Ionophores X537A and A23187. Effects on the permeability of lipid bimolecular membranes to dopamine and calcium.

X537A carries dopamine across lipid bimolecular membranes. The rate of transport increases linearly with the X537A concentration and is independent of an electric field across the membrane. The evidence suggests that the permeating species is a neutral 1:1 complex between dopamine and X537A. A23187 does not transport dopamine. The permeability of the membrane to calcium increases as the square of the X537A concentration; the transport of calcium is also increased by A23187. With both ionophores, calcium is probably transported as an uncharged complex. Neither desmethylimipramine nor cocaine alters the transport of dopamine with X537A.

Effects of polypeptide and protein hormones on lipid monolayers. I. Effect of insulin and parathyroid hormone on monomolecular films of monooctadecyl phosphate and stearic acid.

Insulin in low concentrations inhibits the uptake of Ca(++) by the monooctadecyl (stearyl) phosphate monolayer (at air-water interface) and facilitates the release of Ca(++) adsorbed to the monolayer. These effects of insulin are more pronounced at higher insulin concentrations. Evidence is presented that a relatively intact insulin molecule competes with Ca(++) for the free phosphate group of the monolayer. Albumin has a slight inhibitory action on calcium uptake and parathyroid hormone has no observable action on calcium uptake or release.

alpha-Adrenergic receptor function in schizophrenia. Receptor number, cyclic adenosine monophosphate production, adenylate cyclase activity, and effect of drugs.

alpha-Adrenergic receptor function was assessed in platelets from drug-free schizophrenic patients and control subjects. The number of alpha-receptors was similar in platelet membranes from schizophrenic patients and control subjects. In intact platelets from schizophrenic male, but not female, patients, prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) level was less than in control subjects. This defect may be due, at least in part, to decreased adenylate cyclase activity. In platelet lysates from schizophrenic patients, but not from normal control subjects, adenylate cyclase activity was diminished and PGE1-stimulated adenylate cyclase activity could be restored partially by the addition of guanosine triphosphate. Treatment with neuroleptic drugs or lithium carbonate did not change alpha-receptor number or cAMP production in platelets from schizophrenic patients, but high doses of propranolol hydrochloride increased cAMP production without affecting the number of alpha-receptors. If the production of cAMP in neurons is similar to that in platelets, diminished cAMP production may be associated with a vulnerability to schizophrenia.

Mechanism of interaction between interferon-gamma and antineoplastic agent on the differentiation of HL-60 promyelocytic cells.

Exposure of HL-60 promyelocytic leukemia cells to a combination of interferon-gamma (IFN gamma) and 5-fluorouracil (5-FU), at concentrations ineffective by themselves, induced a significant differentiation into monocyte-like cells. This phenomenon was accompanied by a synergistic antiproliferative effect. Further characterization of these two activities of the IFN gamma/5-FU combination on HL-60 cells was carried out. Whereas a brief pretreatment of the cells with IFN gamma followed by 5-FU was sufficient to exert the synergistic antiproliferative action, the effect on differentiation was dependent on a prolonged concomitant exposure to both drugs. In an attempt to gain more insight into the biochemical mechanisms of these phenomena, we have examined the effects of RNA and protein synthesis inhibitors and of cytoskeleton disrupting agents on the actions of IFN gamma. Inhibition of RNA or protein synthesis by actinomycin D or cycloheximide did not prevent the antiproliferative action of IFN gamma nor the induction of monocytic differentiation, yet these two compounds blocked the priming effect of IFN gamma on the potentiation of 5-FU action. Actinomycin D synergistically potentiated the antiproliferative action of IFN gamma. Colchicine, vinblastine, and cytochalasin B, disrupting the microtubular and microfilament structure, did not interfere with the actions of IFN gamma; higher concentrations of the drugs even improved the priming effect. Exogenous thymidine, known to counteract the antiproliferative effect of 5-FU, also blocked the antigrowth action but not the differentiation induced by the IFN gamma/5-FU combination. The results suggest the existence of two different mechanisms of the IFN gamma/5-FU synergism: one governing the antiproliferative action via an effect on thymidine synthetase, inducible by a short-term IFN gamma pretreatment and dependent on de novo RNA and protein synthesis; and the other mediating the induction of differentiation requiring a long-term exposure of the cells to both drugs. From a clinical point of view, drug combinations such as IFN gamma and 5-FU, inducing differentiation as well as inhibiting proliferation, may suggest a new approach to the treatment of leukemia.

Effect of inhibition of prostaglandin synthesis on sympathetic nervous system function in man.

The effect of inhibition of prostaglandin synthesis by indomethacin on the function of the peripheral sympathetic nervous system was studied in eight normotensive subjects. Sympathetic nervous function was assessed by measurement of plasma norepinephrine, alpha-adrenergic receptor sites on platelet membranes, and urinary excretion of epinephrine and norepinephrine. Treatment with indomethacin for 7 days resulted in significant decreases in basal plasma norepinephrine from 134 +/- 7 to 99 +/- 6 (SEM) pg/ml (P less than 0.01), a 26% decrease. Posturally stimulated norepinephrine concentrations (337 +/- 14 pg/ml in control studies) were 255 +/- 18 pg/ml (P less than 0.02), 25% lower, with indomethacin. Plasma norepinephrine after 5-min compression of hand grip (468 +/- 47 pg/ml in control) was 331 +/- 30 pg/ml (P less than 0.005), 29% lower, with indomethacin. The number of platelet alpha-adrenergic receptor sites did not change with indomethacin, nor did prostaglandin E1-stimulated cAMP production by platelet membranes. In addition, indomethacin produced no change in urinary excretion of norepinephrine or epinephrine. It is suggested that inhibition of prostaglandin synthesis may lead, via baroreceptor feedback, to a decrease in plasma norepinephrine concentration.

Seasonal variations in the endogenous rhythm of dopamine receptor binding in rat striatum.

In four experiments, performed at different months throughout the year, a significant daily rhythm in dopamine receptor binding has been observed. This rhythm is endogenous, as it persists in the absence of time cues. Striking differences in wave form, amplitudes, and timing of peaks during the year suggest that the endogenous rhythm undergoes seasonal variations.

Noradrenergic and neuroradiological abnormalities in tardive dyskinesia.

Previous studies suggest that catecholaminergic overactivity and structural brain damage may contribute to the pathogenesis of tardive dyskinesia (TD). Although dopaminergic (DA) mechanisms, specifically postsynaptic receptor supersensitivity, have been extensively studied, equally plausible noradrenergic (NE) changes have been all but ignored. Likewise, the interaction of neurochemical and neuroradiological abnormalities has received little attention. Over the past 6 years, 111 inpatients were studied with a battery of neurological, behavioral, biochemical, and neuroradiological measures. Forty-one patients met specific diagnostic criteria for TD, based in part on global ratings on the Abnormal Involuntary Movement Scale. Subgroups of patients were also evaluated with the Brief Psychiatric Rating Scale and were assayed for plasma dopamine-beta-hydroxylase (DBH) activity, platelet 3H-dihydroergocryptine (3H-DHE)-alpha 2 adrenergic receptor binding, lumbar cerebrospinal fluid (CSF) monoamines and metabolites [NE, 3-methoxy-4-hydroxyphenylglycol (MHPG), DA-sulfate, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC)], and CT scan indices of brain atrophy, including ventricle/brain ratio (VBR), bifrontal/bicaudate ratio, and cortical atrophy. All patients were studied in the steady state, primarily when free of neuroleptics. Patients with TD had significantly greater DBH activity than those without TD. In addition, 3H-DHE binding and CSF NE were significantly correlated with the severity of TD when present. Finally, TD patients with low DBH activities (below the mean) had significantly larger ventricles than non-TD patients with low DBH activities. Other data suggested that subcortical, rather than cortical, atrophy was more likely to be responsible for the larger VBR in the low DBH TD group. These results suggest an association of NE overactivity and TD in a portion of patients. Moreover, the presence of neuroradiological abnormalities in TD patients with low DBH activity underscores the contribution of heterogeneous factors to the pathogenesis of this disorder and may provide one possible explanation for the discrepant biochemical findings in TD reported by earlier investigators.

Reduced cyclic AMP production in the blood platelets from schizophrenic patients.

The authors assessed alpha-adrenergic receptor function in blood platelets from chronic schizophrenic patients and normal control subjects. The number of receptors was measured by the specific binding of the alpha-adrenergic antagonist [3H]dihydroergocryptine to the platelets. A physiological response of the platelets to agonist occupancy of the alpha-adrenergic receptors was measured by the norepinephrine inhibition of prostaglandin E1(PGE1)-stimulated cyclic AMP (cAMP) production. cAMP production in male schizophrenic patients was lower than in normal male subjects. alpha-Adrenergic receptor function was similar in patients and normal control subjects of both sexes. Normal male subjects had about 1.5 times the number of alpha-adrenergic receptors as normal females and generated about 1.8 times the quantity of PGE1-stimulated cAMP.

Toxic reactions to the combination of monoamine oxidase inhibitors and tryptophan.

The combination of monoamine oxidase inhibitors and tryptophan--a recognized antidepressant regimen--has been reported to cause behavioral or neurologic toxicity. The authors present eight cases of delirious syndromes apparently attributable to this combination of agents.

The roles of protein phosphorylation/dephosphorylation in tumor necrosis factor antitumor effects.

The roles of protein phosphorylation and dephosphorylation in the tumor necrosis factor (TNF) cytotoxic and antiproliferative effects on L-929-transformed fibroblasts were explored. Genistein and erbstatin, specific inhibitors of tyrosine kinase, had antiproliferative but not cytotoxic effects on the cells by themselves and synergistically enhanced the cytotoxic and antiproliferative effects of TNF-alpha. Immunoblot analysis with a monoclonal antiphosphotyrosine antibody revealed that TNF, administered for 5-180 min, induced tyrosine dephosphorylation of two pairs of membranal proteins, 34-36 kDa and 50-52 kDa, and potentiated tyrosine phosphorylation of a 115-kDa protein in both the cytosolic and membranal fractions of the cells. A very brief exposure (30 sec) to TNF induced rapid phosphorylation of several proteins, whereas genistein, but not inhibitors of other protein kinases, enhanced this effect of TNF. The results suggest that TNF activity could be potentiated by the inhibition of tyrosine phosphorylation and point to specific proteins that are dephosphorylated on tyrosine in response to TNF.

Alpha-adrenergic receptors in orthostatic hypotension syndromes.

Alpha-adrenergic receptor function was measured in platelets from patients with orthostatic hypotension and normotensive controls. Patients with idiopathic orthostatic hypotension (IOH) or multiple system atrophy (MSA) had more alpha-receptors than controls. Patients with IOH, but not MSA, produced less prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) than controls. Patients with sympathotonic orthostatic hypotension (SOH) were similar to controls in receptor number and cAMP production. The percent norepinephrine (NE) inhibition of PGE1-stimulated cAMP production was similar in patients and controls. An increase in alpha-receptor number may result from decreased peripheral NE secretion in IOH and MSA. Increased alpha-receptor number and decreased cAMP production, which accompany essential hypertension, may contribute to the supine hypertension of IOH, and an increase in alpha-receptor number may contribute to the supine hypertension of MSA. SOH patients appear to have no abnormalities of alpha-receptor function.

Rapid interferon-gamma-stimulated tyrosine phosphorylation of cytosolic and membranal proteins in HL-60 promyelocytic cells.

The involvement of tyrosine phosphorylation in the early stages of interferon-gamma (IFN gamma)-induced monocytic differentiation of HL-60 cells was studied. Immunoblotting analysis demonstrated that IFN gamma induced rapid changes in the tyrosine phosphorylation of several endogenous cytosolic and membranal proteins. The most prominent of these polypeptides was a 84 kDa protein. In membranes, the IFN gamma-induced phosphorylation of this protein was detectable in 5 min, remained elevated for 3 h and declined thereafter, while a gradual decrease in the phosphotyrosine content was observed in cytosols. In parallel, a 40% increase in the phosphotyrosine phosphatase activity was detected in the later stages of IFN gamma treatment. Rapid changes in tyrosine phosphorylation were detected also in a 64 kDa protein. In contrast, 2-day exposure to IFN gamma was needed to potentiate significantly the tyrosine phosphorylation of a 36 kDa membranal polypeptide. These data support the involvement of tyrosine phosphorylation in the early stages of IFN gamma-induced monocytic differentiation of HL-60 cells.

Partial deletion of distal 17q.

A newborn female was found to have a deletion of the terminal portion of 17q. Prominent manifestations included microcephaly, apparent hypertelorism, epicanthic folds, a broad nasal bridge with anteverted nostrils, posteriorly angulated ears, micrognathia, widely spaced nipples, arachnodactyly with proximal thumbs, and a coxa vara deformity. The unbalanced translocation was inherited from the mother, who had a reciprocal translocation involving the terminal portions of 2p and 17q. To the best of our knowledge, this is the first report of a liveborn infant with deletion of the distal portion of 17q with the exception of reports of patients with ring chromosome 17.

Successful antidepressant treatment of nonparaphilic sexual addictions and paraphilias in men.

Nine of 10 consecutively evaluated men with DSM-III-R nonparaphilic sexual addictions or paraphilias noted improvement in sexual behaviors and depressive symptomatology while treated with fluoxetine, imipramine, or lithium. Depression was measured by means of the Inventory to Diagnose Depression. Sexual behavior was assessed in two dimensions, nonconventional interest and intensified desire, as measured by total sexual outlet. The author conceptualizes these behaviors as sexual dysregulation disorders associated with a primary mood disorder.

A comparative study of nonparaphilic sexual addictions and paraphilias in men.

BACKGROUND: A definition of nonparaphilic sexual addiction (NPSA) is offered and the literature suggesting comorbidity between NPSA and paraphilias (PAs) is reviewed. We describe a study to clarify the relationship between NPSA and PA. METHOD: Thirty consecutive male respondents to an advertisement (PA: N = 15; NPSA: N = 15) were evaluated. The frequency of sexual behaviors, total sexual outlet, intensity of sexual desire, time spent in unconventional sexual behaviors, and a total sexual interest ratio were measured. Group differences were statistically examined using the Fisher's exact probability test (one-tailed). Concomitant psychological, social, work, financial, legal, and medical sequelae were ascertained. RESULTS: The most prevalent lifetime sexual behaviors in both groups were NPSAs, especially compulsive masturbation, ego-dystonic promiscuity, and dependence on pornography. Mean total sexual outlet in both groups was approximately three times that of a comparable "normal" male sample. Components of total sexual outlet were reported in a nonnormative distribution pattern, and NPSA/PA sexual behaviors eclipsed conventional sexual activities in all measures. Group differences in measures of sexual behavior frequency, intensity, and time consumed by these behaviors were not statistically significant. CONCLUSION: The cormorbid presence of multiple NPSAs in 93% of the paraphilic men accompanied by comparable sexual and psychosocial sequelae suggests that NPSAs may represent a culturally adapted form of psychopathology that can also be manifested as PAs. A definition of hypersexual desire is offered, and a relationship between hypersexual desire and unconventional sexual outlet is suggested.

Fluoxetine treatment of nonparaphilic sexual addictions and paraphilias in men.

BACKGROUND: Paraphilias (PAs) and non-paraphilic sexual addictions (NPSAs) may be behaviors that share a common perturbation of central serotonin neuroregulation as a component of their pathophysiology. Fluoxetine was selected as an agent that might mitigate these behaviors, based on the observations that PAs and NPSAs are associated with depression, compulsion, impulsivity, and disinhibited aggression. METHOD: Twenty men (PA, N = 10; NPSA, N = 10) recruited through newspaper advertisement were evaluated for depression and sexual behaviors at baseline and 4-week intervals while receiving fluoxetine pharmacotherapy in an open trial. Sixteen men completed the drug trial. Outcome was determined at 12 weeks using a single-factor, repeated-measures design and an analysis of variance. The general linear models procedure was used to test each of nine dependent measures. RESULTS: Nineteen (95%) of 20 men met non-exclusionary DSM-III-R criteria for dysthymia and 11 men (55%) met criteria for current major depression. At baseline, the paraphilic and the nonparaphilic subgroups were comparable in most intergroup measures of sexual function except total sexual outlet. PAs shared extensive comorbidity with NPSAs (100%). At outcome, statistically significant effects (p < .05) of fluoxetine were found in both groups over time for all variables pertaining to depression and PA/NPSA sexual behaviors. Statistically significant reduction in PA/NPSA response was evident by Week 4, while conventional sexual behavior was not adversely affected by pharmacotherapy. CONCLUSION: Men seeking treatment for PAs/NPSAs reported current depressive symptoms accompanied by a positive history of mood disorders, especially dysthymia and major depression. Fluoxetine selectively reduced both PA and NPSA behaviors in men reporting the presence of mild-severe depressive symptoms. Treatment response of PAs/NPSAs at outcome was independent of baseline depression score. Enhancement of central serotonin neurotransmission by fluoxetine may ameliorate symptoms of mood disorder, heightened sexual desire, and compulsivity/impulsivity associated with these conditions.

Preliminary observations of DSM-III-R axis I comorbidity in men with paraphilias and paraphilia-related disorders.

BACKGROUND: We describe a comorbidity study of DSM-III-R-defined Axis I diagnoses comparing male outpatient paraphiliacs to men with nonparaphilic forms of sexual impulsivity designated as paraphilia-related disorders. METHOD: Data were prospectively collected from 60 consecutively evaluated outpatient males, aged 21-53 years, seeking treatment for the principal disorders of paraphilias (N = 34) and/or paraphilia-related disorders (N = 26). Subjects completed a semistructured psychiatric Intake Questionnaire and Sexual Inventory. The lifetime prevalence of DSM-III-R Axis I diagnoses, including disorders of sexual impulsivity, was assigned by follow-up psychiatric interviews. RESULTS: Both groups of men were diagnosed with an elevated lifetime prevalence of mood disorders (76.7%), especially early-onset dysthymia (53.3%); psychoactive substance abuse (46.7%), especially alcohol abuse (40.0%); and anxiety disorders (46.7%), especially social phobia (31.6%). The predominant forms of sexual impulsivity reported by both groups were "nonparaphilic" paraphilia-related disorders: compulsive masturbation (73.3%), protracted promiscuity (70.0%), and dependence on pornography (53.3%). CONCLUSION: There were no major differences in lifetime Axis I diagnoses to differentiate men with paraphilic disorders from those with paraphilia-related disorders. Both groups were likely to acknowledge multiple paraphilias and/or multiple paraphilia-related disorders suggesting that sexual impulsivity has diverse manifestations, which can include culturally "deviant" as well as "normative" behaviors. Several hypotheses regarding the possible etiologic relationship between depressive disorders and sexual impulsivity are suggested.

Attention-deficit/hyperactivity disorder in males with paraphilias and paraphilia-related disorders: a comorbidity study.

BACKGROUND: We describe a study of DSM-III-R Axis I diagnoses of lifetime comorbid nonsexual disorders in 60 males with paraphilias (PAs; N = 42) and nonparaphilic forms of sexual impulsivity-designated paraphilia-related disorders (PRD; N = 18). METHOD: Subjects completed a semistructured intake questionnaire and sexual inventories, the Inventory to Diagnose Depression, and the Wender Utah Retrospective Scale for the diagnosis of childhood attention-deficit/hyperactivity disorder (ADHD). The lifetime prevalence of Axis I diagnoses of both sexual and nonsexual disorders was ascertained from the aforementioned data and follow-up psychiatric interviews. RESULTS: Subjects in both PA and PRD groups were diagnosed as having a lifetime prevalence of any mood disorder (71.7%), especially dysthymic disorder (66.7%); any anxiety disorder (43.3%), especially social phobia (28.3%); any psychoactive substance abuse disorders (45.0%), especially alcohol abuse (30.0%); and any impulse disorders NOS (25.0%), especially speeding/reckless driving (16.7%). The only diagnosis that statistically significantly distinguished the PA from the PRD sample (p = .01) was retrospectively diagnosed childhood ADHD, identified in 40.0% of the total sample (50.0% PA vs.16.7% PRD). Childhood ADHD was associated with the presence of educational and behavioral problems, lower current mean income, social/legal consequences associated with antisocial impulsivity, cocaine abuse, increased prevalence of comorbid lifetime mood and impulse disorder NOS, and more diagnoses of lifetime Axis I nonsexual and sexual disorders. CONCLUSION: Although depressive disorders were the most common Axis I diagnoses across groups, childhood ADHD was the only Axis I disorder statistically significantly associated with paraphilias, socially deviant and aggressive forms of sexual impulsivity.

Psychostimulant augmentation during treatment with selective serotonin reuptake inhibitors in men with paraphilias and paraphilia-related disorders: a case series.

BACKGROUND: We describe an open trial of psychostimulants (primarily methylphenidate sustained release [SR]) added to selective serotonin reuptake inhibitors (SSRIs; primarily fluoxetine) during the course of pharmacologic treatment of men with paraphilias and paraphilia-related disorders (PRDs). METHOD: Twenty-six men with paraphilias (N = 14) or PRDs (N = 12) were assessed for life-time mood disorders and attention-deficit/hyperactivity disorder (ADHD) as defined by DSM-IV. All men were assessed at baseline for total sexual outlet and average time per day associated with paraphilia/PRD sexual behaviors. The indications for the addition of a psychostimulant to a stable dose of SSRI included the retrospective diagnosis of ADHD with persistent adult symptoms despite pharmacotherapy with an SSRI (N = 17); residual paraphilia/PRD fantasies, urges, and activities despite SSRI pharmacotherapy (N = 16); the persistence or presence of residual depressive symptoms despite SSRI pharmacotherapy (N = 6); relapse or loss of SSRI efficacy during the treatment of sexual impulsivity disorders (N = 4); and treatment of SSRI-induced side effects (N = 4). RESULTS: SSRI pharmacotherapy (mean +/- SD duration = 8.8+/-11.1 months) had statistically significant effects in diminishing paraphilia/PRD-related total sexual outlet (p < .001) and average time/day spent in paraphilia/PRD sexual behavior (p < .001). Addition of methylphenidate SR (mean dose = 40 mg/day; mean +/- SD duration = 9.6+/-8.2 months) was associated with additional statistically significant effects on paraphilia/PRD-related total sexual outlet (p = .003) and average time per day (p = .04) in addition to improvement of putative residual ADHD and depressive symptoms. CONCLUSION: Methylphenidate SR can be cautiously and effectively combined with SSRI antidepressants to ameliorate paraphilias and paraphilia-related disorders for the indications listed above.

Dopamine receptor binding in rat striatum: ultradian rhythm and its modification by chronic imipramine.

To investigate diurnal variations in dopamine receptor binding, the amount of specifically bound 3H-spiroperidol was measured at 4-h intervals over a 24-h period in the striatum of rats which had been housed under a controlled 12-h light-dark cycle (lights on 7 a.m.). A highly significant ultradian rhythm with peaks at 2 a.m. and 2 p.m. was found with an amplitude of about 75%. Chronic imipramine modified the rhythm such that the two peaks occurred 4 h later and amplitude as well as 24-h mean of binding decreased. Scatchard analysis at times of least and greatest binding indicated that the differences in binding were due not to changes in the affinity, but in the number of binding sites. These results are interpreted with regard to the mode of action of psychoactive drugs and to postulated changes of receptor sensitivity in neurological and psychiatric disorders.