Effect of subconvulsive doses of bicuculline on the incorporation of radioactive precursors into glycerolipids in rat brain areas

Bicuculine (either 25 μmol or 12.5 μmol/kg body wt) was administered to rats by intraperitoneal route. Animals treated with 25 μmol/kg experienced convulsions, whereas those receiving 12.5 μmol/kg did not. Controls received saline instead of the drug. Radioactive precursors [2-³H] glycerol and/or [1,2¹⁴C] ethanolamine were injected into cerebral ventriculi simultaneously with bicuculline and the rats were killed 12 min afterwards. Their brains were dissected by hand into four parts (cerebellum, brain stem, hippocampus, cerebral cortex) and the labeling of lipid classes determined after extraction and separation. Although glycerol was incorporated into lipid better than ethanolamine in all areas, the fate of the injected radioactive precursors varied according both to area and treatment. The lowest uptake of radioactivity was in the cerebral cortex and the highest in the brain stem and hippocampus. Moreover, the administration of bicuculline influenced the distribution of radioactivity among lipid classes; these variations, however, were not dependent on the administered doses of bicuculline. We conclude that the effects on glycerolipid metabolism observed in convulsing animals are due to several causes including alterations of systemic parameters (hypertension, hypoxia, etc.). The distribution of glycerol label between phospholipid and neutral lipid is proposed as a biochemical model for the study of convulsive and subconvulsive states.

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Sommario Si somministrava ai ratti bicucullina in ragione di 25 μmoli o di 12.5 μmoli/kg di peso corporeo. Gli animali trattati con la dose più elevata del convulsivante avevano convulsioni, mentre quelli trattati con 12,5 μmoli/kg non ne avevano. Ai controlli si somministrava NaCl al 9‰. I precursori radioattivi ([2-³H]glicerolo e/o [1,2¹⁴C] etanolammina) venivano iniettati nei ventricoli cerebrali contemporaneamente alla bicucullina ed i ratti sacrificati 12 min più tardi. I cervelli erano quindi prelevati e divisi in quattro parti (cervelletto, corteccia cerebrale, ippocampo e tronco cerebrale). La marcatura delle classi lipidiche era determinata dopo estrazione e separazione. Sebbene il glicerolo fosse incorporato in lipidi meglio dell'etanolammina in tutte le aree, il destino del precursore iniettato variava sia in relazione all'area che al trattamento. L'assunzione di radioattività era massima nel tronco e nell'ippocampo e minima nella corteccia cerebrale. La somministrazione di bicucullina influenzava la distribuzione della radioattività fra le classi lipidiche; tuttavia queste variazioni non dipendevano dalle dosi del convulsivante. Le alterazioni sistemiche che accompagnano le convulsioni (ipossia, ipertensione, ecc.) sembrano dunque rilevanti nel determinare il tipo di modificazione del metabolismo lipidico. Viene proposta la distribuzione di marcatura del glicerolo tra fosfolipidi e lipidi neutri come un parametro per studiare gli stati convulsivi e subconvulsivi.

     

Phenobarbital in the prophylaxis of late posttraumatic seizures

390 patients with severe head injuries were treated with phenobarbital (PB) orally for a period of 12 months in order to determine whether this drug could reduce the incidence of posttraumatic epilepsy (PTE). An intramuscular PB dose of 2.5–3 mg/kg body weight per day was administered within 24 hours after the trauma; after 5 days, or longer if the coma persisted, the drug was administered orally. Maintenance dosage adjustments, when necessary, were based on serial plasma concentrations of the drug, sustained at between 5 and 30 g/ml.293 patients completed the study. 66% of these presented one risk factor, while 34% presented two or more.6 patients (2.04%) had at least one seizure during the twelve months. Plasma drug levels at the time of the seizure, with one exception of 15 g/ml, ranged from 20 to 28 g/ml.The results of the study indicate that PB administered during the first twelve months after the trauma, even at relatively low doses, can have a prophylactic effect on PTE.

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Sommario 390 pazienti con gravi traumi cranici sono stati trattati con phenobarbital (PB) per via orale, per un periodo di 12 mesi, al fine di verificare se tale farmaco potesse ridurre l'incidenza dell'epilessia post-traumatica (PTE). Il PB è stato somministrato per via intramuscolare, entro 24 ore dopo il trauma, alla dose di 2.5–3 mg/kg/die; dopo 5 giorni o un periodo di tempo maggiore se il coma persisteva, il farmaco è stato somministrato per via orale. Il mantenimento del livello plasmatico, quando necessario, è stato ottenuto monitorando le concentrazioni plasmatiche del farmaco che sono state mantenute tra 5 e 30 g/ml.293 pazienti hanno completato lo studio. Il 66% presentava un solo fattore di rischio, mentre il 34% presentava due o più fattori di rischio associati.6 pazienti (2.04%) hanno presentato almeno una crisi epilettica entro i 12 mesi. I livelli plasmatici del farmaco al momento della crisi, variavano fra 20 e 28 g/ml, con una eccezione di 15 g/ml. I risultati dello studio indicano che il PB somministrato durante i primi 12 mesi dopo il trauma, anche a dosi relativamente basse, può avere un effetto profilattico sulla PTE.

     

Steroid-responsive and dependent stiff-man syndrome: A clinical and electrophysiological study of two cases

Two female patients with the typical clinical and electrophysiological features of the stiff-man syndrome, both responded to steroid treatment. ACTH infusion produced an immediate clinical relief of muscle contracture and cramps, with parallel marked reduction of the EMG pattern of continuous spontaneous activity in agonist and antagonist muscles. Apart from this effect, a more delayed response to oral prednisone was observed in both cases and steroid-dependence in one of them, who also exhibited instrumental and laboratory findings suggesting an inflammatory process. These data lead us to consider a possible dysimmune pathogenesis of some cases with the stiff-man syndrome.

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Sommario Vengono descritte due pazienti di sesso femminile, ambedue con quadro clinico ed elettrofisiologico compatibile con la diagnosi di “stiff-man syndrome”, ambedue responsive a trattamento steroideo. L'infusione di ACTH ha determinato un'immediata riduzione o scomparsa delle contratture muscolari, con parallela riduzione del “pattern” EMG di attività continua di fibra nei muscoli agonisti ed antagonisti. Oltre a questo effetto acuto, abbiamo osservato un più ritardato effetto risolutivo del prednisone per os, con remissione in un caso e corticodipendenza nel secondo, il quale presentava reperti liquorali e strumentali indicativi di un processo infiammatorio del SNC. Questi dati ci inducono a considerare una possibile patogenesi disimmune almeno di alcuni casi di “stiff-man syndrome”.

     

Terguride in the treatment of Parkinson disease: preliminary experience

Terguride, a partial DA-agonist with both dopaminergic and antidopaminergic properties, was tested in 11 PD patients in the “decompensated” phase of the disease, characterized by the presence of dyskinesias and motor fluctuations. Combined treatment of these patients with 1 mg/day of terguride and stabilized doses of levodopa reduced the severity and frequency of dyskinesias and motor fluctuations along with a slight but significant improvement of parkinsonian clinical picture. The “modulatory” effect of terguride on DA receptors, in this experimental conditions, is discussed.

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Sommario La terguride, DA agonista parziale con proprietà contemporaneamente dopaminergiche ed antidopaminergiche, è stata valutata in 11 pazienti parkinsoniani in fase “decompensata” di evoluzione di malattia, caratterizzata da discinesie e fluttuazioni motorie. Il trattamento combinato di questi pazienti con terguride alla dose di 1 mg/die e levodopa a dosi stabilizzate, ha ridotto la gravità e la frequenza delle discinesie, determinando contemporaneamente un lieve ma significativo miglioramento del quadro parkinsoniano. Viene discusso l'effetto “modulatorio” della terguride sui recettori dopaminergici, in questa condizione sperimentale.

     

Phenobarbital prophylaxis of post traumatic epilepsy

Phenobarbital (PB) was tested for its efficacy in averting post-traumatic epilepsy (PTE) in patients with non-missile head injuries. The protocol envisaged the administration of PB throughout a period of two years in randomly assigned doses ranging from 0.5 to 1.5 and from 1.6 to 2.5 mg/kg/day. The study included neurologic examination, EEG and plasma PB levels. Ninety patients, 83 of whom with serious head injury, followed the prescribed treatment for the entire period. Two adult patients manifested seizures 5 and 10 months after the trauma. They were being treated with doses over 1.5 mg/kg/day. Another patient had a seizure six months after the end of the prophylaxis. Low doses of PB and monitoring permitted a reduction of side effects. The low incidence of PTE indicates that PB has an efficient prophylactic effect. The results also show that a low dosage has a favourable effect.

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Sommario è stata indagata l'efficacia di differenti dosi di fenobarbital (PB) nella profilassi dell'epilessia post-traumatica. Il protocollo prevedeva la somministrazione di PB in quantità comprese fra 0.5 e 1.5 e fra 1.6 e 2.5 mg/kg/die, assegnate in modo randomizzato indipendentemente dall'entità del trauma, per un periodo di due anni. La valutazione neurologica, EEG e dei livelli plasmatici di PB erano assicurati a tutti i pazienti. 90 pazienti, 83 dei quali con trauma cranico grave, seguirono il trattamento prescritto per l'intero periodo. Due presentarono crisi rispettivamente dopo 5 e 10 mesi dal trauma. Entrambi erano trattati con dosi superiori a 1.5 mg/kg/die. Un altro paziente ebbe una crisi sei mesi dopo il termine del trattamento. Questi risultati indicano che il PB svolge un'efficace prevenzione dell'epilessia post-traumatica e che un effetto favorevole può aversi anche con dosi non elevate.

     

Neonatal 6-hydroxydopamine-induced hypo/hyperactivity: blockade by dopamine reuptake inhibitors and effect of acute D-amphetamine

Five experiments were performed to assess the changes in motor activity resulting from neonatal administration of 6-hydroxydopamine (6-OHDA) on Days 1 or 2 postnatal, at doses of either 75 or 100 μg in a volume of 10 μl vehicle, following pretreatment with either GBR 12909 (40 mg/kg, s.c.) or amphonelic acid (4.0 mg/kg, s.c.) or saline. Motor activity was measured either over 60-min test periods on five consecutive days of testing or at 12-min intervals within a single 60-min test session. The initial extent of locomotor hyperactivity was dependent upon the neonatal dose of 6-OHDA: the 100 μg, but not 75 μg, dose induced marked hyperactivity from test day 1 onwards whereas the 75 μg dose did so from test day 3 onwards. The initial hypoactivity for rearing behaviour was observed for both doses of 6-OHDA: this hypoactivity was altered over successive test days so that by test day 5 an hyperactivity by the 75 μg, but not 100 μg, was observed. Pretreatment with either GBR 12909 or amphonelic acid abolished the effects of both doses of 6-OHDA. In the within 60-min test session procedure, 6-OHDA treated rats (both 75 and 100 μg) showed initial hyperactivity for locomotion that intensified, in relation to the other groups, over each 12-min interval and initial hypoactivity for rearing that developed into hyperactivity over each 12-min interval. Pretreatment with either GBR 12909 or amphonelic acid again abolished the effects of both doses of 6-OHDA (75 and 100 μg) rats, compared to the control groups in all four experiments. In Experiment V, a low dose of D-amphetamine abolished the hyperactivity of 6-OHDA (75μg) treated rats whereas a higher dose did so only transiently. Pretreatment with GBR 12909 abolished these effects. These findings underline the neuropharmacological utility of the neonatal 6-OHDA treatment for studying brain receptor system adaptive changes underlying the respective functional alterations and as a possible laboratory model for clinical disorders.     

Effectiveness of bornaprine on parkinsonian tremor

The effectiveness of Bornaprine on parkinsonian tremor was evaluated in a single-blind study of mediumterm treatment. 25 patients were treated with rising doses of Bornaprine per os, one week at each dose-level. The dose at which Bornaprine was most effective was 8 mg daily and its action at this dose was mild but statistically significant. The drug was generally well tolerated in patients with idiopathic parkinsonism, but transient confusion developed in a few patients with secondary parkinsonism.

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Sommario Gli Autori hanno valutato in uno studio a singolo cieco l'efficacia della Bornaprine, sul tremore parkinsoniano durante un trattamento a medio termine. Il farmaco è stato somministrato per os a dosi crescenti da 6 a 16 mg/die ad un gruppo di 25 pazienti. La Bornaprine è stata generalmente ben tollerata in 18 dei pazienti affetti da Parkinson idiopatico mentre nei 7 pazienti affetti da parkinsonismo arteriosclerotico si è notata la frequente comparsa di transitori sintomi confusionali. L'attività tremorolitica del farmaco è apparsa modesta ma statisticamente significativa.

     

Cyclophosphamide in relapsing remitting multiple sclerosis

7 patients with relapsing-remitting multiple sclerosis (MS) were subjected to an intensive course of intravenous (I.V.) cyclophosphamide (CY) therapy. All patients received induction therapy with 11 daily doses of 300 mg/m² and then a single dose every six months for three years. After one year of follow-up all patients showed a decrease in relapse rate (0.57.57); in the two subsequent years of follow-up 2 patients showed a mild worsening while the others were clinically stable. As suggested by others, our results indicate that I.V. CY therapy may influence the clinical course of relapsing-remitting MS.

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Sommario Sette pazienti affetti da Sclerosi Multipla di tipo remittente sono stati sottoposti a terapia immunosoppressiva con ciclofosfamide. Il trattamento consisteva di un ciclo di induzione con dosi di 300 mg/m2 di ciclofosfamide e.v. somminsstrate giornalmente per 11 giorni e di successive singole dosi di mantenimento di 300 mg/m² somministrate ogni 6 mesi per un periodo di 3 anni. Non sono stati osservati gravi effetti collaterali durante lo studio. Dopo il primo anno di trattamento tutti i pazienti hanno mostrato miglioramento nella frequenza di ricaduta; nei due anni successivi 4 pazienti sono rimasti stabili mentre gli altri hanno mostrato un nuovo peggioramento. Come indicato da altri Autori, i risultati dello studio indicano che la terapia immunosoppressiva con ciclofosfamide ad alte dosi non presenta gravi effetti collaterali e può modificare il decorso della Sclerosi Multipla di tipo remittente.

     

An epidemiological study of the clinical impact of pharmacokinetic anticonvulsant drug interactions based on serum drug level analysis

The impact of pharmacokinetic anticonvulsant drug interactions on prescribing patterns and serum drug level distribution in a routine clinical setting was evaluated in a population of 848 patients chronically treated with phenytoin, phenobarbital, carbamazepine and valproic acid (either alone or as two-drug combinations) and referred for therapeutic drug monitoring for the first time. While dosages of each drug did not differ significantly between monotherapy and polytherapy patients, significant differences in serum level distribution were found. The proportion of patients with suboptimal serum carbamazepine and valproic acid levels (<4 and <50μg/ml, respectively) was much greater in the polytherapy than in the monotherapy groups, probably as a consequence of induction of carbamazepine and valproic acid metabolism by combined anticonvulsants. Conversely, the proportion of phenobarbital levels above the upper limit of the optimal range (40μg/ml) was greater among patients receiving phenytoin in combination than among patients taking phenobarbital alone, presumably as a result of phenytoin-induced inhibition of barbiturate metabolism. The therapeutic implications of these findings are discussed.

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Sommario Il presente studio è stato condotto al fine di valutare, in condizioni cliniche rutinarie, i possibili effetti delle interazioni farmacocinetiche degli anticonvulsivanti su: (I) le prescrizioni delle dosi giornaliere e (II) la variabilità dei livelli plasmatici dei singoli farmaci. La casistica comprende 848 pazienti epilettici sottoposti, per la prima volta ad un dosaggio ematico e trattati cronicamente con uno o due dei seguenti farmaci: fenitoina (PHT), fenobarbital (PB), carbamazepina (CBZ) e valproato (VPA). Nessuna differenza significativa è stata osservata nelle prescrizioni delle dosi giornaliere tra i gruppi in monoterapia e quelli in biterapia. Per quanto riguarda la variabilità dei livelli ematici, sono state osservate le seguenti differenze statisticamente significative: (I) una più alta percentuale di pazienti con livelli di CBE e VPA al di sotto dei ?ranges? tereapeutici nei gruppi che assumevano tali farmaci in associazione con uno degli altri considerati, rispetto ai gruppi in monoterapia; (II) una percentuale più alta di pazienti con livelli di PB al di sopra del ?range? nel gruppo trattato con PB e PHT in associazione, rispetto agli altri gruppi considerati. Le implicazioni cliniche di tali dati vengono, quindi, discusse.

     

Repeated administration of dopaminergic agents in the nucleus accumbens and morphine-induced place preference

In the present study, the effects of repeated intra nucleus accumbens (intra-NAc) injections of dopamine receptor agents on morphine-induced conditioned place preference (CPP) in rats were investigated by using an unbiased 3-days schedule of place conditioning design. The animals receiving once daily subcutaneous (s.c.) injections of morphine (0.5-7.5mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner. The maximum response was observed with 5mg/kg of the opioid. Three days intra-NAc injections of apomorphine (0.5 and 1 microg/rat) followed by 5 days free of the drug, increased or decreased, respectively CPP induced by the lower dose of morphine (0.5mg/kg, s.c.). Morphine-induced CPP was also significantly increased in the animals that had previously received the 3-days intra-NAc injections of SKF 38393 (4 and 8 microg/rat) or quinpirole (2 and 4 microg/rat, intra-NAc). The CPP induced by a higher dose of morphine (5mg/kg, s.c.) was significantly decreased in the animals that had previously received the 3-days SCH 23390 (0.005 and 0.01 microg/rat; intra-NAc). On the other hand, the CPP induced by morphine (5mg/kg, s.c.) was significantly increased in the animals that had previously received the 3-days sulpiride administration (5 microg/rat, intra-NAc). The 3-days administration of apomorphine, SKF 38393 or quinpirole, but not SCH 23390 and sulpiride reduced the locomotor activity in the test session. It is concluded that repeated injections of dopamine receptors agents followed by 5 days free of the drugs in the NAc can affect morphine reward.     

Detection of pharmacologically mediated changes in cerebral activity by functional magnetic resonance imaging: the effects of sulpiride in the brain of the anaesthetised rat

Blood oxygenation level dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) was used to study the effects of the D₂-like receptor selective antagonist, sulpiride, at 2 Tesla in the brain of the α-chloralose anaesthetised rat. Region of interest (ROI) analysis indicated significant (P<0.05) bilateral increases in BOLD signal intensity in the frontal cortex following a single administration of sulpiride (10 mg/kg i.v.). BOLD signal changes were slow in onset and increased gradually during the experiment, reaching 8.0±0.5% (mean±S.E.M.) above pre-injection control values 165 min after drug administration. Signal increases remained high at the experiment end (3 h post sulpiride administration). Sulpiride (30 mg/kg i.v.) had a similar effect in the frontal cortex, increasing signal 5.2±1.8% above control values by 174 min; its effects were, however, more variable between rats, and were not statistically significant. Sulpiride (3 mg/kg i.v.) had no significant effect upon BOLD signal intensity in any brain region. No dose of sulpiride resulted in any significant BOLD signal changes in the striatum or cerebellum. These data are supportive of the notion that sulpiride causes an increase in frontal dopaminergic function by antagonism of presynaptically located dopamine D₂ receptors in this brain region, consistent with its therapeutic action. Furthermore, the utility of BOLD contrast fMRI as a means of detecting changes in neuronal activity contingent upon the administration of a psychoactive pharmacological agent has been demonstrated.     

Alterations in cerebral glutamic acid decarboxylase and3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol,sulpiride or clozapine

Summary Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4–1.6 mg/kg/day), sulpiride (102–109 mg/kg/day) or clozapine (24–27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and³H-flunitrazepam binding.Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration.The number of specific³H-flunitrazepam binding sites (B_max) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, B_max for³H-flunitrazepam binding to cerebellar membrane preparations was decreased-by 12 months administration of all drug treatments. The dissociation constant (Kd) for³H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25–100 M) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific³H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.     

Permutation entropy to detect vigilance changes and preictal states from scalp EEG in epileptic patients. A preliminary study

Permutation entropy (PE) was recently introduced as a very fast and robust algorithm to detect dynamic complexity changes in time series. It was also suggested as a useful screening algorithm for epileptic events in EEG data. In the present work, we tested its efficacy on scalp EEG data recorded from three epileptic patients. With a receiver operating characteristics (ROC) analysis, we evaluated the separability of amplitude distributions of PE resulting from preictal and interictal phases. Moreover, the dependency of PE on vigilance state was tested by correlation coefficients. A good separability of interictal and preictal phase was found, nevertheless PE was shown to be sensitive to changes in vigilance state. The changes of PE during the preictal phase and at seizure onset coincided with changes in vigilance state, restricting its possible use for seizure prediction on scalp EEG; this finding however suggests its possible usefulness for an automated classification of vigilance states.

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Sommario è stato recentemente introdotto un algoritmo denominato Permutation Entropy (PE) a cui gli autori Bandt e Pompe (2002) attribuiscono due caratteristiche interessanti: la robustezza e la relativa rapidità di implementazione, proprietà entrambe utili nell’individuazione delle variazioni di complessità in serie temporali. Sulla scia di un iniziale ottimismo, la PE è stata suggerita come un possibile ausilio di ricerca su dati elettroencefalografici relativi a crisi epilettiche. Un primo obiettivo del nostro studio era testare l’efficacia dell’algoritmo, su dati elettroencefalografici di scalpo, registrati da 3 pazienti epilettici. Mediante l’applicazione di una ROC (Receiver Operating Characteristics) analisi abbiamo valutato la separabilità delle distribuzioni delle ampiezze di PE, rispettivamente per la fase preictale per quella interictale, su ogni registrazione di scalpo. Il secondo obiettivo è stato quello di indagare le eventuali correlazioni sussistenti fra l’andamento della PE e gli stati di vigilanza. Troviamo una buona separabilità fra le curve di dati preictali e interictali di ciascun paziente, seppure è evidente che la PE sia sensibile al cambio di stati di vigilanza, poiché spesso l’inizio di un evento accessuale era concomitante a cambi di stati di vigilanza. Alla luce di queste osservazioni, concludiamo che al momento non è possibile valutare l’affidabilità della PE come algoritmo predittore di crisi su dati elettroencefalografici di superficie, mentre appare sicuramente più attendibile come classificatore automatico degli stati di vigilanza.

     

Endocannabinoids mediate anxiolytic-like effect of acetaminophen via CB1 receptors

Acetaminophen (Paracetamol), a most commonly used antipyretic/analgesic agent, is metabolized to AM404 (N-arachidonoylphenolamine) that inhibits uptake and degradation of anandamide which is reported to mediate the analgesic action of acetaminophen via CB1 receptor. AM404 and anandamide are also reported to produce anxiolytic-like behavior. In view of the implication of endocannabinoids in the effect of acetaminophen, we contemplated that acetaminophen may have anxiolytic-like effect. Therefore, this possibility was tested by observing the effects of various doses of acetaminophen in mice on anxiety-related indices of Vogel conflict test and social interaction test. The results from both the tests indicated that acetaminophen (50, 100, or 200 mg/kg, i.p.) or anandamide (10 or 20 µg/mouse, i.c.v.) dose dependently elicited anxiolytic-like effect, that was comparable to diazepam (2 mg/kg, i.p.). Moreover, co-administration of sub-effective dose of acetaminophen (25 mg/kg, i.p.) and anandamide (5 µg/mouse, i.c.v) produced similar anxiolytic effect. Further, pre-treatment with AM251 (a CB1 receptor antagonist; 1 mg/kg, i.p.) antagonized the effects of acetaminophen and anandamide with no per se effect at 1 mg/kg dose, while anxiogenic effect was evident at a higher dose (5 mg/kg, i.p.). None of the treatment/s was found to induce any antinociceptive or locomotor impairment effects. In conclusion, the findings suggested that acetaminophen (50, 100, or 200 mg/kg, i.p.) exhibited dose dependent anxiolytic effect in mice and probably involved endocannabinoid-mediated mechanism in its effect.     

Effects of psychotropic drugs on somatosensory evoked potentials in cerebral ischemia

Several authors have demonstrated a correlation between short latency somatosensory evoked potentials (short latency SEPs) and cerebral blood flow (CBF). It is also known that ischemia may modify the amplitude of the cortical SEP while its latency is less sensitive to CBF fluctuations. Phychotropic drugs — Oxiracetam, SAMe, Naloxone, L-acetylcarnitine and GM1 — affect some parameters of the early components of cortical SEPs, chiefly the amplitude, which makes SEP recording a useful method for monitoring pharmacological activity in acute stroke.

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Sommario Molti studi hanno dimostrato l'esistenza di una relazione fra potenziali evocati a breve latenza (Short-latency SEP) e flusso ematico cerebrale (CBF). è anche noto che condizioni d'ischemia possono modificare l'ampiezza del SEP corticale, mentre la latenza si dimostra meno sensibile a fluttuazioni del flusso ematico cerebrale. La somministrazione di farmaci nootropi — Oxiracetam, SAMe, Naloxone, M-Acetilcarnitina, GM1 —altera alcuni parametri delle componenti precoci del SEP corticale, principalmente l'ampiezza, facendo di tale metodica un utile mezzo per monitorare l'attività farmacologica, nella fase acuta dello stroke.

     

Influence of diltiazem on the behavior of zolpidem-treated mice in the elevated-plus maze test

Summary. The present study was undertaken to investigate the effect of diltiazem, a L-type calcium channel blocker (CCB), on the behavior of zolpidem-treated mice in the elevated plus-maze (EPM). Atypical benzodiazepine zolpidem significantly increased the percentage of open arm entries without influencing the total entries and total distance and average speed at the dose of 5 mg/kg (p.o.). Co-administration of zolpidem (2 mg/kg, p.o.) and diltiazem (5, 10 and 20 mg/kg, p.o.) significantly increased both the time spent and arm entries in the open arms without influencing the total entries and spontaneous activity notwithstanding that zolpidem at dose up to 2 mg/kg (p.o.) and diltiazem at dose up to 20 mg/kg (p.o.) did not show any effects on mice behavior in EPM. Zolpidem also attenuated the anxiogenic effect of 1-(3-Chlorophenyl)piperazine (mCPP, 0.7 mg/kg, i.p.) and 5-hydroxytryptophan (5-HTP, 30 mg/kg, i.p.). Even though the zolpidem at 1 mg/kg and diltiazem at 5 mg/kg were ineffective on mCPP-induced anxiety, respectively, the co-administration of zolpidem (1 mg/kg, i.p.) and diltiazem (5 mg/kg, p.o.) showed inhibitory effect on mCPP-induced anxiety in mice. These results suggested that diltiazem, a L-type CCB may augment the anxiolytic-like effect of zolpidem and also indicated that calcium channel modulation maybe involved in the anxiolytic-like properties of zolpidem.     

Cognitive event-related potentials and reaction time in presenile subjects with initial mild cognitive decline or probable Alzheimer-type dementia

The so-called contingent negative variation (CNV) is a slow brain potential representing a complex of variously overlapped “endogenous” components of behavior related to different reasonably well-known neurocognitive processes. CNV complex evoked with a standard paradigm (S1-2 sec-S2-motor response) and reaction time (RT) to imperative signal (S2) were recorded and measured in 11 patients with initial presenile idiopathic cognitive decline (PICD), 8 with presenile Alzheimer-type dementia (PAD) and 10 healthy age-matched controls. Significant group differences were obtained for measures of some CNV components, particularly of the late pre-S2 CNV. No significant CNV activity, very prolonged RTs and sometimes characteristic post-imperative negative variation (PINV) were observed in the majority of patients with PAD. These results suggest that CNV complex and RT changes similar to those observed in our patients may constitute a valuable clue for the study of pathophysiological brain functioning in the early stages of presenile idiopathic mental deterioration.

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Sommario Scopo della presente ricerca è lo studio mediante metodiche standard di averaging, delle modificazione dell'onda d'aspettativa, sue principali componenti (complesso CNV) e tempo di reazione (RT) delle risposte motorie in pazienti affetti da forme iniziali più o meno gravi di decadimento mentale presenile idiopatico. Sono stati esaminati 19 pazienti (età media: 59.5) e 10 soggetti sani di controllo di pari età (media: 59.6). Otto pazienti presentavano un quadro clinico di demenza presenile di tipo Alzheimer (PAD), mentre in 11 soggetti era stata formulata una diagnosi di possibile forma iniziale presenile di demenza primaria (PICD) poiché non raggiungevano i criteri clinici del DSM-III e del NINCDS-ADRDA Report. Tutti i pazienti sono stati sottoposti preliminarmente and esami clinici, TAC, NMR, EEG con analisi spettrale ed a test psicodiagnostici. Per evocare il complesso CNV-RT si è adottato un parametro di stimolazione molto semplice ed idoneo anche per malati con deterioramento mentale. Oltre all'EOG ed agli RT, l'attività di tipo CNV è stata registrata da regioni frontali, centrali e parietali con referenza bimastoidea. Si sono osservate differenze significative di alcuni componenti fra i gruppi di soggetti esaminati e nella maggioranza dei dementi mancava una vera attività di tipo CNV, gli RT erano enormemente prolungati e sovente si sono registrati caratteristici “post-imperative negative variations” (PINV). I risultati ottenuti confermano l'utilità di queste metodiche nella diagnosi precoce delle demenze primarie presenili.

     

Effects of D2-dopaminergic receptor stimulation on male rat sexual behavior

Summary The effects of selective D₂-dopaminergic receptor stimulation with LY163502 on male rat copulatory behavior were evaluated. LY163502 (25 ng/kg to 25g/kg s. c.) produced increases in the percentage of sexually inactive rats displaying mounting behavior and ejaculating during the test period. Within this same dose range, LY163502 administration induced an increase in the percentage of non-ejaculator rats that were capable of ejaculation. These findings are viewed as evidence that LY163502 can initiate sexual behavior and lower the threshold for ejaculation. The effects of LY163502 were further evaluated in rats that were capable of ejaculation during the test period. LY163502 (25 ng/kg to 25g/kg s. c. or p. o.) induced significant reductions in ejaculatory latency. These effects were blocked by prior treatment with centrally active dopaminergic antagonists, RO 22-1319 and sulpiride, but not with a peripherally active antagonist, domperidone.LY163502 administration was also found to inhibit sexual behavior in low doses of 25 pg/kg –10 ng/kg s. c. and in a much larger dose of 25 mg/kg s. c. These inhibitory effects are viewed as behavioral manifestations of selective dopaminergic autoreceptor activation with low doses and as the disruption of sexual behavior by induction of intense stereotypic behavior with high doses.     

Opioids and sexual behavior in the male rabbit: The role of central and peripheral opioid receptors

Summary The purpose of the present series of experiments was to analyze the effects of morphine and naloxone on sexual behavior in the male rabbit, and to evaluate the role of central and peripheral opioid receptors. Morphine was found to inhibit sex behavior in a dose dependent way. The effects were slight at 5 min postinjection. At 1 hr all aspects of sexual behavior were reduced. This effect lasted at least until 3 hrs postinjection. Subcutaneous (s.c.) injection produced effects at lower doses than intraperitoneal (i.p.) injection. Minimal effective doses were 1.25 and 5 mg/kg, respectively. Naloxone also inhibited sexual behavior. Again, s.c. administration had effects at lower doses than i.p. administration (0.25vs 16 mg/kg). The effects of morphine were reduced but not completely antagonized by several doses of naloxone, independently of whether s.c. or i.p. administration were used. An opioid kappa agonist, bremazocine, inhibited sexual behavior at a low dose (30 μg/kg). It is suggested that the inhibitory effects of morphine may be mediated by the kappa receptor. A peripheral opioid antagonist, methylnaloxone, had no effects by itself and was unable to modify the effects of morphine. It is concluded that the effects of morphine are localized within the central nervous system. This is further supported by the observation that loperamide, a peripheral opiate agonist, had only marginal effects on sex behavior. Parts of these data were presented at the 22nd Annual Conference on Reproductive Behavior, Atlanta, Georgia, June 8–11, 1990 and at the Mexican Physiological Society Annual Meeting, Colima, Mexico, September 8–12, 1991     

Mitochondrial oculoskeletal myopathy: case report

We report a case of oculoskeletal myopathy with abnormal mitochondria in which the chief clinical feature was ophthalmoplegia. Muscle weakness was mild and there were no retinal or cerebellar abnormalities, no deafness and no cardiac defects. The muscle biopsy specimen revealed subsarcolemmal mitochondrial aggregates and ragged red fibers. Electronmicroscopy showed that the aggregates were made up of mitochondria of variable size with structural abnormalities of the cristae and crystalloid inclusions. We believe that this oculoskeletal myopathy is distinct from Kearn-Sayre syndrome.

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Sommario Viene descritto un caso di miopatia oculo-scheletrica con alterazioni mitocondriali, in cui il sintomo maggiormente rappresentato era l'oftalmoplegia, mentre l'ipostenia muscolare era lieve. Il paziente non presentava anomalie retiniche o cerebellari, sordità o difetti cardiaci. La biopsia muscolare evidenziava aggregati subsarcolemmali e fibre rosse raggiate. A livello ultrastrutturale, questi aggregati erano composti da mitocondri di varie dimensioni, con anomalie strutturali delle creste ed inclusioni cristalloidali. Ě stato concluso che questo caso è da ascrivere ad un gruppo di patologia distinto dalla malattia di Kerns-Sayre.