Iontophoresis of morphine into the arcuate nucleus: effects on dopamine concentrations in hypophysial portal plasma and serum prolactin concentrations.

The effects of morphine on the release of dopamine from tuberoinfundibular neurons and the release of PRL from the anterior pituitary gland were studied in diestrous female rats. Morphine ions ejected iontophoretically in minute quantities into the arcuate nuclei (using one electrode per nucleus) were found to reduce markedly the concentration of dopamine in hypophysial portal plasma. Thirty minutes after the iontophoretic ejection of morphine using charges of 3.6 and 6.6 millicoulombs/electrode, the concentrations of dopamine in hypophysial portal plasma were reduced 70% and 83%, respectively, relative to the preiontophoretic values. When morphine was iontophoresed into each arcuate nucleus using a charge of 1.5 millicoulombs/electrode, there was no change in the concentration of dopamine in hypophysial portal plasma. The suppressive effect of morphine on dopamine release was prevented by pretreatment of the animals with naloxone (5 mg/kg, ip). In addition to the reduction of the concentration of dopamine in hypophysial portal plasma, the iontophoresis of morphine into the arcuate nuclei enhanced the serum concentration of PRL. On the basis of the present observations, it is suggested that morphine acts on an opiate receptor within the arcuate nucleus to suppress the secretion of dopamine from tuberoinfundibular neurons into hypophysial portal blood, thereby enhancing pituitary gland secretion of PRL.

Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder.

OBJECTIVE: This study evaluated the efficacy and safety of fixed doses of once-daily extended-release (XR) venlafaxine in outpatients with generalized anxiety disorder without concomitant major depressive disorder. METHOD: Adult outpatients with generalized anxiety disorder but not major depressive disorder with total scores of 18 or higher on the Hamilton Rating Scale for Anxiety and scores of 2 or higher on its anxious mood and tension factors were eligible. Patients were randomly assigned to receive placebo or venlafaxine XR (75, 150, or 225 mg/day) for 8 weeks. Primary efficacy variables were final total and psychic anxiety factor scores on the Hamilton anxiety scale and final severity and global improvement item scores on the Clinical Global Impression (CGI) scale. RESULTS: Of the 377 patients entering the study, 370 were included in a safety analysis and 349 in an efficacy analysis. Adjusted mean scores at 8 weeks (last-observation-carried-forward analysis) were significantly lower for one or more of the venlafaxine XR groups in four of four primary and three of four secondary outcome measures than for the placebo group. These included a change of 1.7 (versus 1.3) from baseline on CGI severity item scores and a final score of 2.2 (versus 2.6) on the CGI global improvement item. All doses of venlafaxine XR were well tolerated. CONCLUSIONS: Venlafaxine XR is an effective and well-tolerated option for the short-term treatment of generalized anxiety disorder in outpatients without major depressive disorder.

Synthesis and structure-activity relationship of substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones: potential anxiolytic agents.

Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.

Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative.

The novel bicyclic compound Wy-45,030 [1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol, hydrochloride] exhibited a neurochemical profile predictive of antidepressant activity. Like the tricyclic antidepressants, it inhibited rat brain imipramine receptor binding and synaptosomal monoamine uptake (dopamine as well as norepinephrine and serotonin). It did not inhibit monoamine oxidase. Unlike the tricyclic antidepressants, it was not antimuscarinic in the guinea pig ileum, nor did it have any appreciable affinity for brain alpha-1 adrenergic or histamine-1 binding sites. Wy-45,030 was also without affinity for alpha-2 or beta adrenergic, benzodiazepine, serotonin-1, serotonin-2, dopamine-2, and opiate receptors. Such a profile is predictive of antidepressant activity devoid of the side-effects common to tricyclic therapy.

Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder.

BACKGROUND: The objective of this randomized, double-blind study was to compare the efficacy and safety of venlafaxine extended release (XR) and buspirone in outpatients with generalized anxiety disorder (GAD) but without concomitant major depressive disorder. METHOD: Male and female outpatients at least 18 years old who met the DSM-IV criteria for GAD and had scores of 18 or higher on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with either venlafaxine XR (75 or 150 mg/day), buspirone (30 mg/day in 3 divided doses), or placebo for 8 weeks. The primary efficacy variables were changes in anxiety as determined by final on-therapy HAM-A total and psychic anxiety scores and Clinical Global Impressions scale (CGI) scores. Other key efficacy variables were HAM-A anxious mood and tension scores and the anxiety subscale scores of the patient-rated Hospital Anxiety and Depression scale (HAD). RESULTS: The efficacy analysis included 365 patients and the safety analysis, 405. At week 8, adjusted mean HAM-A psychic anxiety, anxious mood, and tension scores were significantly lower for venlafaxine XR-treated patients than for placebo-treated patients. On the HAD anxiety subscale, venlafaxine XR, 75 or 150 mg/day, was significantly more efficacious than placebo at all time points except weeks 1 (both dosages) and 2 (150-mg/day dosage only) and significantly more efficacious than buspirone at all time points except week 1. On the CGI-Improvement scale, scores for venlafaxine XR (both dosages) and buspirone were numerically superior to those for placebo at all time points, and statistical significance was observed at weeks 3, 4, 6, and 8 for venlafaxine XR and at weeks 6 and 8 for buspirone. The adverse events were not essentially different between treatment groups. CONCLUSION: Venlafaxine XR is an effective, safe, and well-tolerated once-daily anxiolytic agent in patients with GAD without comorbid major depressive disorder. This agent was significantly superior to buspirone on the HAD anxiety subscale. Buspirone demonstrated statistical significance versus placebo on a measure of anxiolytic response.

Evidence for vasoactive intestinal polypeptide (VIP) altering the firing rate of preoptic, septal and midbrain central gray neurons.

The effect of the iontophoretic application of vasoactive intestinal polypeptide (VIP) on the extracellular electrical activity (neuronal firing rate) of 91 neurons localized in the preoptic (PO), septal (S) region and midbrain central gray (MCG) was studied in urethane-anesthetized female rats. When applied in minute quantities, VIP induced both excitatory (N = 14) and inhibitory (N = 8) changes in the membrane excitability of PO and S neurons (total N = 58), while only inhibitory (N = 9) changes were observed in the MCG neurons (total N = 33; thus 24 MCG neurons were found to be unresponsive to VIP). The latency and duration of the VIP-induced response was, for the most part, characterized by a rapid onset and persisted for the duration of the ejecting pulse. However, five out of the 58 PO and S neurons and one out of the 33 MCG neurons did show responses that were longer and more variable in latency and duration. Of 26 PO neurons recorded and tested with VIP, only five neurons were determined to be antidromically identified (AI) as having their axons in the median eminence. The application of VIP increased the neuronal firing rate in two AI PO neurons, decreased the activity in one, and was ineffective in altering the activity in two other AI PO neurons. The VIP-induced changes in the neuronal firing rate appear to be specific and reproducible, and not related to the ejecting current nor pH of the solution. The results suggest that VIP, a gastrointestinal hormone that is also localized in the brain, can alter the neuronal firing rate of hypothalamic and midbrain neurons, thus providing additional evidence of its possible influence on brain and neuroendocrine function.

Differential effects of morphine, dopamine and prolactin administered iontophoretically on arcuate-ventromedial hypothalamic neurons.

The effect of iontophoretically applied morphine, dopamine and prolactin on the spontaneous, extracellular electrical activity of arcuate-ventromedial hypothalamic neurons was studied in urethane-anesthetized female rats. The deposition of morphine and dopamine suppressed, while prolactin was found to enhance, the rate of spontaneous firing of more than half of the neurons recorded. It is suggested that the present findings may be of significance in the understanding of the interaction of the opioids, dopamine, and prolactin in the regulation of prolactin secretion.

Comparison of firing patterns and sensory responsiveness between supraoptic and other hypothalamic neurons in the unanesthetized sheep.

Adult Southdown ewes were surgically prepared with pituitary stimulating electrodes, carotid and jugular cannulae, and a cranial platform-cylinder arrangement for chronic single unit recording. Isolated neurons (n = 112) in the region of the supraoptic nucleus (SON) were identified by pituitary stalk stimulastion as AD + (antidromically invaded) SON neuroendocrine cells (n = 75) or AD--(not antidromically invaded) SON neurons (n = 37). Spontaneous firing pattern distribution and sensory evoked behavior of these SON region neurons were compared with activity recorded from 112 randomly located non-identified neurons of extra-SON areas of the hypothalamus. Spontaneous discharge activity was categorized into six distinct firing pattern types: continuously active slow (CAS), continuously active fast (CAF), continuously active bursting (CAB), continuously active regular (CAR), low frequency bursting (LFB), and high frequency bursting (HFB). These 6 firing pattern types were characterized by computer analysis and their mean order independent statistical parameters compared. Bursting discharge patterns (LFB, HFB, and CAB) were compared with respect to mean burst duration, burst mean firing rate, and interburst interavls. Ninety-three per cent of all neurons maintained a stable discharge pattern in the absence of apparent stimuli. Occasionally CAS and CAF neurons spontaneously generated spike clusters sufficient to give the transient appearance of a bursting discharge pattern and LFB neurons lapsed spontaneously into CAS acitivity. All 6 firing pattern types recorded from non-identified extra-SON neurons were also recorded in the SON region. However, spontaneously discharging AD+ SON neurons exhibited only continuously active slow (CAS), continuously active fast (CAF), and low frequency bursting (LFB) activity. The total absence of high frequency bursting (HFB), continuously active regular (CAR), and continuously active bursting (CAB) patterns of discharge from AD+ SON neurons suggests that AD- SON neurons exhibiting these firing patterns may function as interneurons, pacemaker neurons, or receptor neurons. A significant number of LFB discharging neurons were recorded in widespread extra-SON regions of the hypothalamus, indicating this discharge pattern may not be unique to magnocellular neuroendocrine cells. AD+ SON LFB neurons sampled in this study demonstrated a significantly longer mean interburst interval (20.86 sec) compared to extra-SON LFB neurons (12.43 sec). No AD+ SON neuron tested was significantly sensitive to non-specific sensory arousal or sleep-waking state changes. In extra-SON areas of the hypothalamus, 11 of 75 neurons tested to sensory arousal and 6 of 19 neurons tested to sleep-waking changes responded with significant changes in mean firing rate (MFR); no significant difference between firing pattern types was demonstrated in arousal or sleep-waking sensitivity...

DMI, Wy-45,030, Wy-45,881 and ciramadol inhibit locus coeruleus neuronal activity.

Wy-45,030 and Wy-45,881 block the uptake of norepinephrine and serotonin in rat brain synaptosomal preparations and share several in vivo and in vitro effects with known tricyclic antidepressants. To further characterize their activity, these compounds were compared to desipramine and ciramadol in electrophysiological studies of their acute effects on noradrenergic neuronal activity. All four compounds inhibited locus coeruleus neuronal activity with a rank order of potency of desipramine greater than Wy-45,881 greater than Wy-45,030 greater than ciramadol. Administration of the alpha-adrenergic blocking drug, piperoxane, increased locus coeruleus firing rate after desipramine, Wy-45,030 and Wy-45-881. Pretreatment with naloxone prevented the reduction in locus coeruleus impulse flow observed after ciramadol administration but had no effect on the inhibition produced by Wy-45,030. Wy-45,030 and Wy-45,881, like classical antidepressants, appear to inhibit locus coeruleus neuronal firing by potentiating neuroinhibitory transmission of locus coeruleus neurons by blocking the uptake of norepinephrine into presynaptic terminals.

WAY100135: a novel, selective antagonist at presynaptic and postsynaptic 5-HT1A receptors.

The novel phenylpiperazine derivative, (+/-)-WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpro pionamide dihydrochloride), is a selective antagonist at both somatodendritic and postsynaptic 5-HT1A receptors. The IC50 of (+/-)-WAY100135 at the rat hippocampal 5-HT1A receptor was 34 nM, whereas its IC50 at a range of other receptor sites was > 2 microM. Up to a dose of 2.5 mg/kg i.v. (+/-)-WAY100135 induced a maximum 30% inhibition of raphe neuronal firing and (at 0.5 mg/kg i.v.) antagonised the inhibition of firing induced by 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) in anaesthetised rats. (+/-)-WAY100135 antagonised the action of 5-carboxamidoiodotryptamine in the guinea-pig ileum, with a pA2 of 7.2. (+/-)-WAY100135 had no agonist-like behavioural effects but antagonised the behavioural syndrome and hypothermia induced by 8-OH-DPAT in the rat and mouse, respectively. The interaction of (+/-)-WAY100135 with the 5-HT1A receptor was stereoselective; the (+)-enantiomer being markedly more active in binding, functional and behavioural studies. These data indicate that (+/-)-WAY100135 is the first highly selective antagonist at both somatodendritic and postsynaptic 5-HT1A receptors.

Rat atriopeptin III alters hypothalamic neuronal activity.

The effect of pressure application of rat atriopeptin III on extracellularly recorded action potentials of 39 hypothalamic neurons was studied in chloral hydrate-anesthetized male rats. Thirteen of these neurons were histologically located within the boundaries of the paraventricular nucleus. Atriopeptin III was a potent inhibitor of the spontaneous activity of 5 (38%) of these neurons and increased the spontaneous activity of one (8%) other neuron (7 paraventricular neurons were unresponsive to atriopeptin III). Neurons not located within the paraventricular nucleus responded similarly to pressure application of atriopeptin III. Twenty-seven percent (n = 7) were inhibited and 12% (n = 3) were excited while the remaining 16 (61%) neurons were unresponsive to atriopeptin III. Similar applications of an inactive fragment of atriopeptin III (amino acid sequence 18-28) did not alter the spontaneous activity of any neuron (n = 6). These results illustrate that atriopeptin III, an atrial peptide which is also present in the brain, can alter the spontaneous activity of hypothalamic neurons. This provides additional evidence for central activity of this peptide.

Action of estrogen and mechanical vaginocervical stimulation on the membrane excitability of hypothalamic and midbrain neurons.

The effect of vaginocervical stimulation (VCS) and estrogen iontophoresis on the electrical activity recorded in urethane-anesthetized female rats from medial preoptic-septal (MPO-S) and midbrain central gray (MCG) neurons was studied during two phases of the estrous cycle, namely metestrus (M) and late proestrus-estrus (LP-E). The spontaneous discharge rate of both MPO-S and MCG neurons varied over the two stages of the estrous cycle. The spontaneous electrical activity of the MPO-S neurons was higher during M than during LP-E whereas MCG unit activity was low during M and higher during LP-E. The VCS-evoked changes in unit activity were specific, in that they were observed in response to mechanical genital stimulation and not in response to painful stimuli and/or nonspecific arousal. These responses were not dependent on the stage of estrous cycle. Finally, the iontophoresis of 17 beta-estradiol hemisuccinate evoked electrophysiological responses from MPO-S and MCG neurons. More MPO-S neurons were responsive to estrogen in LP-E than in M, while fewer MCG neurons were responsive to estrogen in LP-E than in M. The results clearly show that ongoing electrical activity of hypothalamic and midbrain nerve cells can fluctuate between M and LP-E phases of the estrous cycle and change with vaginocervical probing as well as iontophoretically applied estrogen. Furthermore, the results suggest the existence of a reciprocal relationship between the membrane activity of MPO-S and MCG neurons which may be related CNS control of reproductive activities.

Initial report on combined in vivo single cell recording and intracellular staining.

This paper reports preliminary data obtained from the combination of extracellular single unit recording, microiontophoretic testing and intracellular staining of single neurons in the diencephalon of the anesthetized rat. Sixty neurons were recorded extracellularly and iontophoretically tested with glass multibarrelled micropipettes. Thirty-four of these neurons were identified by antidromic invasion from median eminence stimulation. Seventeen of these antidromically identified neurons were subsequently impaled with the micropipette and intracellularly stained with the fluorescent dye lucifer yellow-CH. The average diameter of the antidromically identified neuronal cell bodies was 7.4 microns. The iontophoretic response profiles of these stained neurons were similar to the profiles of non-stained antidromically identified neurons. Four of the remaining 26 neurons were synaptically activated from median eminence stimulation and were successfully marked with lucifer yellow. Average soma diameters of these neurons was 12.8 microns. Twenty-two neurons were not antidromically or orthodromically identified from median eminence stimulation. Three of these neurons were intracellularly stained with lucifer yellow and their soma diameters averaged 6.9 microns. Approximately 50% of all staining attempts, subsequent to extracellular recording and iontophoretic testing, were successful. The combination of these techniques is therefore a feasible approach to the in vivo study of the physiologic, pharmacologic and morphologic properties of single neurons.

Biochemical and electrophysiological studies of the psychotropic compound, amperozide.

Amperozide (AB Ferrosan, FG 5606), a new antiaggressive agent which exhibits a diverse preclinical profile of in vivo and in vitro activities, was examined to determine its acute effects on noradrenergic neurons of the locus coeruleus. The firing rates of all locus coeruleus neurons tested were increased by IV administration of amperozide. The amperozide-induced increase in locus coeruleus firing rate was similar in magnitude to that of an alpha-2 antagonist; however, amperozide was weaker than the alpha-2 antagonist yohimbine in reversing clonidine-induced inhibition of locus coeruleus neuronal activity and had weak affinity at the alpha-2 receptor (Ki = 3.5 microM). Biochemically, amperozide displayed the most significant in vitro affinity at serotonin-2 receptors (Ki = 26 nM) and had low affinities at all other receptors examined. These properties are discussed in the context of amperozide's activation of the locus coeruleus as a part of its hypothetical mechanism of antiaggressive action.

Generalized anxiety disorder. Epidemiology, impact of comorbidity, and natural history.

According to epidemiologic data collected over the last 5 years, GAD is a prevalent psychiatric disorder that is more chronic than most other psychiatric conditions. Excessive worry, which is the definitive diagnostic criterion, is accompanied by secondary psychic and somatic symptoms. GAD often coexists with other psychiatric conditions, which adds to the serious functional impairment caused when it occurs alone. However, even GAD results in substantial psychosocial impairment that is comparable to that caused by panic disorder, major depression, and other psychiatric disorders. Recognition of the need for long-term treatment of GAD is growing now that the medical community has realized that GAD is an independent disorder with an early age of onset and a chronic, unremitting course. Rarely do patients with GAD seek treatment for excessive worry. Rather, help-seeking behavior in this patient population is usually prompted by secondary symptoms. Continued research is imperative to achieve a better understanding of potential therapies for GAD, the reversibility of the disorder, and the impact of early, aggressive intervention on its course.

Electrotonic coupling among neuroendocrine cells in Aplysia.

1. We have discovered and characterized direct electrotonic synaptic coupling among a population of neuroendocrine (bag) cells in the parietovisceral ganglion of the marine gastropod Aplysia dactylomela. Pairs of ipsilateral and contralateral bag cells were impaled in vitro with microelectrodes. Current pulses applied through the electrometer amplifier to either cell influenced the other cell via electrotonic connections. 2. The coupling between bag cells was relatively weak when measured at the somata; the mean ratio of postsynaptic/presynaptic response amplitudes is 0.0075. Junctional rectification was not detected. The latency between pre- and postjunctional responses was long, up to 50 ms, a delay comparable to that for chemical synaptic transmission among neurons in this ganglion. Low-Ca2+/high-Mg2+ bathing solutions did not block transmission between bag cells, but did block chemical synaptic potentials in other identified neurons. 3. Postjunctional electrotonic responses had markedly slow time courses compared to the prejunctional responses, a characteristic that permitted summation of otherwise undetectable electrotonic PSPs and the demonstration of coupling between the two (bilateral) clusters of bag cells. 4. Based on extracellular recordings of their compound action potentials, the neurites of A. dactylomela bag cells extended a shorter distance (approximately 3 mm) along the connective than the neurites of A. californica or A. brasiliana. 5. Electrolytic lesions made along the neurites during intrasomatic coupling measurements significantly shortened the duration of postjuctional electrotonic responses, indicating that the neurites are widely electrically interconnected and, as a population, have a large effective membrane capacitance. The lesions furthermore revealed that an important site of electrotonic coupling is at the base of the pleurovisceral connective just rostral to the bag cell cluster. 6. The small-amplitude, long-latency and prolonged time course of postjunctional responses are interpreted to indicate remote and widespread coupling sites among the bag cells. This electrotonic coupling underlies the synchronized firing of the bag cells.

Interactions between bilateral clusters of neuroendocrine cells in Aplysia.

1. Activity of bilateral clusters of electrotonically coupled neuroendocrine cells (the bag cells) was studied using multiple-site intracellular and extracellular recording techniques in isolated parietovisceral ganglia of three species of Aplysia. Bilateral afterdischarges typically began with spike initiation on one side near the neurite terminals along the pleurovisceral connective; propagation of action potentials then proceeded toward the somata with potentiation to full somatic invasion in the ipsilateral bag cell cluster. This activity potentiated across the parietovisceral ganglion until contralateral spikes were initiated at a point near the bag cell somata (designated site A) and compound bag cell activity was then propagated both inward toward the somata and outward toward the circumesophageal ring of head ganglia. This sequence of events, i.e., "in one side, out the other," could occur several times during an afterdischarge, although outward propagation of activity was rarely maintained for more than 20 spikes. Synchrony between clusters was best during these periods of activity. Usually after a few episodes of this sequence, the sites of spike initiation spontaneously shifted to near the neurite terminals of each side and activity was initiated distally and propagated inward. Asychrony between clusters commonly developed when the sites for spike initiation were near the neurite terminals of each side. 2. Waveforms and temporal sequence of recorded events indicate that at least two sites for spike initiation exist within the neuritic tree of each bag cell cluster. These are the distal terminations of the neurites and a proximal site near the somata. Action potentials could be generated at this proximal site spontaneously or when electrotonically driven by contralateral activity. Removal of the bag cell somata did not interfere with bilateral behavior of the bag cell system. The proximal site is, therefore, not somatic. Activity initiated there was always more synchronous and propagated with a higher conduction velocity than activity initiated at the distal ends of the neurites. 3. Experiments were performed with and without the circumesophageal ring of head ganglia intact. Removal of the head ganglia had no effect on bilaterality of or synchrony within the bag cell system. Systematic stimulations and cuts of head ring connectives suggested that the cerebral ganglion may participate in orthodromic activation of the bag cells. 4. Our findings indicate the bag cells of Aplysia are a homogeneous population of neuroendocrine cells with multiple sites for spike initiation. Either cluster can serve as a pacemaker for the other through potentiation and electrotonic activation of the contralateral cluster at proximal sites on the neurites.

A light and electron microscopic investigation of the neurosecretory bag cells of Aplysia.

The two bilateral clusters of neurosecretory bag cells of Aplysia were studied with both light and electron microscopy. Autoradiography revealed that the bag cells rapidly accumulate 3H-labelled amino acids and that after 1-2 h, heavy concentrations of silver grains appear over Golgi complexes and in the proximal axons. Intrasomatic injections of CoCl2 or lucifer yellow showed clear branch points and numerous varicosities along individual axons. Many of the bag cells are multipolar. Electron-microscopic observations confirmed that individual fibres branch and showed that the varicosities are packed with dense-cored vesicles similar in size (180 nm diameter) and electron density to those found in the somata. The axons of several cells are usually associated into bundles that travel (within the connective tissue sheath) either rostrally up the pleurovisceral connective or toward the contralateral bag cell cluster. Bundled in groups of tens to hundreds, a total of many thousands of axons fill the sheath around each cell cluster and around the proximal 2-5 mm of the pleurovisceral connective; the number of axon bundles in the sheath decreases rapidly with distance from the cluster. Individual axons reaching the outer edges of bundles from neurosecretory endings near blood sinuses in the sheath, creating an extensive neurohemal release area. Dense-cored vesicles are packed into the endings, often in very close apposition to the plasma membrane. Possible release profiles (omega-shaped) and smaller clear vesicles (85 nm diameter) were observed in the axon endings. A number of axons also enter and travel among the conventional (non-neurosecretory) axons in the core of the pleurovisceral connective nerve. These 'core' bag cell axons project for several millimetres beyond the terminations of the bundled axons of the sheath. The findings support the hypothesis proposed in physiological studies that the distribution and branching of the axonal tree are the basis for the extracellularly recorded wave forms and of the potentiation of electrical signals during bag-cell activity. Additional evidence indicates that exocytosis is the means by which bag-cell hormone is released during afterdischarges.

Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial.

CONTEXT: Generalized anxiety disorder (GAD) is a chronic disorder that is associated with debilitating psychic and somatic symptoms. Venlafaxine extended-release (XR) capsules have been shown to be effective in short-term treatment of patients with GAD without major depressive disorder (MDD), but long-term data are needed to establish whether this agent confers persistent benefits. OBJECTIVE: To compare the 6-month efficacy and safety of a flexible dosage of venlafaxine XR in outpatients with GAD without associated MDD. DESIGN: Six-month, randomized, double-blind, placebo-controlled, parallel-group trial conducted May 1996 to October 1997. SETTING: Fourteen outpatient clinics and private psychiatric practices in the United States. PARTICIPANTS: A total of 251 outpatients aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for GAD, had sufficient symptoms to require treatment, and did not have coexisting MDD. INTERVENTIONS: Participants were randomly assigned to receive either placebo (n=127) or venlafaxine XR (75, 150, or 225 mg/d, as required to control symptoms; n=124) for 28 weeks. MAIN OUTCOME MEASURES: Changes from baseline in the Hamilton Rating Scale for Anxiety (HAM-A) total score, the HAM-A psychic anxiety factor score, and the Clinical Global Impressions (CGI) scale Severity of Illness and Global Improvement scores, compared by intervention group. RESULTS: During weeks 6 through 28, response rates in the venlafaxine XR group were 69% or higher compared with rates of 42% to 46% in the placebo group (P<.001). By an evaluable-patient analysis, venlafaxine XR compared with placebo significantly improved anxiety scores from week 1 or 2 through week 28 on all primary efficacy measures, including the HAM-A total (P<.001), the HAM-A psychic anxiety factor (P<.001), and the CGI scale scores (P<.001). Adjusted mean changes from baseline to week 28 using last-observation-carried-forward methods were for HAM-A, venlafaxine XR -13.4, placebo -8.7 (P<.001); for HAM-A psychic anxiety score, venlafaxine XR -7.4, placebo -4.2 (P<.001); and for CGI-Improvement, venlafaxine XR 2.2, placebo 3.0 (P<.001). The most common treatment-emergent adverse event was nausea, followed by somnolence and dry mouth. CONCLUSIONS: This study is the first placebo-controlled demonstration of the long-term efficacy of any drug class in treating outpatients with DSM-IV-diagnosed GAD. Venlafaxine XR is an effective, rapidly acting, safe, once-daily agent for both the short- and long-term treatment of anxiety and may provide an important alternative to currently available anxiolytics. JAMA. 2000.