleplon and zolpidem, short-acting benzodiazepines selective for omega-1 GABA receptors, are effective first-line agents for initiating sleep.

Time-dependent inhibition of hindlimb somatic afferent inputs to nucleus tractus solitarius.

1. In the present investigation, experiments were performed in anesthetized, paralyzed rats (n = 40) to 1) identify and characterize responses of nucleus tractus solitarius (NTS) neurons to hindlimb somatic afferent inputs; 2) determine if hindlimb somatic inputs to NTS undergo time-dependent inhibition similar to that observed among visceral afferent inputs; and 3) determine if somatic afferent-evoked NTS unit discharge is altered by activation of baroreceptor afferent inputs. 2. Extracellular discharge was recorded from single NTS units following electrical stimulation (approximately 500 microA) of the contralateral tibial nerve (TN) (skeletal muscle afferents), sural nerve (SN) (cutaneous afferents), and the ipsilateral aortic nerve (AN) (baroreceptor afferents). To identify possible time-dependent interactions, a paired pulse or conditioning-test stimulation procedure was employed. The activity of NTS neurons was recorded in response to test stimuli delivered to either TN or SN first in the absence and then in the presence of conditioning stimuli delivered to TN, SN, or AN 50, 150, and 250 ms before the test stimuli. 3. The results indicate that among 31 NTS cells activated by somatic nerve stimulation, 14 (approximately 50%) received convergent inputs from both the TN and SN, 9 responded to TN stimulation only and 2 were activated by SN stimulation only. These cells were not spontaneously active but showed two distinct patterns of evoked discharge. Some had only a short latency, unimodal response that averaged 25.5 +/- 2.0 (SE) ms for TN inputs (n = 21) and 27.9 +/- 2.8 ms for SN inputs (n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

AT(1)-receptor blockade in the hypothalamic PVN reduces central hyperosmolality-induced renal sympathoexcitation.

Autonomic neurons in the hypothalamic paraventricular nucleus (PVN) are innervated by osmotic-sensitive regions of the lamina terminalis, receive input from ANG II-containing cells, and express AT(1) ANG II receptors. Therefore, we hypothesized that ANG II actions within the PVN could underlie hyperosmolality-induced increases in renal sympathetic nerve activity (RSNA). In anesthetized baroreceptor-denervated rats, graded concentrations of NaCl (0.30, 0.9, 1.5, and 2.1 osmol/l) were injected (300 microl) centrally via the internal carotid artery (ICA) and produced corresponding increases in mean arterial pressure (MAP) and RSNA. In addition, equivalent hyperosmotic loads (1.5 osmol/l) of NaCl, glucose, and mannitol each significantly (P < 0.05) increased MAP and RSNA. The same stimuli had no effect when administered intravenously. Bilateral PVN microinjections (100 nl) of the AT(1)-receptor antagonist losartan (80 nmol) before osmotic challenge had no effect on resting RSNA but significantly (P < 0.05) reduced RSNA responses to hyperosmotic NaCl (n = 7), glucose (n = 6), and mannitol (n = 6). Increases in RSNA evoked by hyperosmotic NaCl were significantly (P < 0.05) attenuated approximately 20 min after losartan injection and recovered within 60-120 min. In contrast, losartan outside the PVN as well as vehicle (saline) within the PVN failed to alter RSNA responses to ICA hyperosmotic NaCl. Results suggest that elevated RSNA after central sodium/osmotic activation is mediated, at least in part, by a synaptic mechanism involving AT(1)-receptor activation within the PVN.

Responses of neurons in the nucleus tractus solitarius to stimulation of heart and lung receptors in the rat.

To characterize central integration of reflex responses to stimulation of mechanically and chemically sensitive receptors in the heart and lung, male rats (350 to 425 g) were anesthetized (pentobarbital, 50 mg/kg IP) and paralyzed (gallamine triethiodide, 25 mg/kg IV) and then they underwent bilateral sinoaortic denervation. Extracellular activity of neurons in the nucleus tractus solitarius (NTS) was recorded in response to bolus intra-atrial saline (50, 100, 200, or 300 microL) or phenylbiguanide (PBG, 16 micrograms/kg in 100 microL) administered in random sequence. Changes in mean arterial pressure (MAP), mean right atrial pressure, and right atrial systolic pressure (RASP) were measured as correlates of stimulus intensity, and heart rate (HR) and renal sympathetic nerve activity (RSNA) were used to assess efferent reflex effects of cardiac and pulmonary receptor stimulation. NTS neurons with possible afferent input from stretch and chemically sensitive receptors were identified by an excitatory evoked response to electrical stimulation of the ipsilateral vagus nerve (1 Hz, 500 microA, 1-millisecond duration). Thirty-eight vagus nerve-evoked NTS units with onset latencies of 25.3 +/- 0.9 milliseconds displayed excitatory or inhibitory responses to saline or PBG injections or to both interventions. Saline administration elicited volume-dependent transient increases in MAP and RASP, which were followed by reflex decreases in MAP, HR, and RSNA. PBG injections also evoked hypotension, bradycardia, and sympathoinhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

A loading-dose strategy for converting from oral to depot haloperidol.

OBJECTIVE: The author's aim was to evaluate the safety and efficacy of a loading-dose regimen for initiating use of a depot medication, haloperidol decanoate, with patients who had been maintained on oral haloperidol. Patients were given a loading dose of about 20 times their oral maintenance dose in divided injections during the first two weeks of conversion to depot medication. The dose of haloperidol decanoate was gradually reduced, dropping to about ten times the oral dose in the third and fourth months. No supplemental oral medication was used. METHODS: Haloperidol decanoate was initiated using the loading-dose regimen in 16 chronically ill patients. Lower initial doses of haloperidol decanoate were used in two other groups of patients, one that received supplemental oral haloperidol and one that did not. Plasma levels of haloperidol, severity of illness, and side effects were monitored from baseline to 56 days after the beginning of depot therapy. RESULTS: Patients who received the loading-dose regimen showed statistically significant clinical improvement and reduced side effects over baseline by the 28th day. The second group of patients also maintained therapeutic response but improved no further. The third group relapsed during the first month and were returned to a regimen of oral haloperidol by the second month. CONCLUSIONS: A loading-dose regimen for initiating treatment with haloperidol decanoate is safe and effective and can be useful in a clinical setting.