Homocysteinemia and schizophrenia as a case of methylation deficiency

Summary MK-801, a non-competitive antagonist of NMDA receptors, is known to exhibit a beneficial action in many animal models of Parkinson's disease. The aim of this study was to examine the influence of MK-801 on the reserpine-induced muscle rigidity. The rigidity was estimated by a direct mechanomyographic method. This method consists in successive bending and traightening of a rat's hind foot in the ankle joint and measuring the resistance of the foot to passive movements. Reserpine in doses of 5–10 mg/kg ip, given alone or in combination with -methyl-p-tyrosine (MT, 250 mg/kg ip), induced rigidity. The strongest muscle rigidity was induced by 10 mg/kg of reserpine 1 hour after administration. MK-801 (0.32–1.28 mg/kg sc) injected 70 min after reserpine (10 mg/kg ip) decreased the rigidity induced by the latter compound. Similarly, MK-801 (1.28 mg/kg sc), administered 27 h 40 after joint treatment with reserpine (10 mg/kg ip) and MT (250 mg/kg ip), strongly inhibited the reserpine-induced muscle rigidity. The obtained results show that the glutamatergic hyperactivity plays a significant role in the reserpine-induced rigidity. As the reserpine-induced motor disturbances are commonly accepted to be an animal model of parkinsonian symptoms, it may be assumed that the NMDA receptor blocking component may contribute substantially to the therapeutic action of antiparkinsonian drugs.     

The effect of β-alanine on motor behaviour,body temperature and cerebral monoamine metabolism in rat

Summary Intracerebroventricular (ICV) injection of-alanine produced a decrease in rectal temperature, inhibition of exploratory behaviour and motility, and changes in the metabolism of cerebral monoamines. Dopa and 5-HTP accumulation after inhibition of L-aromatic amino acid decarboxylase, NSD 1015 (3-hydroxybencylhydrazine HCl, 100mg/kg i.p.) was found to be significantly increased in all the dissected cerebral regions of animals treated with-alanine, as compared to the controls. Levels of tyrosine and tryptophan did not show any significant change. Endogenous levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA), did not change. After inhibition of the catecholamines synthesis with-methyltyrosine (-MT), dopamine depletion was retarded and noradrenaline accelerated, but without reaching statistical significance. After intraperitoneal (i.p.) injection of-alanine, significant changes in motor behaviour were found. Body temperature and metabolism of brain catecholamine were unchanged. This lack of effect could be explained by poor penetration through the blood-brain barrier.     

Paroxetine,a potent selective long-acting inhibitor of synaptosomal 5-HT uptake in mice

Summary The high-affinity uptake of tritium labelled tryptophan (TRY), 5-hydroxytryptophan (5-HPT), 5-hydroxytryptamine (5-HT), noradrenaline (NE), dopamine (DA), glycine and glutamic acid into forebrain synaptosomes, and serum 5-HT concentrations were studied in mice.In vitro the rank order of potency (the concentration causing 50 percent uptake inhibition) of seven inhibitors of 5-HT uptake was paroxetine>citalopram femoxetine>fluoxetine>alaproclateimipramine>zimelidine. Paroxetine was a weak inhibitor of the NE and DA uptake without any effect on the synaptosomal accumulation of TRY, 5-HTP, glycine or glutamic acid. Dose related inhibition of synaptosomal 5-HT uptakeex vivo was found one hour after intraperitoneal single dose administered paroxetine (ED₅₀=0.3 mg/kg i.p.) and 75% inhibition persisted 24 hours after 10 mg/kg i.p. (=ED₁₀₀). Chronically administered paroxetine produced a slight decrement of synaptosomal NE uptake. Serum 5-HT concentrations were found dose dependently reduced during chronic paroxetine treatment. A dose level of paroxetine which reduced serum 5-HT concentrations with 50% produced an almost complete inhibition of synaptosomal 5-HT uptake.     

Prevention of nimodipine-induced impairment of learning by the selective σ ligand PRE-084

Summary The high selectivity of the phencyclidine derivative PRE-084 for sigma () sites is demonstrated. We previously reported that this compound is able to markedly attenuate the impairment of learning induced in mice by the non-competitive NMDA antagonist MK-801, and the cholinergic nicotinic antagonist mecamylamine. In this study, we examined the effect of PRE-084 on the impairment of learning induced by acute administration of the calcium channel antagonist nimodipine. Nimodipine (0.3mg/kg i.p.) impaired the spontaneous alternation behaviour in a Y-maze, decreased the step-down latency (SDL) in a passive avoidance task, and altered place learning and retention in a water-maze paradigm, with no marked effect on the motility observed using an open-field test. Preadministration of PRE-084 resulted in an attenuation of the impairment of alternation, in the 0.3–1 mg/kg s.c. range, in a marked increase in SDL, at 1–3 mg/kg, and improved place learning and retention in the water-maze, at 1 mg/kg. The effects on alternation behaviour and passive avoidance were completely prevented by co-administration of the purported antagonist BMY-14802 (10 mg/kg i.p.), implicating the sites. These results confirm the beneficial effect of the ligand PRE-084 on pharmacological models of learning impairments, and indicate that sites may modulate Ca²⁺ fluxes through VDCC, which may in turn bear some as yet unknown relationship to the previously described interaction with neurotransmitter systems.Abbreviations SDL step-down latency - EL escape latency - VDCC voltage-dependent calcium channel - NMDA N-methyl-D-aspartate - LTP long-term potentiation - DTG 1,3-di-(2-tolyl) guanidine     

Antagonism by pindolol,but not betaxolol,of 8-OH-DPAT-induced facilitation of male rat sexual behavior

Summary 8-OH-DPAT (0.25 mg/kg s.c.) produced a facilitation of the male rat sexual behavior, characterized by a decrease in the number of intromissions preceding ejaculation and in the time to ejaculation. This facilitation of the sexual behavior was antagonized by administration of the 5-HT and -adrenoceptor antagonist pindolol (4mg/kg i.p.), but not by the selective -adrenoceptor antagonist betaxolol (4 mg/kg i.p.). Neither pindolol (2–8 mg/kg), nor betaxolol (2–8 mg/kg), produced any statistically significant effects per se on the male rat sexual behavior, as observed here (mounts, intromissions, ejaculation latency or the post-ejaculatory interval). A higher dose (16mg/kg) of betaxolol produced a statistically significant reduction in the number of intromissions preceding ejaculation and in the ejaculation latency. The antagonism by pindolol of 8-OH-DPAT-induced effects on male rat sexual behavior suggests an involvement of 5-HT_1A receptors in the facilitation of this behavior produced by 8-OH-DPAT.     

Involvement of 5-HT1B receptors in the anticonflict effect of m-CPP in rats

Summary The anticonflict activity of m-CPP, a non-selective agonist of 5-HT receptors, was studied in the drinking conflict test in rats. m-CPP administered in doses of 0.125–0. 5 mg/kg increased the number of punished licks, the maximum effect having been observed after a dose of 0.25 mg/kg. The anticonflict effect of m-CPP (0.25 mg/kg) was antagonized by the non-selective 5-HT antagonist metergoline (1–4 mg/kg) and by the -adrenoceptor blocker SDZ 21009 (2 and 4 mg/kg) with affinity for 5-HT_1A and 5-HT_1B receptors. On the other hand, the 5-HT_1A receptor antagonist NAN-190 (0.5 and 1 mg/kg), the 5-HT₂ receptor antagonist ritanserin (0.25 and 0.5 mg/kg), and the -blockers betaxolol (8 mg/kg) and ICI 118,551 (8 mg/kg) with no affinity for 5-HT receptors did not affect the effect of m-CPP. The effect of m-CPP was not modified, either, in animals with the 5-HT lesion produced by p-chloroamphetamine.These results suggest that the anticonflict effect of m-CPP described above results from stimulation of 5-HT_1B receptors — most probably these which are located postsynaptically.     

Effect on hypothalamic self-stimulation of the novelβ-carbolines ZK 93 426 (a benzodiazepine receptor antagonist) and ZK 91296 (a putative partial agonist)

Summary Low doses (300/kg-1.0 mg/kg) of the novel-carboline, ZK 91 296, a putative agonist at the benzodiazepine receptor, produced a significant increase in the rate of variable-interval self-stimulation responding, similar to that found with typical benzodiazepines. This effect was blocked by simultaneous administration of the specific benzodiazepine-receptor antagonists Ro 15-1788 (2.0 mg/kg), and ZK 93 426 (10 mg/kg). Neither antagonist, ZK 93 426 (100g/kg-10 mg/kg) or Ro 15-1788 (2.0 mg/kg), had any effect on self-stimulation when given alone. Unlike all benzodiazepine-receptor agonists previously tested, higher doses of ZK 91 296 did not depress self-stimulation response rates, even at a dose-level 100 times greater than the maximally stimulant dose. It is uncertain why ZK 91 296 lacks depressant effects: available evidence does not conclusively favour any single current explanation, but is consistent with it acting as a partial agonist.     

Selective blockade of brainα 2-autoreceptors by yohimbine: Effects on motor activity and on turnover of noradrenaline and dopamine

Summary The motor activity of groups of three mice was increased by yohimbine at doses up to 3 mg/kg intraperitoneally. The turnover of dopamine and noradrenaline in the mouse brain, as assessed by the disappearance of catecholamines following treatment with the tyrosine hydroxylase inhibitor-methyltyrosine, was accelerated by yohimbine with a peak effect after 10 mg/kg intraperitoneally. Prazosin (3 mg/kg i.p.) completely antagonized the stimulatory effect of yohimbine on motor activity and on dopamine turnover but it somewhat potentiated the stimulatory effect on the turnover of noradrenaline. Amphetamine reversed the prazosin-induced hypomotility, indicating that prazosin can selectively block postsynaptic ₁-receptors.Yohimbine did not stimulate motor activity following 10 mg/kg and it retarded the turnover of dopamine following 30 mg/kg. These actions might be due to blockade of postsynaptic-receptors by yohimbine.The data indicate that yohimbine at low doses stimulates motor activity and dopamine turnover by selectively blocking ₂-autoreceptors leading to increased release of noradrenaline and subsequent activation of postsynaptic ₁-receptors.     

Interaction of haloperidol and γ-butyrolactone with (+)-amphetamine-induced changes in monoamine synthesis and metabolism in rat brain

Summary The interaction of (+)-amphetamine with haloperidol and-butyrolactone on synthesis of monoamines in rat brain regions was investigated using anin vivo method, in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) was measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine. The accumulation of 3-methoxytyramine (3-MT) after inhibition of the monoamine oxidase with pargyline was taken as an indicator of thein vivo release of dopamine (DA) into the extraneuronal space.(+)-Amphetamine at doses of 1-3 mg/kg caused an increase of dopa formation in the DA-rich areas c. striatum and mesolimbic forebrain but had no effect on dopa formation in neocortex and 5-HTP formation in all brain regions investigated. At a dose of 10 mg/kg (+)-amphetamine decreased dopa as well as 5-HTP formation in all brain regions studied.3-MT accumulation in whole rat brain was stimulated by (+)-amphetamine as well as haloperidol and inhibited by-butyrolactone.Combined treatment with haloperidol and (+)-amphetamine not only potentiated the stimulation of dopa formation but also the increase of 3-MT accumulation. Pretreatment with-butyrolactone antagonized the stimulation of 3-MT formation induced by (+)-amphetamine at a dose of 10 mg/kg. This dose of (+)-amphetamine markedly counteracted the-butyroiactoneinduced increase in dopa formation especially in the DA-rich areas.The data support the view that impulse flow in DA neurons facilitates the effect of (+)-amphetamine on DA release and DA synthesis. Inhibition of catecholamine synthesis after high doses of (+)-amphetamine may be due to an increase in cytoplasmatic DA concentration causing end-product inhibition of tyrosine hydroxylase.A preliminary report has been given recently (Kehr, 1976 b).Data of this communication are part of W.S.'s thesis for an M.D.     

Involvement of 5-HT2 receptors in the LSD- and L-5-HTP-induced suppression of lordotic behavior in the female rat

Summary Copulatory behavior in the ovariectomized rat, the lordotic response (L. R.), was induced by estrogen followed by progesterone. L. R. is inhibited by lysergic acid diethylamide (LSD) (0.05 mg/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (2.5 mg/kg). The effects of the putative 5-HT antagonists lisuride, metergoline, methysergide, mianserin, cinanserin, cyproheptadine, pirenperone and altanserin on the LSD-induced inhibition of L. R. were tested. Lisuride, metergoline, methysergide and mianserin were found to have no LSD-blocking effect. In contrast, cinanserin, cyproheptadine and pirenperone acted antagonistically to LSD, within a critical dose range. The selective 5-hydroxytryptamine₂ (5-HT₂) receptor antagonist altanserin effectively prevented the LSD-induced inhibition of L. R., and the doses required (0.05–0.20 mg/kg) indicated a comparatively high antagonistic potency. In addition altanserin (0.2 mg/kg) effectively prevented the lordosis inhibitory effect induced by L-5-HTP (2.5 mg/kg), after pretreatment with pargyline and RO4-4602. It is suggested that the suppression of copulatory behavior caused by LSD and L-5-HTP is mediated by 5-HT₂ receptors.     

Effect of interferon-α on DOI-induced wet-dog shakes in rats

Summary Acute (1h) intraperitoneal (ip) treatment with interferon (IFN)--2a (300IU/g) significantly inhibited wet-dog shakes (WDS) induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI; 0.5, 1.0mg/kg), which is mediated by serotonin (5-hydroxytryptamine; 5-HT)₂ receptor in rats. IFN- did not affect spontaneous locomotion. The inhibition of DOI (0.5mg/kg)-induced WDS by IFN- was dose (90–300 IU/g)- and time (1–6 h)-dependent, and was prevented by 30 min pretreatment with naltrexone (NLTX; 1.0mg/kg, ip), an opioid receptor antagonist. Acute (1h) intracerebroventricular (icv) treatment with IFN- (1,500IU/rat) also inhibited DOI (0.5mg/kg)-induced WDS, and the effect was blocked by NLTX (50g/rat, icv). These results suggest that IFN- may modulate 5-HT₂ receptor-mediated behavior through opioid receptors in the central nervous system.Abbreviations CNS central nervous system - DOI (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane - 5-HT 5-hydroxytryptamine (serotonin) - icv intracerebroventricular - IFN interferon - ip intraperitoneal - IU international unit - NLTX naltrexone - sc subcutaneous - WDS wet-dog shakes     

Importance of central catecholamines in the mediation of lordosis behaviour in ovariectomized rats treated with estrogen and inhibitors of monoamine synthesis

Summary The effect of-methyl-p-tyrosine methylester hydrochloride (-MT) (100 mg/kg i.p.) orp-chlorophenylalanine methylester hydrochloride (PCPA) (150 mg/kg i.p.) on lordosis behaviour in estrogen pretreated spayed rats was investigated. The effect of-MT was studied 1, 2, 4, 8 and 26 hours after the drug injection and the observations after PCPA were done 2, 4, 8, 26 and 50 hours after the injection. Facilitation of lordosis was seen 2–8 hours after both treatments. Biochemical experiments were done in parallel and the injection of either-MT or PCPA resulted in a transient decrease in brain catecholamines which was correlated in time with the facilitation of the lordosis response. Furthermore PCPA resulted in a gradual decline in brain 5-HT. However, when 5-HT depletion was most pronounced and the brain catecholamines had returned to control levels no increase in lordosis behaviour occurred. Our findings suggest a role for central catecholamines in the mediation of lordosis behaviour in ovariectomized estrogen-drug-treated rats.     

The effect of a 5-HT3 receptor antagonist,ondansetron, on brain stimulation reward,and its interaction with direct and indirect stimulants of central dopaminergic transmission

Summary 5-HT₃ receptors are abundant in central dopamine (DA) terminal areas. They do not affect basal DA turnover but appear to modulate DA release by e.g. morphine and nicotine. The interpretation of these findings is uncertain, and it is unclear whether 5-HT₃ receptors also influence the activity of compounds such as amphetamine and cocaine, which act more directly on the DA synapse. Variable-interval (VI), threshold-current hypothalamic self-stimulation can provide a continuous index of central dopaminergic activity, but is relatively insensitive to changes in 5-HT and thus offers a means of investigating this question. In the present study, a selective 5-HT₃ receptor antagonist, ondansetron (GR 38032F) (1.0 to 1000 g/kg sc), had no effect on VI self-stimulation, nor did a 100 g/kg dose affect facilitation of responding byd-amphetamine (500 jig/kg ip). Ondansetron (100 g/kg) reduced the initial depression of self-stimulation by high-dose nicotine (400 g/kg), but not the ensuing facilitation. Similar results were obtained in rats sensitized to nicotine by prior chronic exposure. These results support the proposal that 5-HT₃ receptors, normally quiescent under basal conditions, mediate the excitatory effect of compounds acting upstream from the DA neuron, such as nicotine, but do not affect the dopaminergic synapse directly.     

Bromocriptine-induced locomotor stimulation in mice is modulated by dopamine D-1 receptors

Summary Mice were pretreated with reserpine plus-methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plus-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.     

Effects of 5-HT and 8-OH-DPAT on forebrain monoamine synthesis after local application into the median and dorsal raphe nuclei of the rat

Summary 5-HT (10 and 40 g) and 8-OH-DPAT (1 and 5 g) were locally applied into the dorsal or median raphe nuclei in awake, unrestrained, rats. All animals were also treated with the 5-HTP and DOPA decarboxylase inhibitor NSD-1015, 100mg kg^–1 SC, 30 min before decapitation. 5-HT or 8-OH-DPAT were administered 5 min before NSD-1015. The regional brain in vivo rate of tyrosine and tryptophan hydroxylase activity was estimated by measuring the accumulation of DOPA and 5-HTP. The following brain regions were sampled: neocortex, hippocampus, dorso-lateral neostriatum, ventro-medial neostriatum, nucleus accumbens, olfactory tubercle, globus pallidus, septum and the amygdala.Compared to normal controls, there were small and inconsistent effects on forebrain 5-HTP accumulation by saline injections into the dorsal or the median raphe (an increase in 3 out of 36 experiments), whereas strong effects by the injection procedure were noted on forebrain DOPA accumulation (an increase in 15 out of 36 experiments).Injections of 5-HT (same effect by 10 or 40 g) into the dorsal raphe, produced a decrease in 5-HTP accumulation in all forebrain areas except for the hippocampus and the septum, whereas no effects were seen in any area after median raphe injections. In contrast, 8-OH-DPAT preferentially produced a decrease in forebrain 5-HTP accumulation after median raphe injections and less, but statistically significant effects by dorsal raphe injections. The 8-OH-DPAT injection into the median raphe primarily affected limbic forebrain areas (hippocampus, nucleus accumbens, ventro-medial neostriatum, amygdala and the septum).This dissociation of the effects of 5-HT and 8-OH-DPAT on forebrain 5-HT synthesis after local application into the dorsal or the median raphe strongly supports the contention of heterogeniety in the brain 5-HT receptor population in terms of receptor subtypes and/or receptor regulation.     

Dose-dependent pharmacokinetics of α-methyl-p-tyrosine (α-MT) and comparison of catecholamine turnover rates after two doses of α-MT

Summary Groups of rats were injected i.p. with 0.407 or 1.02 mmoles/kg of D, L--methyl-p-tyrosine methylester HCl (-MT). The time-courses for-MT in plasma and brain were followed together with the endogenous brain dopamine (DA) and noradrenaline (NA) contents.The elimination of-MT from plasma and brain was markedly delayed after the high-MT dose compared with the low dose. At 40 hours after the injection of 1.02 mmoles/kg of-MT both plasma and brain levels were high, whereas no-MT could be detected in plasma or brain at 16 hours after the lower dose.The brain catecholamines were decreased to very low values after the higher-MT dose (DA 14% and NA 10% of controls at 8 and 24 hours respectively). There was no complete recuperation at 40 hours of any of the amines. After the lower-MT dose, the DA concentration was back to control levels at 16 hours and NA at 12 hours. Between 16–40 hours after the high-MT dose a majority of the rats showed prominent signs of sedation, weight loss and dehydration. No such signs were observed in rats receiving 0.407 mmoles/kg. During the first hour after the-MT injection the declines of DA and NA respectively were almost identical for both-MT doses. When the whole time-course (0–8 hours) after the high dose was considered, biphasic declines were obtained for both DA and NA, suggesting at least two different catecholamine pools. However, due to toxic effects after the high-MT dose, turnover data have to be interpreted with caution.     

Refraktärperioden und frequente Impulsfortleitung im gemischten N. ulnaris des Menschen bei Polyneuropathien

Zusammenfassung Bei 30 Patienten mit Neuropathien unterschiedlichen Schweregrades (subklinisch, leicht, mittelschwer und schwer) wurden am N. ulnaris neben den üblichen neurophysiologischen Parametern [distale Latenz, maximale motorische und gemischte Nervenleitgeschwindigkeit (Nlg.)] die Refraktärperioden (Rp.) (absolute Rp. und relative Rp.-Amplitude und -Latenz) und die unteren Grenzfrequenzen (u. F.) (u. F.-Amplitude und -Latenz) bestimmt.Beim Vergleich mit einem Normalkollektiv (n=31, s. Lowitzsch u. Hopf, (1972a)) war die Nlg. nur in 37% der Fälle pathologisch verlangsamt, während die relative Rp.-Latenz in ca. 80% und die u. F.-Latenz in ca. 60% pathologisch verändert waren.In zwei Stichproben (13 Normalfälle und 13 Polyneuropathien) mit einer normalen gemischten Nlg. von 51,0–63,5 m/sec unterschieden sich die Mittelwerte für die distale Latenz sowie die motorische und gemischte Nlg. statistisch nur auf dem 1%-Niveau, für die relative Rp.-Latenz und die u. F.-Latenz hingegen auf dem 0,5-Niveau.Die Bestimmung der Refraktärperioden, insbesondere der rel. Rp. L., sowie der unteren Grenzfrequenz (u. F. L.), stellt eine im Vergleich mit den üblichen neurophysiologischen Verfahren (Nlg.-Bestimmung) wesentlich empfindlichere Untersuchungsmethode zur Erfassung auch geringer (subklinischer) Funktionsstörungen des peripheren Nervensystems dar.Die unterschiedliche Beeinflussung der Refraktärperioden und der Grenzfrequenzen durch die Art des zugrundeliegenden pathologischen Prozesses (axonale Degeneration — segmentale Demyelinisierung — Mischtyp) wird an Hand der in 9 Fällen nervenbioptisch (N. suralis) gewonnenen Befunde diskutiert.

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Refractory periods and frequent impulse conduction in mixed N. ulnaris of man in polyneuropathies

Summary Some electrophysiological parameters were studied in the ulnar nerve of 30 patients suffering from neuropathy of various origin and severity.Absolute and relative refractory periods and lower limiting frequencies were measured and compared to the usual parameters (distal motor latency, conduction velocity of motor fibres, and the mixed nerve action potential).The conduction velocity was indicative of the diseased function in 37% whereas the relative refractory period (latency) was abnormal in nearly 80% and the lower limiting frequency (latency) in about 60%.Two samples taken at random, each of them consisting of 13 patients with normal conduction velocities between 51.0 and 63.5 m/sec showed differences only at the 1% level (p<0.01) as far as the mean values of the distal latency and the maximum conduction velocity were concerned. The difference between the mean values of the relative refractory period (latency) and of the lower limiting frequency (latency), however, was highly significant (p<0.0005). Thus, in our experience, the relative refractory period (latency) and the lower limiting frequency (latency) are more sensitive indicators of mild functional disturbances of peripheral nerves than the maximum conduction velocity.

Die Untersuchungen wurden in dankenswerter Weise von der Deutschen Forschungsgemeinschaft unterstützt.     

Swim-induced grooming in mice is mediated by a dopaminergic substrate

Summary Grooming induced in mice after a period of swimming was potently and dose-dependently blocked by neuroleptics. The order of potency of the neuroleptics was spiroperidol>haloperidol>cis-flupenthixol>pimozide>chlorpromazine>thioridazine. The trans isomer of flupenthixol was inactive at 40M/kg. The-adrenergic receptor antagonists, phentolamine and phenoxybenzamine, and the catecholamine synthesis inhibitor,-methyl-p-tyrosine were essentially without effect on the grooming behaviour. Amitriptyline inhibited grooming behaviour only in doses which severely affected the animals motor function. Fluoxetine was without effect. Cisflupenthixol was less active in inhibiting grooming in animals chronically treated with haloperidol than in control animals, indicating the presence of supersensitive dopamine receptors. The data indicate that swim-induced grooming in mice is mediated via dopaminergic systems.     

Alaproclate,a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia

Summary Alaproclate, a new specific 5-HT uptake inhibitor, was examined for its action on several receptors in the brain, for its action on the NA, DA and 5-HT uptake mechanismsin vivo and for its action on brain biogenic amine content. Alaproclate was practically devoid of action on a number of receptors as examined in binding studiesin vitro: 5-HT, histamine-H₁, ₁,- ₂-adrenergic and dopamine D₂ receptors. Alaproclate had also a weak affinity for³H-norzimeldine binding sites in contrast to imipramine. Unlike the tricyclic antidepressants alaproclate had a negligible action on muscarinic receptors and failed to block muscarinic induced stimulationin vivo. Contrary to clomipramine alaproclate failed to block NA uptakein vivo. Alaproclate was found to display a regional selectivity in blocking 5-HT uptakein vivo (measured with the H 75/12-method). The compound was most potent in the hippocampus and hypothalamus followed by striatum and cerebral cortex with a low potency in the spinal cord. The results are discussed in relation to a previously presented carrier site model for serotonin reuptake.     

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice,evidenced by antidepressants

Summary The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5–50 g) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 g per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6–11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 g, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 g, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH 23390 (100 g/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.