Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment

There is preclinical and clinical evidence suggesting that one neural mechanism responsible for antipanic efficacy is a reduction in brain noradrenergic function. Alprazolam, a triazolobenzodiazepine, has been demonstrated to have antipanic properties; however, to our knowledge, its effects on noradrenergic function have not been established. To assess whether alprazolam alters noradrenergic function, the effects of alprazolam on baseline plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and yohimbine-induced increases in plasma MHPG level, anxiety-nervousness, blood pressure, and somatic symptoms were studied in 14 patients with agoraphobia and panic disorder. Long-term alprazolam treatment significantly reduced plasma MHPG baseline and blunted the yohimbine-induced increases in plasma MHPG, anxiety-nervousness, and sitting systolic blood pressure. These observations suggest that the antipanic mechanism of action of alprazolam may be due in part to an interaction between benzodiazepine-sensitive and noradrenergic neural systems.     

The effect of long-term imipramine treatment on carbon dioxide-induced anxiety in panic disorder patients

The authors examined whether long-term treatment with imipramine would decrease CO2-induced anxiety in 10 patients with panic disorder. The patients underwent CO2 testing after single-blind placebo testing and again after imipramine treatment. Scores on self-rated visual analog mood scales and panic attack symptom scales showed that the anxiogenic effects of CO2 were significantly reduced during long-term imipramine treatment. These results suggest that the mechanisms underlying CO2-induced anxiety may be similar to those involved in the pathophysiology of panic disorder.     

Dopaminergic mechanism of imipramine action in an animal model of depression

Rats, subjected chronically (10-12 weeks) to a variety of mild, unpredictable stressors, showed a decrease in their consumption of weak sucrose solutions; normal behavior was restored by chronic (5-9 weeks) treatment with the tricyclic antidepressant imipramine. Acute administration of the dopamine receptor antagonist pimozide or the specific dopamine D2 receptor antagonist raclopride had no effect in nonstressed animals and in vehicle-treated stressed animals, but both drugs selectively reversed the improvement of performance in imipramine-treated stressed animals. The 5HT antagonist metergoline increased sucrose consumption in all groups. The data suggest that the mechanism of action of imipramine in this model is an increase in functional activity at dopamine (DA) synapses.     

The mammillary body is a potential site of antianxiety action of benzodiazepines

The present study was designed to examine the anticonflict action of benzodiazepines injected into the mammillary body (MB) using the rat conflict-punishment procedure. Diazepam 20 micrograms/microliters, chlordiazepoxide 60 micrograms/microliters and midazolam 30 micrograms/microliters, bilaterally injected into the MB, produced a significant increase in the punished responses without changes in the unpunished responses. These findings have demonstrated for the first time that the MB could be a potential site of antianxiety action of benzodiazepines.     

Adrenergic receptor function in panic disorder. II. Neutrophil beta 2 receptors: Gs protein coupling, effects of imipramine treatment and relationship to treatment outcome.

Panic attacks are associated with increased autonomic symptoms, suggesting increased beta 2-adrenergic receptor (beta 2AR) function in PD. Tricyclic antidepressants downregulate beta AR function. Previous studies on beta AR function in PD, however, are inconsistent. We recently found increased beta AR coupling and density in neutrophils of symptomatic drug-free PD patients. This study evaluated beta AR coupling to Gs protein in 28 controls, 25 drug-free PD patients and 8 PD imipramine-treated patients. PD patients had significantly higher coupling and receptor density, particularly in the high-conformational state. Differences were more pronounced in patients with less depressive symptomatology. Treatment with imipramine was associated with decreased beta AR coupling and density in the high-conformational state. Several beta AR binding parameters were related to severity of anxiety symptoms and treatment outcome. Antidepressants downregulate beta AR density and induce uncoupling from Gs protein in PD. Future studies may investigate beta AR coupling in relationship to treatment outcome and the role of beta AR kinase in PD.     

Effects of desipramine and fluvoxamine treatment on the prolactin response to tryptophan. Serotonergic function and the mechanism of antidepressant action

It has been hypothesized that enhancement of brain serotoninergic (5-HT) function is involved in the mechanism of action of some antidepressants. To test this, the prolactin response to intravenously administered tryptophan, a clinical measurement of 5-HT function, was assessed before and during antidepressant treatment. Depressed patients received the tricyclic desipramine hydrochloride (N = 24) or the 5-HT reuptake inhibitor fluvoxamine maleate (N = 30). The prolactin response was significantly enhanced after long-term treatment (4 weeks) but not as reliably increased after short-term (1-week) desipramine treatment. Fluvoxamine enhanced the prolactin response after both short- and long-term treatment. Enhancement of the prolactin response was not clearly correlated with clinical improvement. The results of this study are consistent with preclinical evidence of enhanced 5-HT function during treatment with these classes of antidepressants, but also indicate that enhanced 5-HT function is not a sufficient condition for antidepressant efficacy.     

Studies on the action mechanism of the antihemostatic effect of lodopeptides.

A synthetic iodopeptide having a glutamic acid-diiodotyrosine molar ratio of 1:1 has been shown to be an effective anticoagulant both in vivo and in vitro. Contrasted with heparin the following general conclusions may be made regarding its action. The iodopeptide does not act through the inactivation of thrombin in plasma. Iodopeptide does interact with fibrinogen to form a complex which, in vitro, is not soluble in buffered saline at physiological pH. At pH 8, iodopeptide interacts with fibrinogen to form a soluble complex in the presence of 0.9% NaCl that is not coaguable either by thrombin or Crotalus venom enzymes. All the available evidence indicates that the fibrinogen to fibrin conversion is not inhibited under these conditions, but that fibrin, once formed, is not able to polymerize due to interference by iodopeptide. Similar results were obtained with heparin in vitro with thrombin-fibrinogen mixtures in the absence of NaCl. Studies with Russell's viper venom in native PRP strongly suggest that the iodopeptide also interferes with processes in the early coagulation pathway associated with prothrombin activation.     

Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine.

A double-blind clinical trial was carried out to evaluate the efficacy of S-adenosyl-L-methionine (SAMe) in speeding the onset of action of imipramine (IMI). SAMe is a naturally occurring substance that has been shown to possess antidepressant activity with a rapid mode of onset and minimal side effects. Sixty-three outpatients with moderate to severe depression were included in the study. After an initial 1-week placebo period, only 40 patients entered the active treatment phase. During the first 2 weeks of the trial, half of these patients received 200 mg/day of SAMe intramuscularly, while the other half received placebo. Simultaneously, oral IMI was administered to all patients at a fixed dose of 150 mg/day. The onset of clinical response was determined by evaluating patients every second day. By the end of week 2, the parenteral treatment was suppressed and IMI was adjusted according to individual needs. Depressive symptoms decreased earlier in the patients who were receiving the SAMe-IMI combination than in those who were receiving the placebo-IMI combination.     

Prophylactic effect of lithium and imipramine in unipolar and bipolar II patients: a preliminary report.

Relapse rates of the first 35 unipolar and bipolar II manic-depressive patients who entered the controlled phase of a continuing evaluation of the prophylactic value of lithium alone or in combination with imipramine were analyzed. Lithium had a prophylactic effect in unipolar patients and possibly in bipolar II patients. Imipramine did not have a prophylactic effect in either group of patients.     

Noradrenergic function and the dexamethasone suppression test in depression

We measured the plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the serum cortisol levels before and after the oral administration of dexamethasone. There was not a significant difference in the plasma free MHPG levels between the patients with major depression and normal subjects. There was a significant positive correlation between the plasma MHPG levels and postdexamethasone cortisol levels in patients with major depression. This indicates that there exists a certain relation between abnormalities of the central noradrenergic systems and hypothalamic-pituitary-adrenal axis in patients with major depression. The mean total scores of the Hamilton Rating Scale for Depression of the first (MHPG less than 5 ng/ml) and third (10 ng/ml less than or equal to MHPG) groups were significantly higher than those of the second (5 less than or equal to MHPG less than 10 ng/ml) group.     

The effect of long-term antipsychotic treatment on prolactin

OBJECTIVE: This naturalistic, cross-sectional study was designed to assess the risk of prolactin level elevation and associated side effects in youths taking long-term atypical antipsychotic medication. METHOD: Subjects were enrolled from outpatient child psychiatric treatment settings in upstate New York who were taking risperidone, olanzapine, or quetiapine for at least 6 months. Demographic data, medication history, and side effects were elicited at the initial interview. Two fasting morning serum prolactin levels were obtained 1 month apart, and the results were averaged. RESULTS: Fifty outpatient youths, with a median age of 13 years, were enrolled in the study. The median overall duration of use of an atypical antipsychotic was 22.1 months. The median dose of medication for risperidone was 1.5 mg/day, for olanzapine 10 mg/day, and for quetiapine 200 mg/day. The mean prolactin level among all patients on risperidone was significantly greater than controls, as well as for those on quetiapine or olanzapine. CONCLUSIONS: The risk of hyperprolactinemia with long-term use of risperidone appears to be significantly greater than for olanzapine or quetiapine. Overt side effects were infrequent in the overall sample, but serum prolactin assessment is recommended for youths taking risperidone chronically. Because of variability found in sequential prolactin samples, repeat samples may be warranted.     

Noradrenergic modulation of the masseteric reflex in behaving cats. II. Physiological studies

Studies in the preceding paper demonstrated that the amplitude of the masseteric reflex in behaving cats is augmented by pharmacological manipulations that increase norepinephrine (NE) tone in the motor trigeminal nucleus (MoV) through exogenous means. The present studies examine whether such a relationship also exists under physiological conditions, i.e., whether physiological increases in NE synaptic activity are correlated with increases in the reflex amplitude. The masseteric reflex was elicited in behaving cats by electrical stimulation of the mesencephalic trigeminal nucleus (MesV) and the response recorded via electrodes permanently placed in the masseter muscle. Following baseline measures of the reflex amplitude, the reflex was gain elicited while cats were exposed to various environmental stimuli known to activate NE neurons: 15 min of 100-dB white noise, confrontation with a dog, or auditory clicks presented repetitively at various intervals prior to MesV stimulation. Presentation of the white noise or the dog significantly facilitated the reflex response for the duration of the exposure. The clicks produced reflex facilitation at 100 and 150 msec following their presentation and reflex suppression at 20 msec. Two approaches were then employed to determine whether NE mediated, at least in part, augmentation of the reflex produced by these environmental conditions. In the first, cats were given either the alpha-1-noradrenergic antagonist prazosin (5 mg/kg, i.p.) or the serotonin antagonist methysergide (0.5 mg/kg, i.p.). In all cases, prazosin blocked the reflex augmentation whereas methysergide was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

The mechanism of action of methylprednisolone in the treatment of multiple sclerosis

Methylprednisolone plays an important role in the current treatment of multiple sclerosis (MS), particularly in the acute phase of relapse. It acts in various ways to decrease the inflammatory cycle including: dampening the inflammatory cytokine cascade, inhibiting the activation of T cells, decreasing the extravasation of immune cells into the central nervous system, facilitating the apoptosis of activated immune cells, and indirectly decreasing the cytotoxic effects of nitric oxide and tumor necrosis factor alpha. This paper reviews the most recent observations on these mechanisms both to understand the disease mechanism and its treatment. As more becomes known about these mechanisms, it may become possible to design treatment regimes that are more specific towards both the individual and the disease state.     

Acetazolamide treatment of hypokalemic periodic paralysis. Probable mechanism of action.

Following administration of glucose and insulin to three patients with hypokalemic periodic paralysis, serum K+ fell 1.9 mM. After administration of acetazolamide, 250 mg four times daily, serum K+ fell 0.9 mM, a substantial difference. In normal persons glucose and insulin lowered serum K+ 0.5 mM, and this was not changed substantially by acetazolamide. The metabolic acidosis induced by the drug appears to be responsible for the change in decrement of serum K+ and for the amelioration of symptoms in the patients. The findings agree with earlier reports that metabolic acidosis lowers the rate of entry of K+ into muscle, thus opposing the heightened or pathological entry of K+ into muscle cells during attacks of the disease.