Changes in tyrosine hydroxylase mRNA expression in the rat locus coeruleus following acute or chronic treatment with valproic acid.

Valproate has proven effective in treating bipolar disorder. Though some biochemical effects of valproate are rapid, mood-stabilizing effects can take weeks, suggesting that regulatory changes in gene expression in brain neurotransmitter systems may be involved. Given a presumed role for norepinephrine (NE) in bipolar disorder, as well as the actions of mood-stabilizing drugs, we examined changes in mRNA expression for tyrosine hydroxylase (TH), the NE transporter (NET) and alpha 2A autoreceptor in the rat locus coeruleus after valproate treatment.

The elusive nature of intrinsic efficacy.

In the discipline of pharmacology, drugs (ligands) are used as tools to elucidate the processes of biological systems. Because of this, pharmacologists strive to delineate all characteristics of drugs. Decades of research have resulted in the proposal that ligands possess two properties that are intrinsic to the ligand and are invariant of the system in which their effects are investigated.

Short-term potentiation of carotid sinus nerve inputs to neurons in the nucleus of the solitary tract.

Reflex studies have shown that the effects of afferent stimulation can persist beyond the period of stimulation. To determine if some form of 'short-term potentiation' occurs during the initial integration of afferent inputs within the nucleus of the solitary tract (NTS), the synaptic responses of NTS neurons to high frequency carotid sinus nerve (CSN) stimulation were examined in anesthetized rats. In extracellular recording experiments, high frequency CSN stimulation (1-3 sec, 100-300 Hz) increased the number of action potentials evoked by 30 CSN stimuli from 31 +/- 3 to 38 +/- 4 (P < 0.

Site-directed mutagenesis and yeast two-hybrid studies of the insulin and insulin-like growth factor-1 receptors: the Src homology-2 domain-containing protein hGrb10 binds to the autophosphorylated tyrosine residues in the kinase domain of the insulin receptor.

To characterize the structural basis for the interaction between hGrb10 and the insulin receptor and the insulin-like growth factor-1 receptor, different mutant receptors containing a segment of deletion in either the juxtamembrane domain or in the C terminus of the receptors, or containing tyrosine-to-phenylalanine point mutations in these regions of the insulin receptor, were generated. Yeast two-hybrid and in vitro binding studies of the interaction between the mutant receptors and hGrb10 revealed that tyrosine residues in these regions are not essential for the binding of hGrb10. To further identify the binding site for hGrb10, all conserved tyrosine residues in the kinase domain of the insulin receptor were replaced with either phenylalanine or alanine by site-directed mutagenesis.

Pharmacology of antidepressants.

This review covers mechanisms of action, efficacy, side effects, and toxicity of various classes of antidepressants: tricyclic antidepressants, monoamine oxidase inhibitors, second-generation antidepressants including the selective inhibitors of serotonin reuptake, and novel drugs such as mirtazapine, nefazodone, and venlafaxine.

Convergent carotid sinus nerve and superior laryngeal nerve afferent inputs to neurons in the NTS.

A population of 43 neurons in the nucleus of the solitary tract (NTS) was identified in pentobarbital sodium anesthetized, paralyzed, and artificially ventilated cats that received convergent inputs from carotid sinus nerve (CSN) and superior laryngeal nerve (SLN) afferents. In 21 neurons, electrical stimulation of the CSN and SLN each evoked an excitatory postsynaptic potential (EPSP; mean onset latency +/- SE of CSN-evoked input = 7.2 +/- 0.

5-hydroxytryptamine2C receptor activation inhibits 5-hydroxytryptamine1B-like receptor function via arachidonic acid metabolism.

We previously reported that in Chinese hamster ovary (CHO) cells, 5-hydroxytryptamine (5-HT)1B-like (CHO/5-HT1B) receptor-mediated inhibition of forskolin-stimulated cAMP accumulation is inhibited by activation of transfected human 5-HT2C receptors but not 5-HT2A receptors. In the current study, we investigated the mechanism involved in the regulation of receptor-mediated inhibition of adenylyl cyclase as a means to further elucidate differences between the signal transduction cascades of the 5-HT2A and 5-HT2C receptor subtypes. Activation of 5-HT2C receptors with 5-HT or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane increased release of arachidonic acid via a phospholipase A2 (PLA2)-dependent mechanism.

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.

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.

Chronic neurosteroid treatment produces functional heterologous uncoupling at the gamma-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons.

We have investigated the effects of chronic treatment with the neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha) on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic 5 alpha 3 alpha treatment (up to 2 microM, 5 days) did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H]Ro15-1788, and [3H]Ro15-4513 was not altered after the chronic treatment.

Vascular cell interactions modulate the expression of endothelin-1 and platelet-derived growth factor BB.

Endothelin (ET)-1 and platelet-derived growth factor (PDGF) BB are important regulators of vascular cell growth and contractile function. We tested the hypothesis that interactions between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) regulate the expression of these two factors. Bovine and rat cocultures of EC-VSMC that allowed cell contact and exchange of soluble mediators were studied.

Chronic GABA treatment downregulates the GABAA receptor alpha 2 and alpha 3 subunit mRNAS as well as polypeptide expression in primary cultured cerebral cortical neurons.

Chronic GABA exposure of mammalian primary cultured cortical neurons results in a downregulation of the GABA-benzodiazepine receptor complex. In the present study, the mRNA levels, as well as polypeptide expression, for the GABAA receptor alpha 2 and alpha 3 subunits in cultured embryonic mouse cerebral cortical neurons (7 day old) were examined using northern analysis and immunoblotting techniques following chronic GABA treatment. The alpha 1 subunit mRNA or polypeptide could not be detected in these neurons.

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.

Effects of lateral parabrachial nucleus lesions in chronic renal hypertensive rats.

Neuroanatomic studies describing forebrain projections to the lateral parabrachial nucleus suggest a central integrative role in cardiovascular regulation. We performed this study to examine the role of this pontine nucleus in the maintenance of one-kidney, figure-8 renal-wrap hypertension. Bilateral ibotenic acid ablation of the lateral parabrachial nucleus was performed 4 weeks after induction of hypertension or sham operation.

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.

Chronic ethanol treatment upregulates the GABA receptor beta subunit expression.

The molecular mechanisms associated with ethanol-induced tolerance and physical dependence have yet to be elucidated. In previous studies we have demonstrated that chronic ethanol administration produced a decrease in the GABAA receptor mRNA level of alpha 1, alpha 2, alpha 5 subunits, and a decrease in the polypeptide (alpha 1, alpha 2, and alpha 3) expression in the rat cerebral cortex. In this study we examined the effect of chronic ethanol treatment on the mRNA levels and the expressions of the beta-subunits of the GABAA receptors in rat cerebral cortex.

Ethanol enhancement of GABA-induced 36Cl- influx does not involve changes in Ca2+.

The effect of changes in intracellular Ca2+ on ethanol enhancement of GABA-mediated 36Cl- influx was investigated in mammalian cortical neurons in culture. Ethanol potentiated the effect of submaximal concentrations of GABA on the 36Cl- influx, and at 50 mM ethanol directly activated 36Cl- influx in these neurons. Pretreatment of the neurons with dantrolene (an agent that depletes intracellular Ca2+) and the Ca2+ ionophore, A 23187, did not alter the effect of GABA or ethanol enhancement of GABA-mediated 36Cl- influx.

Laryngeal afferent inputs to the nucleus of the solitary tract.

The following study was undertaken to examine the integration of laryngeal afferent inputs within the nucleus of the solitary tract (NTS), the primary site of termination of laryngeal afferent fibers. Intracellular recordings were obtained from 63 cells that responded to electrical stimulation of the superior laryngeal nerve (SLN) with an excitatory postsynaptic potential (EPSP; n = 49), an excitatory-inhibitory postsynaptic potential (EPSP-IPSP) sequence (n = 13), or an IPSP (n = 1). Mechanical stimulation of laryngeal mechanoreceptors revealed a variety of response patterns (e.