Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients.

Plasma-free homovanillic acid, a major metabolite of dopamine, was measured in chronically ill schizophrenic patients both before and during treatment with the antipsychotic phenothiazine, fluphenazine. Neuroleptic treatment was associated with a significant time-dependent decrease in plasma homovanillic acid from pretreatment values, which were significantly elevated when compared with those of age- and sex-matched healthy control subjects. Further, both the absolute concentrations as well as the neuroleptic-induced reductions in plasma homovanillic acid determined over 5 weeks of neuroleptic treatment were statistically significantly correlated with ratings of psychosis and improvement in psychosis, respectively. These findings suggest that the delayed effects of neuroleptic agents on presynaptic dopamine activity may more closely parallel their therapeutic actions than do their immediate effects in blocking postsynaptic dopamine receptors and that a decrease in dopamine "turnover" may be responsible for their antipsychotic effects.

[Venezuelan consensus guidelines on the use of magnetic resonance in diagnosis and follow up of patients with multiple sclerosis]. / Consenso venezolano para el uso de la resonancia magnetica en el diagnostico y seguimiento de pacientes con esclerosis multiple.

INTRODUCTION: The clinical use of magnetic resonance (MR) in patients with multiple sclerosis (MS) has advanced markedly over the past few years. Several groups around the world have developed consensus guidelines about the role of MR in MS at diagnosis and during follow up. However, in some regions is difficult to extrapolate the recommendations. AIM: To provide recommendations for the implementation of MR in MS patients at diagnosis and follow up in Venezuela. DEVELOPMENT: A group of experts from Venezuela that included neurologists and radiologists, by using the online surveys methodology as well as face to face meetings developed the intended consensus for the use of MR during the diagnosis and follow up of MS patients in Venezuela. Seventeen recommendations were established based on published evidence and the expert opinion. Recommendations focused on the role of conventional MR techniques and brain atrophy measurement in MS patients both at diagnosis and during follow-up. CONCLUSIONS: The recommendations of this consensus guidelines attempts to optimize the health care and management of patients with MS in Venezuela.

TITLE: Consenso venezolano para el uso de la resonancia magnetica en el diagnostico y seguimiento de pacientes con esclerosis multiple.Introduccion. El uso de la resonancia magnetica (RM) en el diagnostico y seguimiento de pacientes con esclerosis multiple (EM) se ha incrementado considerablemente durante los ultimos años. Diversos grupos de trabajo internacionales han intentado clarificar y normativizar el uso de la RM tanto en el momento del diagnostico como durante el seguimiento de los pacientes. Sin embargo, en muchas ocasiones se extrapolan datos de otras regiones que no contemplan la realidad de cada lugar o son dificiles de implementar. Objetivo. Elaborar un consenso venezolano para el uso de la RM en el diagnostico y seguimiento de pacientes con EM. Desarrollo. Un grupo de expertos de Venezuela, conformado por neurologos y radiologos, mediante metodologia de ronda de encuestas a distancia y reuniones presenciales, llevo adelante la elaboracion del consenso pretendido para el uso de la RM en el diagnostico y seguimiento de pacientes con EM en Venezuela. Se establecieron 17 recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el papel de las tecnicas convencionales de RM, asi como en el de la medicion de la atrofia cerebral en pacientes con EM, tanto en el momento del diagnostico como durante el seguimiento. Conclusion. Las recomendaciones establecidas en el presente consenso permitiran optimizar el cuidado y el seguimiento de los pacientes con EM en Venezuela.

Clinical and biochemical effects of verapamil administration to schizophrenic patients.

We administered verapamil hydrochloride, a calcium channel antagonist, to seven chronically ill schizophrenic patients for five weeks under double-blind, placebo-controlled conditions. No therapeutic effect was noted. Worsening in hostile and uncooperative behaviors and a syndrome of heightened emotional tone was observed during verapamil treatment and during the postverapamil placebo period. Verapamil produced significant increases in cerebrospinal fluid (CSF) and plasma levels of homovanillic acid and in plasma levels of prolactin, as well as significant decreases in plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol. Verapamil and its active metabolite, norverapamil, were partitioned into CSF with CSF/plasma ratios of 0.06 and 0.04, respectively. The lack of therapeutic effects of verapamil in schizophrenic patients differs from earlier reports of its usefulness in treating manic patients. The biochemical and clinical data from our study suggest the possibility that verapamil exerts behaviorally relevant central nervous system activity in schizophrenic patients.

Circadian variation of plasma homovanillic acid levels is attenuated by fluphenazine in patients with schizophrenia.

Plasma homovanillic acid (HVA) levels were measured hourly for a 24-hour period in 10 patients with schizophrenia during treatment with placebo and fluphenazine. Ten age- and sex-matched normal volunteers were similarly studied. Diet and activity were carefully controlled and monitored in both patients and controls. A circadian rhythm of the plasma HVA level was found in controls with a nadir in the afternoon and peak values in the early morning hours; when the patients were free from drugs, they showed a similar rhythm with lower amplitudes. Fluphenazine treatment significantly reduced the plasma concentrations of HVA and abolished the 24-hour rhythm. These data suggest that a 24-hour rhythm of the plasma HVA level exists in humans and that the amplitude of this rhythm may be less pronounced in patients with schizophrenia. Treatment with neuroleptic drugs reduces both the absolute levels and the normal circadian rhythm of the plasma HVA level.

Longitudinal measurement of plasma homovanillic acid levels in schizophrenic patients. Correlation with psychosis and response to neuroleptic treatment.

The plasma levels of homovanillic acid (HVA), a major circulating dopamine (DA) metabolite, were measured in schizophrenic patients during five weeks each of double-blind placebo-controlled neuroleptic treatment (N = 16) and withdrawal (N = 11). Both neuroleptic treatment and withdrawal were associated with time-dependent changes in the plasma levels of HVA; treatment was associated with decreases and withdrawal with increases. The levels of plasma HVA measured longitudinally during both conditions were highly correlated with psychosis ratings. Moreover, changes in individual mean weekly levels of plasma HVA were predictive of treatment response, including changes in both positive and negative symptoms of schizophrenia. These data are consistent with the suggestion that the mechanisms of action of antipsychotic drugs involve, in addition to short-term DA receptor blockade, a slowly developing decrease in presynaptic DA activity.

Neurotransmitter-stimulated inositol phosphate accumulation in hippocampal slices.

The agonist-induced accumulation of [3H]IP in the presence of lithium represents a sensitive method for studying a number of receptor-mediated events in brain. In the presence of lithium, receptor-mediated [3H]IP3 formation in brain is difficult to demonstrate. It is possible that lithium itself may prevent the formation if IP3 and, thus, the presence of lithium in the incubation may account for such a discrepancy. It is likely that the effects of lithium on the PI cascade are more complex then previously envisioned. The recent identification of the inositol polyphosphates, myo-inositol 1,3,4-trisphosphate and myo-inositol 1,3,4,5-tetrakisphosphate, indicates that other inositol phosphates need to be considered in future studies of receptor-mediated PI metabolism.

Differential regulation of mu-opioid receptor mRNA in the nucleus accumbens shell and core accompanying amphetamine behavioral sensitization.

Repeated amphetamine (AMPH) administration results in behavioral sensitization. To investigate the participation of the opioid system in this phenomenon, we examined the effects of acute and repeated AMPH administration on mu-opioid receptor (MOR) mRNA levels in the nucleus accumbens (NAc) and striatum (STR) of rats, by quantitative non-radioactive in situ hybridization. Five injections of d-AMPH (1.5 mg kg-1, i.p., once every other day), resulted in a sensitization response profile and a significant down-regulation of MOR mRNA levels in the NAc shell, whereas no change was observed in MOR mRNA levels in the NAc core compared to the saline controls. Conversely, MOR mRNA levels were up-regulated in the rostral STR of AMPH-sensitized rats compared to saline controls. No changes in MOR mRNA levels were observed after acute AMPH treatment in any of the brain regions studied. These results suggest that the opioid system participates in the neurobiological underpinnings of behavioral sensitization and that opioid receptor (OR) expression in the STR and NAc shell and core is differentially modulated by repeated AMPH exposure.

Differential effects of haloperidol on negative symptoms in drug-naive schizophrenic patients: effects on plasma homovanillic acid.

After 5 weeks of haloperidol, positive symptoms in drug-naive schizophrenic patients substantially subsided. Negative symptoms, although with a different temporal pattern, decreased after the fifth week of haloperidol treatment; specifically, a decrease was seen in anhedonia and affective flattening, whereas avolition-apathy and attentional impairment presented no changes. Alogia showed a decrease during the third week and a trend to return to placebo scores during weeks 4 and 5. Changes in affective flattening, alogia and attentional impairment correlated with changes in positive symptoms. During placebo, plasma homovanillic acid (HVA) correlated with negative symptoms and with changes presented by negative symptoms between the first and the fifth treatment week. These data show that negative symptoms respond differentially to neuroleptics and suggest that avolition-apathy may represent a different behavioral component of the schizophrenia process.

Effects of in vitro ethanol and chronic ethanol consumption on the release of excitatory amino acids in the rat hippocampus.

In CA1-CA3 hippocampal slices, in vitro ethanol (EtOH) (10-100 mM) evoked, as a function of EtOH concentration, a differential release of aspartate (Asp) and glutamate (Glu). Omission of Ca2+ ions from the superfusion media completely abolished the EtOH-induced release of Asp but not that of Glu. In addition, at 20 mM, EtOH enhanced K(+)-evoked release only of Asp. Finally, delayed changes were observed on NMDA-evoked release of [3H]noradrenaline (NA) in the dentate gyrus (DG) after withdrawal from EtOH for 30 days.

Autoradiographic visualization and characterization of [3H]ouabain binding to the Na+,K+-ATPase of rat brain and pineal.

Ouabain binds to the catalytic subunit of Na+,K+-ATPase and specific [3H]ouabain binding can be used as a measure of the number of active enzyme molecules present in a given tissue. Specific [3H]ouabain binding can be demonstrated in frozen, cryostat sections from rat brain and pineal and these sites have the characteristics of Na+,K+-ATPase. Incubations carried out in the absence of ATP or the presence of excess unlabeled ouabain reduces specific binding by greater than or equal to 98%. The addition of K+ or omission of Mg2+ also result in a decrease in specific binding. Strophanthidin, digoxin and digoxigenin displace [3H]ouabain binding with IC50 values of 0.73, 0.48 and 1.4 microM, respectively. Scatchard analyses of specific [3H]ouabain binding in brain sections shows a single class of non-interacting binding sites with an apparent affinity (Kd) of 339 nM and a maximal binding capacity (Bmax) of 34.9 pmol/mg protein. [3H]Ouabain binding is unevenly distributed throughout the brain with the olfactory nuclei, superior colliculus, dentate gyrus, pontine nuclei and pineal gland having a relatively high density of binding sites. The outer layers (1-3) of the cerebral cortex show more labeling than the inner layers (4-6) and most other brain areas have intermediate levels of [3H]ouabain binding sites, whereas white matter has virtually no specific binding. Computer-assisted densitometry was used to measure changes in specific [3H]ouabain binding after kainic acid injection into the caudate nucleus. An initial increase in [3H]ouabain binding was observed at 1 and 24 h after lesioning and a decrease in [3H]ouabain binding was evident by 9 days after lesioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute stress enhances the activity of the GABA receptor-gated chloride ion channel in brain.

The effect of acute swim stress on the functional activity of the gamma-aminobutyric acid (GABA) receptor/chloride ion channel was studied using an assay to measure 36chloride (36Cl-) uptake into rat brain synaptoneurosomes. Muscimol-stimulated 36Cl- uptake in cerebral cortex, hippocampus, but not cerebellum, was enhanced (increased potency and efficacy) in rats subjected to 10 min of swimming, compared to non-stressed, control rats. The effect of swim stress on the activity of the GABA receptor/Cl ion channel was prevented by adrenalectomy.

Chronic corticosterone administration in rats: behavioral and biochemical evidence of increased central dopaminergic activity.

Chronic corticosteroid treatment in humans in frequently complicated by behavioral changes. The present study suggests that chronic steroid administration in rats has distinct neurochemical consequences which are behaviorally relevant. Ten male Sprague-Dawley rats received 7 daily injections of corticosterone, following which they exhibited increased caudate homovanillic acid as well as an attenuated decline in vertical and ambulatory movement (functional measures of dopamine activity) compared to placebo-treated rats. A subgroup of steroid-treated rats which was more behaviorally responsive to corticosterone also showed increased caudate 5-hydroxyindole acetic acid and decreased prefrontal cortex dopamine and serotonin. These results are discussed in relation to the known behavioral side effects of chronic corticosteroid administration in man and the psychiatric manifestations of naturally occurring states of hypercortisolemia.

N-Methyl-D-aspartate receptors and release of newly-synthesized [3H]dopamine in nucleus accumbens slices and its relationship with neocortical afferences.

1. The effects of excitatory amino acid agonists on the release of newly-synthesized [3H]dopamine was examined in slices of nucleus accumbens of the rat. 2. L-glutamate and N-methyl-D-aspartate stimulated the release of newly-synthesized [3H]dopamine, which was completely inhibited by physiological concentrations of magnesium and by the selective and non-competitive antagonist MK-801. 3. Other ligands for excitatory amino acids subtype receptors, such as AMPA and kainic acid, had no effect of newly-synthesized [3H]dopamine release. 4. Frontal cortical ablation produced a significant increase on the N-methyl-D-aspartate-stimulated release of [3H]dopamine. 5. These data suggest that dopaminergic function in the rat nucleus accumbens is modulated by N-methyl-D-aspartate receptors, the sensitivity of which is determined, at least in part, by glutamatergic and/or aspartergic afferents from the frontal cortex.

Effects of D-amphetamine administration on the release of endogenous excitatory amino acids in the rat nucleus accumbens.

1. The effects of acute D-amphetamine administration to rats on the release of endogenous excitatory amino acids from nucleus accumbens slices were studied. 2. D-amphetamine (5 mg/kg and 10 mg/kg; i.p.) significantly increased the spontaneous release of aspartate and glutamate from nucleus accumbens slices. 3. In contrast, D-amphetamine either produced no change or rather decreased K+ (40 mM)-evoked and N-methyl-D-aspartate (100 microM)-evoked release of aspartate and glutamate from the slices, respectively. 4. When D-amphetamine treated rats were pretreated with haloperidol, the effects of D-amphetamine on the spontaneous release of excitatory amino acids were not produced, whereas its effects on N-methyl-D-aspartate-evoked release remained unchanged. 5. These data suggest that amphetamine produces changes in excitatory amino acid-mediated transmission in the nucleus accumbens, that may play a role in amphetamine-induced behavioral or psychotomimetic effects.

Effects of pimozide on the psychopathology of delusional disorder.

1. The effects of pimozide on the psychopathology of delusional disorder were studied. 2. After six weeks, pimozide (2-12 mg/day) administration had no effect on the Brief Psychiatric Rating Scale, or in the psychological, social and occupational functioning, as measured by the Global Assessment of Functioning Scale. 3. When the different dimensions of the delusional experience were looked upon, no modifications were observed in any of them after six weeks of pimozide treatment. 4. These data failed to support the therapeutic role of pimozide in the treatment of delusional disorder and may suggest, when compared to other disorders with prominent delusions such as schizophrenia, a different neurobiology for the illness.

A central 6-hydroxydopamine lesion prevents fluphenazine-induced increase in plasma homovanillic acid.

Plasma and brain levels of the dopamine metabolite, homovanillic acid, were measured in rats after acute and chronic treatment with fluphenazine. After acute administration, homovanillic acid levels were increased in the whole frontal cortex, caudate nucleus, nucleus accumbens, anterior cingulate (supragenual) cortex, prefrontal cortex and plasma. Following chronic administration, the effects of single doses of fluphenazine in increasing homovanillic acid were markedly attenuated in the caudate nucleus, nucleus accumbens, the whole frontal cortex, anterior cigulate cortex and plasma, but not in the prefrontal (anteromedial) cortex. Following fluphenazine administration plasma homovanillic acid levels were correlated with homovanillic acid concentrations in whole frontal cortex (r = 0.63, p less than 0.01) and caudate nucleus (r = 0.51, p less than 0.05). Further, prior intracerebroventricular administration of 6-hydroxydopamine prevented the fluphenazine-induced increase in plasma homovanillic acid. These data suggest that in the rat, plasma and brain (caudate nucleus and whole frontal cortex) homovanillic acid levels change in a similar fashion during acute and chronic neuroleptic administration.

Characterization of neurotransmitter receptor-mediated phosphatidylinositol hydrolysis in the rat hippocampus.

The stimulation of phosphatidylinositol hydrolysis by various neurotransmitter agonists was investigated in rat hippocampal slices using a rapid and sensitive radioisotopic method. Slices were preincubated with [3H]-myo-inositol and the accumulation of [3H]-myo-inositol-1-phosphate induced by various agonists was determined in the presence of 10 mM lithium. The latter resulted in a marked amplification of the response to all agonists tested. The agonist-induced accumulation of [3H]-myo-inositol-1-phosphate was dependent on tissue, lithium, [3H]-myo-inositol concentration, as well as incubation time. The hydrolysis of phosphatidylinositol in hippocampal slices is induced by carbachol, serotonin, norepinephrine and phenylephrine. The carbachol-induced response is sensitive to atropine, a muscarinic-cholinergic antagonist, but not mecamylamine a nicotinic-cholinergic antagonist, while that of norepinephrine is blocked by the alpha 1 adrenoreceptor antagonist prazosin, but not the specific alpha 2 antagonist Rx 781094. Phenylephrine, another alpha 1 adrenoreceptor agonist produced a partial or submaximal response when compared to norepinephrine. The concentration response curve for serotonin-induced phosphatidylinositol hydrolysis is bimodal and the effect is blocked by metergoline, but not mianserin, indicating that the effect of serotonin in the hippocampus may be mediated by 5HT1 receptors. Our results suggest that the measurement of agonist-induced [3H]-myo-inositol-1-phosphate accumulation, in the presence of lithium, represents a sensitive method for studying a number of receptor-mediated events in brain.

Dexamethasone increases plasma HVA but not MHPG in normal humans.

Several recent studies in animals and man indicate that corticosteroids may alter catecholaminergic activity in both the peripheral and central nervous systems. We administered 1 mg of the synthetic glucocorticoid, dexamethasone, to 12 drug-free healthy volunteers and measured plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Dexamethasone was administered at 11 p.m. and blood was collected at 4 p.m. on the preceding and subsequent days. Dexamethasone administration resulted in a significant increase in plasma HVA but did not consistently affect MHPG. All subjects showed a suppression of serum cortisol to values less than 5 micrograms/dl while prolactin levels were unaltered. In an additional group of nine volunteers, we administered 2 mg of dexamethasone and observed a similar increase in plasma HVA without change in plasma MHPG, indicating a selective effect on dopamine metabolism. Implications of these findings for an understanding of the neurochemical and behavioral changes seen with steroid administration and in explaining previous results on plasma MHPG/HVA ratios in delusional depression are discussed.

Accuracy in tunnel placement for ACL reconstruction. Comparison of traditional arthroscopic and computer-assisted navigation techniques.

The purpose of this randomized, prospective study was to compare accuracy in tunnel placement as performed with a traditional arthroscopic anterior cruciate ligament (ACL) reconstruction technique and with KneeNavTM ACL, a computer-assisted surgical navigation technique. Two surgeons experienced in ACL reconstruction, but inexperienced in computer-assisted surgical navigation technique, each randomly used traditional arthroscopic guides or KneeNavTM ACL to drill a tunnel in twenty identical foam knees. Placement of the resulting tibial and femoral tunnels was measured with a computer-assisted digitizing method and compared to traditional biplanar radiographs. Statistical analysis with Student's t-test was used to compare the distance from the ideal tunnel placement to the femoral and tibial tunnels. Accuracy of tunnel placement with KneeNavTM ACL was significantly better than that obtained with the traditional arthroscopic technique. Distances from the ideal tunnel placement to the femoral and tibial tunnels were 4.2 +/- 1.8 mm (mean +/- SD) and 4.9 +/- 2.3 mm, respectively, for the traditional arthroscopic technique, and 2.7 +/- 1.9 mm (femur) and 3.4 +/- 2.3 mm (tibia) for KneeNavTM ACL. These differences were statistically different. Tunnel placement for ACL reconstruction with KneeNavTM ACL, an image-based, computer-assisted surgical navigation device with a simple and intuitive interface, was more accurate than with the traditional arthroscopic technique.