Catecholamines in murine bone marrow derived mast cells.

Cultured murine bone marrow derived mast cells (BMMC) were found to store high levels of dopamine (3753+/-844 pg/10(7) cells) and occasionally produce norepinephrine and epinephrine. The catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine, decreased intracellular catecholamine concentrations, and activation with ionomycin stimulated dopamine release. Neither dopaminergic receptor antagonists nor exogenous dopamine < or =10 microM affected IL-3-induced cell proliferation. High exogenous dopamine (20-100 microM) decreased proliferation and increased apoptosis, and the anti-oxidant ascorbic acid prevented these effects. Increased expression of the anti-apoptotic factor Bcl-2 or loss of pro-apoptotic Bax expression attenuated dopamine-induced apoptosis, suggesting the apoptosis proceeds through a mitochondrial pathway.

A study of the potential confounding effects of diet, caffeine, nicotine and lorazepam on the stability of plasma and urinary homovanillic acid levels in patients with schizophrenia.

Ten men inpatients who met DSM-III-R criteria for schizophrenia participated. On five occasions at least one week apart, each subject had an intravenous line placed at 0730 after an overnight fast. On each occasion blood samples were drawn at 0800 and hourly thereafter through 1200 noon for measurement of plasma homovanillic acid (HVA). Total four-hour urine collections were obtained for measurement of urinary HVA. Subjects received five experimental conditions, in randomized sequence: no intervention, smoking one cigarette per hour, drinking one caffeinated cola per hour, lorazepam 2 mg IV push, or a high monoamine meal. Baseline (0800) plasma HVA measures showed only minor intrinsic variability. The average standard deviation in baseline plasma HVA over five occasions of measurement was low relative to the changes in HVA produced during treatment with antipsychotic medications. The high monoamine meal significantly elevated plasma HVA, with a similar trend for urinary HVA. Neither caffeine, nicotine, nor lorazepam significantly affected plasma or urinary HVA.

Impaired distribution of alpha-methyl-L-p-tyrosine in diabetic rats.

Although alpha-methyl-L-p-tyrosine (alpha-MPT), an inhibitor of catecholamine synthesis, has been used to study catecholamine turnover in diabetic animals, effects of diabetes on metabolism of the drug have not been investigated. In this study, administration of a standard dose of alpha-MPT (250 mg/kg initially and 125 mg/kg at 2 h intervals) resulted in lower plasma and tissue levels of alpha-MPT and its metabolites in streptozocin-diabetic rats than in controls. Two to six hours after the initial dose of alpha-MPT, concentrations of alpha-MPT were 2-8-fold lower in the hypothalamus, medulla/pons, and plasma of diabetic animals than in controls. Brain and plasma levels of the alpha-MPT metabolite, alpha-methyl DOPA (alpha-MD) were 2-10-fold lower in tissues of diabetic animals. Levels of the alpha-MPT metabolite alpha-methyl norepinephrine (alpha-MNE), measured only in the hypothalamus, were 4-fold lower in diabetic rats than in controls. There were no differences in the ratio of free/conjugated alpha-MPT in plasma. Treatment of diabetic rats with insulin restored alpha-MPT and alpha-MD to control levels. These findings indicate that i.p. administration of alpha-MPT does not result in equivalent levels of the drug in diabetic and control rats and suggest caution in the use of alpha-MPT to compare catecholamine turnover in diabetic and healthy animals.

Cardiovascular responses and central catecholamines in streptozocin-diabetic rats.

Brain catecholamine levels, spinal cord levels of the norepinephrine metabolite methoxy-hydroxy-phenylglycol (MHPG), and heart rate were measured in nondiabetic and streptozocin-diabetic rats after sham surgery or bilateral carotid ligation. Although carotid ligation increased heart rate in both diabetic and nondiabetic rats, in diabetic animals the response did not differ from the response to sham surgery. Carotid ligation increased epinephrine concentrations in the medulla/pons of diabetic animals but was not associated with alterations in other central catecholamines. In all diabetic rats spinal ratios of MHPG/norepinephrine (an index of noradrenergic activity) were higher than in nondiabetics, and the change in heart rate (post-surgical-pre-surgical rate) correlated inversely with hypothalamic dopamine (R = -0.60). In sham-operated diabetic rats there were high inverse correlations of the change in heart rate with medullary epinephrine and of pre- and post-surgical heart rate with spinal MHPG/NE (R = -0.87 to -0.95). Central catecholamines and heart rate were not correlated in nondiabetic animals and correlated only weakly when nondiabetic and diabetic animals were pooled. Correlations in diabetic animals were usually abolished or reduced by carotid ligation. These findings suggest a link between central catecholamines and heart rate in diabetic rats subjected to surgical stress. Whether catecholaminergic neurons contribute to abnormal chronotropic responses in diabetic rats or respond to stimuli that affect both heart rate and neural function remains to be determined.

Identification of metabolites of 3,4-methylenedioxymethamphetamine in rats.

Liquid chromatography with electrochemical detection (LC/ECD) and gas chromatography/mass spectrometry (GC/MS) were used to identify metabolites of N-methyl-3,4-methylenedioxyamphetamine (MDMA) in samples of rat plasma and urine. Several potential metabolites, based on what is known about the metabolism of the desmethyl analog (i.e., MDA), were synthesized as standards to aid in the identification of the MDMA metabolites. MDA and N-methyl-1-(4-hydroxy-3-methoxy-phenyl)-2-aminopropane (3b) were identified in urine by HPLC and confirmed by GC/MS. 1-(4-Hydroxy-3-methyoxyphenyl)2-aminopropane, (3a), N-methyl-1-(3-hydroxy-4-methoxyphenyl)-2-aminopropane (2b) and 1-(3,4-dihydroxyphenyl)-2-aminopropane (4a) were tentatively identified by LC/ECD but insufficient sample size precluded confirmation by mass spectrometry. MDA was also identified in brain and plasma extracts. Because MDA is a metabolite of MDMA in humans, and because it has been speculated that the neurotoxic effects of MDA and MDMA may be due to a metabolite, the results of the present study may ultimately aid our understanding of the neurotoxic mechanism of these drugs of abuse.

Relation of serum molindone levels to serum prolactin levels and antipsychotic response.

The antipsychotic drug molindone is considered to be atypical in its mode of action and to have mild side effects. Currently no data are available on the range of serum levels of this drug during treatment. By means of a high performance liquid chromatographic technique, serum molindone levels were measured in 14 psychotic patients receiving a wide range of doses of this drug. Molindone levels as high as 350 ng/mL were obtained and were not associated with any toxic effects. Significant relations were noted between the serum level of the drug and both serum prolactin level and treatment response. The authors suggest that molindone may have a range of serum levels consistent with therapeutic benefit. Serum molindone and prolactin levels might help assess resistance to molindone treatment.

Activation of cortical tryptophan hydroxylase by acute morphine treatment: blockade by 6-hydroxydopamine.

Acute morphine produced a dose-dependent, naloxone-sensitive, reversible increase in tryptophan hydroxylase activity in low speed supernatants of midbrain, pons-medulla and cerebral cortex but not spinal cord. The increase in cortical enzyme activity was blocked by 6-hydroxydopamine pretreatment, could be reversed in vitro by incubation with alkaline phosphatase and was non-additive with the increase in enzyme activity induced in the presence of phosphorylating conditions. Morphine administration produced an increase in Vmax but no change in Km of cortical enzyme for substrate, tryptophan, or the artificial reduced pterin cofactor, 6-methyl-5,6,7,8-tetrahydropterin. The failure of morphine to increase spinal tryptophan hydroxylase activity despite enhancement of enzyme activity in medulla indicates regional differences in responsiveness of the enzyme to in vivo activation.

Phencyclidine in CSF and serum: a case of attempted filicide by a mother without a history of substance abuse.

A previously healthy 30-year-old black woman with no history of substance abuse was hospitalized after she attempted to drown her 4-year-old son. She had become progressively confused and delusional after a flu-like illness 2 weeks before. Serum and lumbar CSF samples assayed for phencyclidine (PCP) by gas chromatography-mass spectrometry with d5 PCP as an internal standard were positive. The patient recovered rapidly after treatment with haloperidol and acidification of her urine. Suspicion of PCP abuse should remain high among patients with psychosis, even for those with no history of substance abuse.

Tryptophan hydroxylase: increase in activity by electrical stimulation of serotonergic neurons.

Electrical stimulation of the rat midbrain dorsal raphe nucleus, which contains clusters of 5-HT containing cell bodies, increased the activity of tryptophan hydroxylase prepared in low speed supernatant extracts from cerebral cortex, a region containing 5-HT projections arising from the dorsal raphe nucleus. In contrast, activity of enzyme from hippocampus, which receives its 5-HT innervation primarily from the median raphe was unaffected by dorsal raphe stimulation. The activity of cortical enzyme increased maximally at a stimulation frequency between 10 and 15 Hz. The increase in activity took 20 min to reach maximum at a stimulation frequency of 10 Hz and had returned to control levels 30 min after cessation of stimulation. The increase in enzyme activity is associated with a significant increase in V(max) without any change in K(m) for substrate tryptophan or the artificial reduced pterin cofactor, d-6-methyl-5,6,7,8-tetrahydropterin. These findings may provide a basis for the increase in synthesis of 5-HT which occurs in response to nerve stimulation through the enhanced conversion of tryptophan to 5-hydroxytryptophan.

Posttraumatic stress disorder from pentaborane intoxication. Neuropsychiatric evaluation and short-term follow-up.

Fourteen individuals briefly exposed to a toxic industrial compound, pentaborane, were evaluated for neuropsychiatric abnormalities four to 12 weeks after exposure. Results of physical, neurological, and routine laboratory evaluations were normal. Initial and persistent psychiatric symptoms, neuropsychological deficits, electroencephalographic changes, elevated central nervous system neurotransmitter levels, and ventricular brain ratios (computed tomographic scan) provide evidence of central nervous system damage. Seven patients met diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, ed 3, for posttraumatic stress disorder, and seven patients had neuropsychological test evidence of mild brain dysfunction. No statistically significant relationship was found between neuropsychiatric test results and psychiatric diagnoses. These results contradict previous literature that reports most symptom resolution within the first week after exposure to pentaborane. Results suggest that patients suffered a combination of organic brain insult and psychological trauma.

Brain ventricular size and CSF monoamine metabolites in an adolescent inpatient population.

The cerebrospinal fluid monoamine metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA), were compared with ventricle-brain ratios (VBRs) in a group of adolescent inpatients who were divided into psychotic and nonpsychotic groups. HVA, 5HIAA, and VBR did not differ significantly between the two groups. There were no significant relationships between these variables in the nonpsychotic group. Psychotic adolescents, however, displayed significant negative correlations between VBR and HVA, and between VBR and 5HIAA. The relationship between VBR and monoamine metabolites appears to occur in psychoses other than schizophrenia, is present early in the course of illness, and probably does not represent a dilutional effect.

Amphetamine response in borderline patients.

The behavioral and biological responses to d-amphetamine have been studied extensively in patients with schizophrenia and depression, and to a lesser degree in bipolar affective disorders. Because of theories linking borderline personality disorder to those illnesses, amphetamine, 30 mg, p.o., was administered to eight borderline patients in a double-blind, placebo-controlled study and the results were compared to the responses of normal subjects under identical conditions. Amphetamine led to symptoms of psychosis in four out of eight (50%) borderline patients. No normal subject became psychotic during the procedure. Global ratings of well-being were significantly elevated in the borderline group compared to the normal group. In addition the global response was highly inversely correlated with the patient's score on the Diagnostic Interview for Borderlines. Borderline patients had a nonsignificantly decreased growth hormone response following amphetamine compared to normals. Thus, borderline patients appear to be pharmacodynamically separable from normals.

Effect of clonidine on the activity of tryptophan hydroxylase from rat brainstem following in vivo or in vitro treatment.

In vivo administration of clonidine hydrochloride (Catapres) via tail vein injection produced a rapid increase in brainstem tryptophan hydroxylase activity assayed in vitro under subsaturating conditions of reduced pterin cofactor, 6MPH4. Enzyme activity returned to and remained at control levels about 60 min after treatment with low doses of clonidine (5 micrograms/kg). However, with higher doses of the drug (15 micrograms/kg), enzyme activity fell to below control levels for about an hour. Incubation of brainstem slices with clonidine also produced a dose-dependent increase in enzyme activity. The increase in enzyme activity appears to be mediated indirectly since it was abolished when brain catecholamine levels were depleted by pretreatment with 6-hydroxydopamine 8 days prior to clonidine treatment. The kinetic properties of tryptophan hydroxylase prepared 25 and 90 min after clonidine administration indicate that the initial increase and subsequent decrease in enzyme activity seen under these conditions may be due to changes in apparent Vmax of the enzyme.

The neuroendocrine and behavioral response to dextroamphetamine in normal individuals.

Dextroamphetamine 30 mg and placebo were administered by mouth in a double-blind randomized cross-over trial to ten subjects. Behavior was assessed and blood samples analyzed for growth hormone (GH), prolactin (PRL), homovanillic acid (HVA), and amphetamine. There was a statistically significant increase in well-being following d-amphetamine as compared to baseline and placebo on both the Amphetamine Interview Rating Scale and the Hopkins Mood Scale. No subject became psychotic. There was a statistically significant increase in GH from baseline to peak following d-amphetamine ingestion. When compared to placebo, the increase in GH was invariable and statistically significant for the 90-min sampling. PRL decreased from baseline following both d-amphetamine and placebo and there was no significant drug-placebo difference. Serum HVA was measured at baseline and 120 min, for eight subjects. Six subjects had an increase in HVA following d-amphetamine but there was no significant drug effect.

Beyond the therapeutic window: a case presentation.

The relationship of haloperidol dose and plasma concentration to psychotic symptoms of schizophrenia is described. The authors present evidence supporting a therapeutic window hypothesis, in which an individual patient's course follows an inverted U curve. The clinical implications for dosage strategies are discussed.