Enduring changes in dopamine receptor cells of pups from drug administration to pregnant and nursing rats.

A decrease in specific [3H]spiroperidol binding to rat caudate tissue and a parallel decrease in sensitivity to apomorphine in eliciting stereotyped behavior was observed in the offspring of rat mothers treated with either haloperidol or alpha-methyl-p-tyrosine-methyl ester during pregnancy. In contrast, evidence of increased dopamine-receptor sensitivity was observed in the pups if haloperidol was administered to their mothers postpartum during nursing rather than during pregnancy.

5-methyltetrahydrofolic acid is not a methyl donor for biogenic amines: enzymatic formation of formaldehyde.

Contrary to previous reports, 5-methyltetrahydrofolic acid does not mediate the methylation of dopamine to epinine. Instead, this methyl donor is degraded enzymatically to formaldehyde, which condenses with dopamine to form a tetahydoisoquinoline derivative. The latter has chromotographic characteristics very similar to those of epinine, which likely accounts for the original misidentification of the product.

Plasma homovanillic acid as a predictor of response to neuroleptics.

Fourteen schizophrenic subjects were evaluated for degree of psychosis before and after treatment with the antipsychotic drug haloperidol and for plasma homovanillic acid concentration after four and 28 days of treatment. A significant correlation was found between an increase in homovanillic acid concentration on day 4 or a decrease from day 4 to day 28 and the degree of improvement after four weeks of treatment. Thus, those patients who had the greatest change in plasma homovanillic acid in response to neuroleptic blockade showed the greatest improvement. These and other observations have led us to propose that the central dopaminergic system, through adaptive changes in activity, serves as a physiologic buffer system protecting against destabilization of mental function from diverse biologic or psychologic insults.

A phosphoinositide-linked dopamine D1 receptor mediates repetitive jaw movements in rats.

BACKGROUND: We have demonstrated that rats injected with D1 agonists SKF 38393 or A68930 demonstrate repetitive jaw movements (RJM). These agonist-induced movements in rats are similar in their appearance to those induced in rats by long-term treatment with antipsychotic drugs. Over recent years D-1 receptors were discovered which showed linkage not only to c-AMP but also to PI hydrolysis. We examined the effect of EEDQ inactivation of D1 receptors on D-1 mediated PI hydrolysis and RJM. METHODS: Twenty four hours following EEDQ or vehicle administration D-1 agonists or vehicle were administered. The number of RJM episodes was assessed in EEDQ and vehicle treated rats. D-1 receptor density and inositol phosphate formation were determined in the striata. RESULTS: EEDQ administration resulted, 24 hours later, in 70-80% selective depletion of D-1 receptors in the striata but did not modify the rate of RJM induced by D-1 agonists. There was no significant difference in D-1 mediated PI hydrolysis in EEDQ treated rats when compared to vehicle treated group. CONCLUSIONS: The present data support the earlier demonstration of D-1 agonist induced RJM, an effect mediated by a subpopulation of a D-1 receptor subtype and constitute the first behavioral evidence for the existence of a behavioral response mediated by D-1 like dopamine receptors linked to an alternate second messenger system-PI hydrolysis.

Phenethylamine in normal urine: failure to verify high values.

The phenethylamine (PEA) level in daytime urine samples of 18 normal subjects was measured by an isotope dilution technique. Purification of PEA from other urinary substance, after the addition of 1-14C-PEA to urine samples, was achieved by the sequence: thin-layer chromatography (TLC), derivatization, TLC, and finally, gas chromatography (electron capture). The estimated mean daily output of PEA was 10.3 mug/day. A circadian rhythm was not evident on the basis of analyses of 24-hr urine collections from four normal subjects. Three acute schizophrenics had levels within the normal means.

Human platelet MAO in drug-free and medicated schizophrenic patients.

The authors compared platelet monoamine oxidase activity in drug-free chronic and acute schizophrenic patients, medicated chronic schizophrenic patients, and normal controls. A significant decrement in MAO activity was found only in medicated chronic schizophrenic patients. The possible mechanism for this finding is discussed.

Paradoxical reaction to L-dopa in schizophrenic patients.

The authors administered 6 g of L-dopa to 8 schizophrenic patients and 750 mg of chlorpromazine to 7 schizophrenic patients. Chlorpromazine showed only a modest advantage over L-dopa and only on some Brief Psychiatric Rating Scale factor scores, and at maximum dosage the thought disturbance factor score in the L-dopa-treated group was not worse than at baseline. The results suggest that L-dopa is associated more with toxic than with schizophreniform symptoms and that there is adaptation to its effects. The authors discuss implications of these findings for the dopamine hypothesis of schizophrenia.

Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life.

OBJECTIVE: This study was designed to evaluate the comparative efficacy and safety of sertraline and nortriptyline for the treatment of major depressive disorder in older adults. METHOD: A double-blind, parallel group design was used to compare 210 outpatients, 60 years of age and older, who met DSM-III-R criteria for major depressive episode and had a minimum Hamilton Depression Rating Scale score of 18. The patients were randomly assigned to 12 weeks of treatment with either sertraline (50-150 mg/day) or nortriptyline (25-100 mg/day). RESULTS: The safety profiles of the two treatments were similar except that nortriptyline treatment was associated with a significant increase in pulse rate, whereas sertraline was associated with a nonsignificant decrease. Efficacy of both drugs was similar for both treatments at all time points, with 71.6% (N=53 of 74) of the sertraline-treated patients and 61.4% (N=43 of 70) of the nortriptyline-treated patients achieving responder status by week 12. Time to response was also similar, with more than 75% of the improvement in scores on the Hamilton depression scale having occurred by week 6. Secondary efficacy measures (posttreatment measures of cognitive function, memory, and quality of life) revealed a significant advantage for sertraline treatment. CONCLUSIONS: Primary efficacy measures showed sertraline and nortriptyline to be similarly effective. With secondary outcome measures there was consistent evidence of an advantage for the sertraline-treated group. The clinical impact of these measures on the long-term well-being of elderly depressed patients should be examined in a study of maintenance treatment.

Gilles de la Tourette's syndrome. Familial occurrence and precipitation by methylphenidate therapy.

Gilles de la Tourette's syndrome was independently ascertained in two male cousins once removed. Previous studies have shown familial clustering of individuals with tics, but no consistent pattern of inheritance of Tourette's syndrome has been apparent. The onset and later exacerbation of symptoms in our younger patient were associated with the administration of CNS stimulants given for excessive motor activity. The adverse effects of methylphenidate and dextroamphetamine therapy on Tourette's syndrome supports the hypothesis that this condition results from a relative excess of CNS catecholaminergic activity. Physicians prescribing these agents should inquire about the presence of tics in patients and their families.

Repeated inescapable stress produces a neuroleptic-like effect on the conditioned avoidance response.

This study tests the hypothesis that the dopaminergic system mediates a restitutive response by decreasing its own activity in the face of events like persistent inescapable stress that threaten to interrupt organized mental activity. It is well established that neuroleptic drugs inhibit the conditioned avoidance response (CAR), but not the escape response, probably via a reduction in subcortical dopaminergic activity. We trained rats to perform the CAR and then subjected them to acute and chronic stress to determine whether this would result in inhibition of the CAR. Rats subjected to twice daily tailshock stress for 8 days showed inhibition of the CAR and a reduction in dopamine (DA) utilization in the nucleus accumbens. These findings are compatible with the hypothesis that an endogenous DA-dependent mechanism exists that mimics neuroleptic effects in the face of repeated stress. In humans this response may serve as a protection against psychotic decompensation from chronic endogenous or exogenous insult.

Effects of prenatal exposure to neuroleptic drugs on children's growth.

The effect of prenatal exposure to neuroleptic drugs on height and weight from birth to 7 years was examined in children of psychiatrically normal parents and of parents with a history of psychiatric treatment, using data from the Collaborative Perinatal Project of the National Institute of Neurological Diseases, Communicative Disorders, and Stroke. Analysis of covariance was used to control for potential confounding factors. We found that prenatal exposure to dopamine receptor-blocking neuroleptic drugs was associated with increased height in one or more of our groups at 4 months, 1 year, and 7 years and less consistently with increased weight. Seven-year-old children who had been exposed to these drugs for more than 2 months during gestation were approximately 3 cm taller than unexposed controls (p less than 0.05). Prenatal exposure to dopamine-depleting agents was associated with decreased height at 4 months but not later. Possible mechanisms for these effects, including a permanent decrease in the number of brain dopamine receptors and effects on various hormones, are discussed.

Follow-up of children overexposed to lead.

The purpose of this study is to assess the nature and magnitude of the deleterious health effects of subclinical over-exposure to lead in children. The study stems from concerns about the impact on the health of children in city slums who ingest leaded paint without overt evidence of poisoning and the health implication of rising levels of lead in the environment from automotive emissions. The study sample was derived mainly from a registry of children on whom blood lead determinations had been made by the New York City Department of Health and was supplemented by siblings of the registry cases and children from a lead belt area who had extractions of deciduous teeth in dental clinics. Information was obtained through parental interview, medical records, and psychometric evaluation. The data show that deleterious health effects occur in children who were treated for severe lead poisoning and in children without diagnosed lead poisoning who had elevated blood leads (>/=0.06 mg-%). In the absence of diagnosed lead poisoning or elevated blood leads, excess lead exposure, measured in terms of high levels of lead in teeth, was not associated with deleterious health effects.

Schizophrenia: gender, family risk, and plasma homovanillic acid.

Plasma homovanillic acid concentration was assessed in 60 young schizophrenic patients, with and without first-degree relatives with schizophrenia, before treatment, and 3 days after starting haloperidol treatment. The baseline concentration of homovanillic acid in plasma was no different in the two groups before treatment; it was, however, significantly higher in the patients with relatives than in those without relatives diagnosed of schizophrenia after 3 days of haloperidol treatment.

A comparison of the onset of action and therapeutic efficacy of amoxapine and amitriptyline.

A total of 61 moderately to severely depressed outpatients were treated for four weeks with either amoxapine (a dibenzoxapine tricyclic) or amitriptyline. This double blind study showed that amoxapine was as effective as amitriptyline and had an earlier onset of action. Maximum doses used were 300 mg of amoxapine and 150 mg of amitriptyline. Side effects were similar for the two drugs, except for impotence or loss of libido in eight male amoxapine, as against three amitriptyline patients. Laboratory, EKG, and vital signs findings showed no pathological trends.

Onset of action of amoxapine and doxepin in outpatients with "mixed anxiety/depression".

In a parallel-group double-blind study, 142 outpatients with "mixed anxiety/depression" were treated with amoxapine or doxepin for 4 weeks in mean maximum daily dosages of 260 mg and 130 mg, respectively. Patients in both groups improved significantly during treatment as shown by changes in the Hamilton, Zung, Patient Self-Evaluation, and Clinical Global Impressions scales. From 24 to 31 of the 71 subjects receiving amoxapine and 16 to 24 of the 71 receiving doxepin were rated as "unquestionably improved" at the end of the treatment period on these scales. The time to achieve this degree of response was significantly shorter with amoxapine on both the CGI (p = .018) and Hamilton (p = .005) scales. Side effects were roughly comparable with two exceptions: doxepin-treated patients experienced more daytime drowsiness (p less than or equal to .05) and amoxapine-treated patients experienced more constipation (p less than or equal to .01).

Causes of haloperidol discontinuation in patients with Tourette's disorder: management and alternatives.

BACKGROUND: Neuroleptics are considered the mainstay of treatment in Tourette's disorder, and haloperidol is deemed the treatment of choice by many. Factors such as treatment efficacy and the side effects that appear in response to neuroleptic administration have been implicated in affecting medication compliance. However, a detailed evaluation of these factors has yet to be undertaken in Tourette's disorder. METHOD: Of 51 consecutive referrals to a Tourette's disorder clinic, 48 met DSM-III-R criteria for Tourette's disorder. Of these 48, 28 had previously received neuroleptics. In this set of 28 patients, 24 (16 male, 8 female) had initially received treatment with haloperidol, and they made up the present sample; their ages ranged from 10.4 to 47.9 years (mean = 27.1), and age at onset ranged from 2 to 16 years. Each patient completed an evaluation consisting of a Tourette Syndrome Questionnaire and a clinical interview with the patient and involoved family members. Charts were also reviewed to gather information concerning side effects and other factors that led to haloperidol discontinuation and/or noncompliance. RESULTS: Duration of treatment ranged from 3 days to 14 years (mean = 3.6 years). In this sample, 12.5% (3/24) of the subjects continued medication without interruption (mean +/- SD = 8.4 +/- 5.1 years of medication). Of the 21 patients who discontinued haloperidol, 66.7% (14/21) did so because they experienced intolerable side effects, 9.5% (2/21) because of the fear of experiencing certain side effects, and 14.3% (3/21) because of a combination of these factors. The principal side effects that led to discontinuation included dysphoric reactions, akathisia, nervousness, sedation, dystonic reactions, and cognitive dulling/feeling drugged. CONCLUSION: Careful monitoring of side effects and efficacy is essential to continued compliance with haloperidol. In addition, psychoeducation about potential consequences of medication administration may help promote compliance in those patients who develop fears of possible adverse reactions.

Tonic inhibition of striatal dopamine transmission: effects of benzodiazepine and GABAA receptor antagonists on extracellular dopamine levels.

At present, it is unclear whether ligands which bind at the benzodiazepine/GABA receptor complex play a tonic modulatory role with regard to striatal dopamine (DA) transmission. The present study was designed to examine the effects of Ro15-1788, a benzodiazepine (BZ) receptor antagonist, and SR 95531, a GABAA receptor antagonist, on striatal extracellular DA (DA[e]) concentrations in anesthetized and awake rats using the technique of in vivo microdialysis. Local administration of Ro15-1788 resulted in a dose-dependent increase in DA[e] in both anesthetized and awake animals. The Ro15-1788-induced increase in DA[e] was blocked by coadministration of the BZ agonist diazepam, as well as GABA. Local administration of SR 95531 also resulted in a dose-dependent alteration in striatal DA levels in both anesthetized and awake animals. The SR 95531-induced increase in DA was blocked by coadministration of GABA. The results suggest that GABA may play a tonic inhibitory role with regard to striatal DA transmission.

Alterations in GABAA receptor binding in the prefrontal cortex following exposure to chronic stress.

The present study was designed to examine the effects of chronic stress on GABAA receptor binding. Animals were randomly assigned to either a control, acute, or chronic stress condition and changes in specific binding were assessed using the GABAA receptor antagonist [3H]SR 95531. Exposure to chronic restraint stress led to a significant reduction in GABAA receptor binding in the prefrontal cortex. Alterations in specific binding were not observed in the cerebellum, caudate-putamen, hippocampus, or cingulate cortex however, suggesting that the effects of chronic stress may be regionally specific. Exposure to acute restraint did not lead to a significant alteration in [3H]SR 95531 binding in any brain region examined.

Effects of repeated amphetamine treatment on regional GABAA receptor binding.

The present study examined the effects of repeated exposure to amphetamine on GABAA receptor binding in cortical and subcortical areas. The goal of the study was to determine whether changes in specific binding were related to behavioral sensitization. Animals were exposed to either saline (0.3 ml, s.c.; n=12) or d-amphetamine (2.5 mg/kg, s.c.; n=12) for 6 consecutive days and sacrificed after a 14-day withdrawal period. Differences in GABAA receptor binding in these two groups of animals were assessed using the GABAA receptor antagonist [3H]SR 95531. To verify that the preceding treatment regimen led to the development of behavioral sensitization, a separate set of animals (n=8/group) was exposed to the same regimen and challenged with d-amphetamine (2.5 mg/kg, s.c.) after the 14-day withdrawal period. As expected, preexposure to amphetamine led to the development of amphetamine sensitization. There were no differences in GABAA receptor binding in animals preexposed to saline and amphetamine in the prefrontal cortex, caudate-putamen, hypothalamus, or cerebellum. These findings do not provide support for the idea that changes in GABAA receptor binding in the medial prefrontal cortex or various subcortical areas are related to the development of behavioral sensitization.

Development of specificity and stereoselectivity of rat brain dopamine receptors.

Prenatal exposure to the neuroleptic haloperidol has been reported to produce an enduring decrement in the number of dopamine D2 receptors in rat striatum and a persistent diminution of a dopamine dependent behavior, stereotypy. The ontogeny of rat brain dopamine binding sites has been studied in terms of the kinetic properties and phenotypic specificity in rat fetal brain through early postnatal development. Sites showing some properties of the D2 binding site can be found prior to gestational day (GD) 18, can be labeled with [3H]dopamine or [3H]spiroperidol and can be displaced with dopaminergic agonists and antagonists. Saturation kinetics for specific [3H]spiroperidol has previously been found to occur on or about GD 18. It is of interest that the critical period for the prenatal effect of haloperidol to reduce striatal D2 binding sites, GD's 15-18, coincides with the period during which dopamine binding sites lack true specificity, but can be labeled with dopaminergic ligands. In these experiments the development of stereoselectivity of brain dopamine binding sites has been examined. When rat mothers were given either the neuroleptic (+)-butaclamol or its therapeutically inactive isomer (-)-butaclamol during the critical period GD's 15-18, the number of [3H]spiroperidol binding sites in striata of offspring was significantly reduced by both stereoisomers. This is in marked contrast to the postnatal treatment effect by a neuroleptic in which upregulation of striatal D2 binding sites occurs only by treatment with the therapeutically active isomer (+)-butaclamol. In vitro studies of the direct effect of the stereoisomers of butaclamol indicate that the recognition sites detected during fetal brain development with [3H]spiroperidol do not distinguish between the isomers of butaclamol.(ABSTRACT TRUNCATED AT 250 WORDS)