Effect of a benzoquinolizine (RO 4-1284) on granulated vesicles of the rat brain.
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Animals↗
Biomedical subjects
A Halaris
Publications and source records attributed to A Halaris.
Norepinephrine and 5-hydroxytryptamine in the CNS of rats under continuous illumination and total darkness.
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Animals↗
Platelet I1-imidazoline binding sites are elevated in depression but not generalized anxiety disorder.
Depressed patients have been reported to have a higher than normal density of platelet binding sites for 3H-clonidine, an alpha 2-adrenoceptor agonist. Paradoxically, other studies using 3H-alpha 2, antagonists have found no differences from controls. Because 3H-clonidine interacts with platelet alpha 2-adrenoceptors to form G-protein complexes, whereas 3H-alpha 2-antagonists bind with uncoupled receptors, an elevation in G-protein coupling might explain this paradox. Another possibility is that depression might be associated with increased non-adrenergic I1-imidazoline binding sites, which are also clonidine sensitive. To distinguish these possibilities, we utilized p125I-clonidine to measure density (Bmax) and affinity (KD) of platelet G-protein coupled alpha 2-adrenoceptors as well as platelet I1 binding sites, and compared diagnostic groups of major depressive disorder (MDD), generalized anxiety disorder (GAD) and healthy subjects. Specific inhibition of binding by norepinephrine (NE = 10 microM) was used to selectively quantify alpha 2-adrenoceptors, whereas inhibition by 10 microM moxonidine (a > 100-fold selective I1 ligand) quantified I1 binding sites under a NE mask. I1 sites were found to be markedly elevated by, on average, +136% in MDD patients (p = .0007), whereas there was only a marginal increase in alpha 2-adrenoceptor Bmax values in MDD patients (p = .08; GAD and healthy subjects did not differ). Treatment of MDD patients for 6-8 weeks with desipramine downregulated I1 sites as well as alpha 2-adrenoceptors. Positive correlations were also noted for both sites: (a) between Bmax values and the severity of depression (using the Hamilton Depression Rating Scale); and (b) between end-of-treatment plasma desipramine concentrations and the extent of downregulation in Bmax values when subject groups were pooled. None of the binding parameters was associated with plasma catecholamine concentrations. The results suggest that an increased density of platelet I1 binding sites may partially explain the utility of radiolabeled clonidine as a potential biological marker for depressive illness, although an additional increase in G-protein coupling cannot be excluded.
Adult↗
Elevated P-selectin on platelets in depression: response to bupropion.
Increased platelet activation has been suggested as a possible reason for the increased vulnerability of depressed patients to ischemic heart disease (IHD). Translocation of P-selectin, an integral alpha-granule membrane protein, to the platelet surface is a measure of platelet activation. Herein, western blots of platelet plasma membranes containing P-selectin were quantified in patients with major depression (n=19; mean age=39 +/- 2 years) and healthy comparison subjects (n=17; mean age=36 +/- 2 years). None evidenced clinical signs of IHD, and only two patients had a lifestyle IHD risk factor (smoking). Blood was obtained from all 19 depressed patients before treatment, and 15 returned after 6-8 weeks of open-label bupropion treatment. Bupropion was chosen as the antidepressant because it did not elevate plasma norepinephrine or serotonin, endogenous agonists that can induce platelet degranulation. Western blotting revealed more P-selectin immunoreactivity (75 kD band) in depressed patients compared to healthy controls (P=0.003). After bupropion treatment, P-selectin remained high in depressed patients. beta3-Integrin, a reference plasma membrane protein that does not translocate during activation, was of equivalent density in depressed patients and healthy control subjects, and was unchanged after treatment with bupropion. P-Selectin failed to correlate with severity of illness based on the Hamilton Depression scale, or with the post-treatment plasma concentration of bupropion. The results suggest an elevation in P-selectin on platelet plasma membranes might be a trait marker for depression.
Adolescent↗
Alpha 2-adrenoceptors and I1-imidazoline binding sites: relationship with catecholamines in women of reproductive age.
A comparison is presented between plasma catecholamine concentrations and platelet [125I]-p-iodoclonidine binding sites in 16 healthy women. Blood samples were obtained at six regularly spaced intervals over two consecutive menstrual cycles from healthy women with regular menstrual periods. Although no cycle-related changes were observed per se, there were significant correlations between the platelet binding sites and plasma norepinephrine and epinephrine concentrations. The densities of platelet alpha 2-adrenoceptors were negatively correlated in an exponential fashion (r2 = 0.694, P = 0.009) with plasma epinephrine concentrations, implying agonist-induced downregulation. On the other hand, platelet I1-imidazoline binding sites were positively correlated with plasma concentrations of norepinephrine in a linear fashion (r2 = 0.326, P = 0.021). This is the first indication that I1 binding sites might be upregulated by a physiological factor. Furthermore, the data suggest that elevations in plasma norepinephrine might explain reports of upregulated I1 binding sites in depressed patients.
Adult↗
Effect of bupropion on immunodensity of putative imidazoline receptors on platelets of depressed patients.
A substantial number of studies have demonstrated increased imidazoline receptors (I1 binding sites) on platelets of depressed patients and downregulation following antidepressant treatments. Herein, imidazoline receptor binding protein (IRBP) antiserum was used to quantify imidazoline receptors on platelets of depressed patients before and after treatment with the atypical aminoketone antidepressant, bupropion. Western blots revealed an increase in IRBP-immunodensity (p = 0.01, two-tailed) in a 33 kDa protein band in untreated depressed patients (n = 21) as compared with controls (n = 17). This band has been positively correlated with I1 binding sites on platelets. Following 6 weeks' treatment with bupropion, IRBP-immunodensity was downregulated in depressed patients (p = 0.03, paired t-test); predominantly in responders (p = 0.005). Patients non-responsive to bupropion (n = 5) were significantly different from responders (p = 0.05) by exhibiting no elevation in IRBP-immunodensity at pre-treatment and no downregulation of the 33 kDa band after treatment. IRBP-immunodensity was negatively correlated (r = -0.79, p = 0.01) with plasma concentrations of bupropion and its metabolites at week-4 of BUP treatment. Thus, a 33-kDa IRBP on platelet plasma membranes is elevated in depression and normalized in responders to bupropion.
Adolescent↗
Psychoendocrine sequelae of chronic testosterone deficiency.
The precise role of testosterone in regulating mood, especially in alleviating depression, remains unclear although converging evidence indicates that androgens may exert antidepressant action. A model that may potentially assist in the clarification of androgen-mediated effects on mood is the study of cryptorchid men who may grow up with varying degrees of testosterone deficiency depending on the time in their life when cryptorchism is corrected. In this report, we describe a rare case of bilateral cryptorchism that did not come to the attention of the physician to implement effective substitution with testosterone until much later in adult life. The patient developed severe and suicidal depression which responded solely to testosterone. In addition, the patient experienced a delayed but accelerated puberty without any adverse events. These observations, although based on a single case, provide strong evidence that testosterone may exert powerful antidepressant action in the absence of concomitant antidepressant agents.
Adult↗
Plasma MHPG response to yohimbine treatment in women with hypoactive sexual desire.
The use of yohimbine to treat impotence has suggested that decreased male sexual desire may relate to decreased activity of central noradrenergic neurons. Previous trials of yohimbine to treat female sexual problems are not available. Yohimbine is an alpha 2-adrenergic antagonist that stimulates norepinephrine (NE) release. In the present study, plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), the major central nervous system metabolite of NE, were measured in 9 women diagnosed with hypoactive sexual desire. Daily logs of mood and sexual activity, and trimonthly MHPG blood drawings, were obtained over an initial baseline menstrual cycle followed by two subsequent treatment cycles (yohimbine or placebo), in randomized order. Blood samples were obtained at 9:00 a.m. during (a) the early follicular phase of each cycle (24 hr after the onset of each cycle), (b) the ovulatory phase (i.e., within 1 day of an oral temperature rise), and (c) the midluteal phase (i.e., 20-25 days into each cycle). Comparisons were made with a group of 7 healthy female controls. Women with hypoactive sexual desire had slightly lower plasma MHPG values than controls at baseline, although there was only a trend toward significance during the early follicular phase (p = .09). Yohimbine (5.4 mg orally, 3 times daily, beginning at menses) caused a sustained rise in plasma MHPG of similar magnitude to that reported in men. However, in terms of improved sexual desire, yohimbine had no obvious therapeutic effect. Thus, plasma MHPG and the alpha 2-adrenergic response to yohimbine appeared within normal ranges in women with hypoactive sexual desire, with no therapeutic response to yohimbine.
Adrenergic alpha-Antagonists↗
Antidepressant drug therapy in the elderly: enhancing safety and compliance.
This review article addresses some of the complex issues surrounding antidepressant drug usage among elderly depressives. While primarily geared toward the psychiatrist in general practice, the article provides useful information for the nonpsychiatric physician who is frequently called upon to evaluate and treat affective disorders in the geriatric population. Since tricyclic antidepressants and lithium are the most commonly used psychotropic drugs in the treatment of depression, their side effects and adverse reactions are discussed specifically as these relate to the elderly. Suggestions are offered on how to improve safety and enhance compliance. Brief mention is made of the monoamine oxidase inhibitors and the second generation antidepressants. Dose ranges are recommended for use of these agents in geriatric patients. Finally, a section of the article reviews the most commonly encountered encountered drug interactions between tricyclic and a variety of other psychotropic and nonpsychotropic drugs.
Aged↗
MHPG circadian rhythmicity in blood of healthy subjects.
An earlier study showed that plasma concentrations of total 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite of norepinephrine, display a circadian rhythm in 6 male healthy subjects. In the previous study, the period of the rhythm was not fixed to 24 h thereby undermining the reliability of the cosinor parameter estimates. The present study extends the findings to a larger group of 12 clinically healthy male volunteers. Plasma total MHPG concentrations were determined every 3h for one full day. The data were fitted to a cosinor model fixing the period of the putative MHPG rhythm at 24 h. Several estimation techniques were utilized including Fourier analysis and time domain analysis with 4 variations. It is concluded that a circadian rhythm indeed characterizes MHPG blood concentrations. The concordance among the various parameter estimates is discussed.
Adult↗