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Narcolepsy in 7 dogs was tentatively diagnosed on the onset of cataplexy, before or during young adulthood. Confirmatory polygraphic sleep recordings were done in 3 of the dogs. In 2 dogs, treatment with neostigmine did not cause the signs to disappear, thus ruling out myasthenia gravis; trials with imipramine reduced catapletic attacks. Data from case histories, polygraphic recordings, drug trials, and clinical tests were used to compare and contrast the disease in man and in the dog.

Experiments were held not only to determine clinical differences in reaction for neuroleptics and antidepressants, but also to place them in relation to pharmacological data gained from animal experiments. For the tranquilizers, only a scheme of clinical impressions, could be offered since with this group of psychotropics the differences in reaction are as a rule too small to be secured statistically.

The behavioral effects of lopramine [N-methyl-N-(4-chlorobenzoyl-methyl)-3-(10, 11-dihydro-5H-dibenz (b,f) azepin-5-yl) propylamine hydrochloride] were investigated in mice and rats and compared with those of amitriptyline and imipramine. Lopramine inhibited reserpine hypothermia and haloperidol catalepsy in mice and tetrabenazine ptosis in rats. In addition the drug potentiated the effects of methamphetamine, and DOPA- or apomorphine-induced stereotypy in mice, whereas it suppressed muricide of the rat induced by either olfactory bulbectomy or delta9-tetrahydrocannabinol, similar to the responses seen with imipramine and amitriptyline. On the other hand,lopramine increased spontaneous motor activity and markedly potentiated methamphetamine hyperactivity. In contrast to imipramine and amitriptyline, lopramine failed to counteract both the lethal effect of physostigmine and oxotremorine tremor in mice, indicating that the drug had no central anticholinergic effect. Lopramine, even at such a large dose as 5,000 mg/kg p.o., caused neitherimpairment of coordinated motor activity nor muscle relaxation. It is concluded that lopramine is a new type of tricyclic antidepressant with extremely low toxicity and without central anticholinergic action.

The development, clinical course, and electrophysiologic characteristics of narcolepsy were evaluated in 50 adults who had a current complaint of sleep attacks and cataplexy. In most of the patients, the first symptoms, usually excessive daytime sleepiness and sleep attacks, developed during childhood or adolescence. The condition was invariably chronic. Patients frequently had family histories of some disorder of excessive daytime sleepiness. In nocturnal sleep or daytime nap recordings, all but three of the patients demonstrated a rapid-eye-movement (REM) period at sleep onset. Sleep apnea was found in only one patient. Our findings indicate that sleep laboratory recordings to detect a sleep-on-set REM period are of little diagnostic value when the narcoleptic patient has cataplexy. Furthermore, narcoleptic patients require sleep laboratory evaluation for sleep apnea only when the presence of apnea is suggested by the sleep history.

Following introduction of triftazine (2 mg/kg) and phthoracizine 8 mg/kg, separately and in combination, the intensity of catalepsy, the content of dopamine, norepinephrine (fluorometrically), of acetylcholine (biologically) and the activity of cholinesterase (calorimetrically) in the caudate nuclei and the frontal part of the cortex were determined in rats. It was established that with its one-time administration phthoracizine, while keeping down the intensity of triftazine-induced catalepsy, prevents, at the same time, the development of a number of biochemical effects, viz. there appears a distinctly pronounced tendency toward mormalization of the dopamine, acetylcholine levels and of the cholinesterase activity. A multiple joint administration of the drugs is also attended by lowering the intensity of catalepsy. Then, biochemical changes manifest themselves in more complex interrelations.

In a previous study, anticataleptic action of cyproheptadine was reported. The present investigation deals with the influence of WA-335 (9,10-dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol), another antagonist of serotonin, on catalepsy induced in rats with spiroperidol, pimozide, fluphenazine and reserpine. WA-335 antagonized catalepsy induced by these neuroleptics (the effect on reserpine-induced catalepsy was weakest). Joint administration of WA-335 and L-DOPA with an inhibitor of peripheral decarboxylase, or WA-335 and amantadine produced a stronger antagonistic effect (spiroperidol catalepsy) than either of these substances separately. WA-335 did not prevent catalepsy induced with physostigmine.

A new series of thyrotropin-releasing hormone (TRH) analogues, obtained by further modifications of our most potent central nervous system (CNS) stimulating neutral tripeptides at both termini, were synthesized by the pentafluorophenyl ester method and tested for CNS and thyrotropin (TSH) releasing activity. Replacement of pyroglutamic acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid or gamma-butyrolactone-gamma-carboxylic acid and that of proline by pipecolic acid, thiazolidine-4-carboxylic acid, or homoproline in [Leu2]- and [Nva2]TRH led to tripeptides structurally widely different from TRH. In spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have stronger anticataleptic effect than TRH, with negligible or no hormonal potency. The highest CNS activity was achieved when pyroglutamic acid was replaced by pyro-2-aminoadipic acid at the N-terminus [pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2,2]. A novel synthesis of L-2-aminoadipic acid suitable for large-scale preparation is also described.

Two case reports and data from literature on the subject are used by the authors to describe characteristics of pathogenetic importance of neuroleptic induced stupor (NIS). The origin of NIS is outlined briefly and some fundamental clinical and experimental facts are presented, all of which stress the importance of the acute blockade of postsynaptic DA-ergic receptors. Emphasis is placed on the significance of the possible relationship and similarity between NIS and catatonic stupor, and on the theoretical possibilities which this offers.

The N-methyl-D-aspartate (NMDA) antagonist MK-801 was administered to rats in three doses (0.08, 0.16, 0.33 mg/kg) in order to examine its effects on catalepsy that was induced by haloperidol (0.5 mg/kg). The degree of catalepsy was assessed 30 and 60 min after application of drugs by placing the rat on a horizontal bar, on a podium and on a vertical grid. Animals having received saline and haloperidol showed a higher degree of catalepsy than animals having received MK-801 and haloperidol (except for the lowest dose of MK-801). These findings may suggest a therapeutic potential of MK-801 and possibly of other NMDA antagonists in the treatment of Parkinson's disease.

Behavioral effects of amantadine, especially on abnormal behavior in mice and rats, were reevaluated, in comparison with those of tricyclic antidepressants, methamphetamine and L-DOPA. 1) Amantadine at 10 approximately 50 mg/kg, i.p., tended to decrease ambulation and rearing in rats and mice. The drug at 50 mg/kg, i.p., caused piloerection and hyperirritability and at doses over 80 mg/kg, i.p., it impaired coordinated motor activity in rats. 2) Amantadine inhibited methamphetamine-induced hyperactivity, but apomorphine-induced stereotyped behavior was unaffected in rats. 3) Amantadine was equipotent to imipramine in suppressing haloperidol-induced catalepsy in rats, but L-DOPA was without effect. On the other hand, amantadine was 40 and 400 times as potent as imipramine and L-DOPA, respectively, in suppressing delta 9-tetrahydrocannabinol (THC)-induced catalepsy in rats. 4) Amantadine was as potent as imipramine in suppressing the muricide of olfactory bulbectomized rats, but was 3.5, 8.8 and 225.5 times as potent as methamphetamine, imipramine and L-DOPA, respectively, in inhibiting THC-induced reversible muricide in rats. 5) Amantadine at 50 mg/kg did not elicit circling behavior in the rat with unilateral nigral lesion induced by 6-hydroxydopamine. 6) Amantadine at high doses caused irritable aggression characterized by squealing in rats pretreated with intraventricular 6-hydroxydopamine. The most important characteristic of amantadine is its prominent effect suppressing the THC-induced catalepsy and muricide. This may be a reflection of the feature of amantadine activating the dopaminergic as well as the serotonergic systems.

Haloperidol-induced catalepsy in rats is reduced by low dose baclofen and is potentiated by high dose baclofen. This biphasic behavioral effect is consistent with reported differences between presynaptic and postsynaptic GABA receptors. Low dose baclofen could have an anti-cholinergic effect by activating presynaptic GABA receptors that inhibit the release of acetylcholine. High dose baclofen could have an anti-dopamine effect by activating postsynaptic GABA receptors that inhibit the firing of dopamine neurons.

Mice were treated acutely or chronically with apomorphine (APO) (0.1 and 1.0 mg/kg) or L-DOPA (150 mg/kg) plus benserazide (50 mg/kg). The decrease of homovanillic acid (HVA) caused by APO was greater in acutely treated animals. After APO or L-DOPA pretreatment the animals received single doses of haloperidol (HALO) (1.5 mg/kg) or saline and were submitted to behavioral and biochemical analysis in order to determine changes in dopaminergic receptor sensitivity. When the acutely and chronically treated groups were compared, we found no difference in the cataleptogenic effect of HALO nor any difference in the effect of HALO in increasing brain HVA levels. The data suggest that chronic treatment with dopaminergic agonists leads to changes in receptor sensitivity for the agonist but not for the antagonist effect.

In recent years the clinical study of pharmacopsychiatric basic reactions has directed our attention to syndromatic complex-structures in the impulse-range, which we have temed as basic syndromes. In so doing, a series of significant psychotic symptoms are being neglected, when these are not of primary pharmacopsychiatric relevance. This applies particularly to such psychopathological conceptions, which in addition prejudice at the same time a nosological coordination and thereby reduce the valency of other parameters. The limiting of basic psychopathological conditions now allow us to probe syndromatically through polarisation (stimulated-inhibited) and further differentiations in the quantitative and qualitative spheres the psychosis-spectrum. The four basic functions discovered hereby (Hyper- and Hypo- as well as Para- and Dys-functions) now show themselves with explicit reference to their nosological independence in various psychopathological planes eg. motoricity, affectivity, perception, power to experience, intrapsychical consumption-modality etc. With a process of this kind in our view not only is psychiatric pathology pharmacotherapeutically determined, but also the medico-curative connection is more exactly definable. Furthermore these results contribute directly to current experimental projects on the use of material for documentation.

The influence of taurine on cataleptogenic effect of neuroleptics was investigated in male Wistar rats. It was found that taurine 900 micrograms/rat icv reduced significantly haloperidol or fluphenazine-induced catalepsy. In rats receiving taurine in a dose of 450 micrograms, not influencing catalepsy, with low doses of anticholinergic antiparkinsonian agents (trihexyphenidyl and pridinol) strong anticataleptic effect was observed. The results suggest that taurine facilitates neurotransmission in nigrostriatal dopaminergic neurons.

Central activity, antihypertensive action and antiulcerogenic actions of Neurotropin (NSP), an extract isolated from vaccinia virus-innoculated skin or tissues of rabbits were investigated herein. When actions of NSP were examined in isolated muscle preparations by the Magnus-method, peristalsis and ACh-induced contraction in the small intestine isolated from crayfish were not influenced, peristalsis and ACh-induced contraction in the small intestine from mice were slightly accelerated, but adrenaline-induced relaxation in the small intestine from mice was not affected. Histamine-induced contraction in the small intestine and tracheal muscles isolated from guinea pigs was antagonized slightly, or not at all by NSP in a high concentration. NSP had no direct action nor anti-ACh action on abdominal muscles from frogs. NSP had no influence on E1-mice-convulsions. Both spontaneous motor activities and exploratory movements in mice were depressed. Sleeping time induced by hexobarbital-Na was prolonged in mice. Tremorine-induced tremor in mice was inhibited by NSP, while perphenazine-induced catalepsy in rats was not. Normal blood pressure in Wistar rats was not influenced, but high blood pressure in SHR (spontaneously hypertensive rats) decreased close to normal levels after NSP. NSP had antiulcerogenic effects on Takagi's restraint-plus-water-immersing ulcers in rats and histamine-induced duodenal ulcers in guinea pigs, but no influence on Shay ulcers in Wistar rats. From the data obtained herein, it may be concluded that NSP has many central depressant-like activities.

N-[(1-butyl-2-pyrrolidinyl)methyl]-2-methyl-5-sulfamoyl-2,3- dihydrobenzofuran-7-carboxamide hydrochloride (Y-20024) was synthesized in our laboratories in anticipation of developing a new psychotropic drug. In the present study, the pharmacological properties of Y-20024 were compared with those of sulpiride (SPR) and haloperidol (HPD). Administered orally, Y-20024 was 10 times stronger than SPR in inhibiting apomorphine (0.5 mg/kg, s.c.)-induced hyperactivity in mice; administered intravenously or intracerebroventricularly, it was 2 times or one third as strong, respectively. Y-20024 was almost equipotent to SPR in antagonizing apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs. Combined with methamphetamine (5 mg/kg, i.p.), Y-20024 and SPR induced mortality dose-dependently in rats, but HPD did not. The mammotropic activity of Y-20024 administered orally once a day for 5 days was almost equipotent to that of SPR. From these results, Y-20024, pharmacologically similar to SPR, but superior in bioavailability and penetration through the blood brain barrier, may have potential usefulness as an antipsychotic drug.

Injection of a dose of haloperidol that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. Chronic GM1 ganglioside administration improves the behavioral impairments, partially restores striatal dopamine (DA) content and prevents DA D-2 receptor up-regulation. Discontinuation of GM1 ganglioside treatment results in a time-dependent decline of striatal DA content to pretreatment pathological levels, return of haloperidol-induced sensorimotor deficits and a rise of DA D-2 receptor density in the striatum. Apparently, continuous administration of GM1 ganglioside is necessary to maintain the biochemical and behavioral recovery in the MPTP-treated mouse. These observations may provide useful cues for understanding the mechanism of action of GM1 ganglioside.

Preliminary phytochemical investigation of the leaves of Synclisia scabrida indicated the presence of two alkaloids in the water extracts and five alkaloids in the ethanol extracts. The alkaloidal fraction obtained from the cold ethanol extract furnished on column-chromatography, a homogeneous amorphous solid which has been designated as alkaloid C. Alkaloid C showed positive test for alkaloids. The UV and IR spectra and colour reactions of alkaloid C indicated that the compound may be a phenolic bisbenzylisoquinoline alkaloid. All the extracts delayed the onset and shortened the duration of apomorphine-induced stereotyped behaviour in chicks. In addition, 40 mg kg-1 i.p. of the ethanolic extract induced catalepsy in rats. The cold water extract (CWE) synchronized the EEG of the hyperstriatum, optic tectum and the reticular formation while the EMG activity was slightly enhanced. The hot ethanol alkaloidal extract (HEE) inhibited the growth of Pseudomonas aeruginosa and Staphylococcus aureus. The minimum inhibitory concentration of HEE on Pseudomonas aeruginosa strains I and II were 5 and 2.5 micrograms/ml while for Staphylococcus aureus strains I and II were 5 and 10 micrograms/ml, respectively. Up to 1 g kg-1 i.p. of the extract failed to induce any lethal effect in chicks and rats. These effects of the leaf extracts of Synclisia scabrida Miers support some of the local uses of the plant by traditional medical practitioners.

Alpha-methyl-DOPA increased the duration of excitation induced by L-DOPA in mice, alpha-methyl-DOPA potentiated the anticataleptogenic activity of L-DOPA in mice pretreated with reserpine or haloperidol. Alpha-methyl-DOPA given to cats 30 min prior to L-DOPA diminished the influence of L-DOPA on the blood pressure and the contraction of the nictitating membrane. When given 4 to 6 hours prior to L-DOPA alpha-methyl DOPA enhanced the reaction of the blood pressure and contraction of the nictitating membrane induced by L-DOPA or dopamine.

In acute and chronic experiments on mice, rats, cats and rabbits in a wide range of tests, a study was conducted of the biological properties of alpha-asarone (1-propenyl-2,4,5- methoxybenzol)--etherophenol, isolated by the authors from the roots of Asarum europaeum. It was determined that the LD50 of asarone for mice in enteral administration was 417.6 mg/kg, in intra-abdominal--310 mg/kg. The preparation has quite diverse biological activity--tranquilizing, sedative, antiulcer, spasmolytic and antisclerosing. In its pharmacological properties the studied asarone is identical with asarone obtained from Acorus calamus and Guatteria.

Dihydroergocryptine (DHECP), an ergot alkaloid with potent dopaminergic activity, was injected acutely or subchronically to aged (24 months old) male rats of the F344 strain, at the dose of 0.05 or 0.1 mg/kg. The immobility in the "despair" test (constrained swim) was longer in 24-month-old rats than in younger animals. This behavioral change was reduced in rats treated subchronically with DHECP, but no significant change was found in animals with acute treatment. Aged rats showed an increased haloperidol-induced catalepsy and a reduced motor performance and coordination as compared to animals of 2 and 10 months of age. Acute treatment with DHECP was followed by an attenuation of haloperidol-induced catalepsy and an improvement of motor performance and coordination of aged rats. Similar results were obtained after subchronic treatment with DHECP, but the effect on the rotorod behavior was more potent after subchronic treatment than after acute injection of the drug. It is possible that the improvement of behavioral deficits of aged rats after the treatment with DHECP depends on the facilitating effect of this drug on central dopamine transmission that may be impaired in these animals.

The novel anxiolytic drug, buspirone, reverses catalepsy induced by haloperidol. A series of aryl-piperazine analogues of buspirone and other 5-hydroxytryptaminergic agonists were tested for their ability to reverse haloperidol induced catalepsy. Those drugs with strong affinity for 5-hydroxytryptamine1a receptors were able to reverse catalepsy. Drugs with affinity for other 5-HT receptors or weak affinity were ineffective. However, inhibition of postsynaptic 5-HT receptors neither inhibited nor potentiated reversal of catalepsy and leaves open the question as to the site or mechanism for this effect.