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The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.

This study was conducted to characterize the opiate dependence potential of a number of opiate and non-opiate psychoactive drugs in morphine-dependent cynomolgus monkeys (Macaca fascicularis). In addition, the agonist/antagonist profiles of buprenorphine and butorphanol were directly compared. Six male cynomolgus monkeys were maintained on morphine (3.0 mg/kg, q.i.d.) for 6 months. On evaluation days, monkeys were scored for opiate withdrawal signs 18 h after the last dose of morphine. Single dose suppression studies were conducted by giving subcutaneous injections of morphine (3 or 6 mg/kg), naloxone (0.01, 0.05 or 0.1 mg/kg), buprenorphine (1, 3, 10, 30 or 100 µg/kg), butorphanol (0.01, 0.1, 1.0 or 3.2 mg/kg), haloperidol (0.01, 0.05 or 0.1 mg/kg), imipramine (2, 5 or 10 mg/kg) or saline and measuring the number and frequency of withdrawal signs that appeared over a 2-h period. In a separate precipitation experiment either saline or 0.01 or 0.1 mg/kg butorphanol was administered 2 h after the last maintenance dose of morphine. In the single dose suppression test, morphine completely suppressed most withdrawal signs while naloxone increased the severity of withdrawal. All doses of buprenorphine increased many withdrawal signs such as backward gait, rearing, chafing face, chain biting, vomiting, masturbation, and vocalizations after intimidation. Only a few signs were reduced, but the overall withdrawal scores were not significantly increased. Low doses of butorphanol suppressed some signs while the highest dose almost completely eliminated all withdrawal signs. Butorphanol also failed to precipitate opiate withdrawal, and actually reversed the signs present in the saline-treated monkeys. Imipramine and haloperidol had little effect on the morphine withdrawal syndrome. These data suggest buprenorphine exerts only opioid antagonistic activity and butorphanol exerts only opioid agonistic activity over a wide range of doses studied in morphine-dependent cynomolgus monkeys.

Postural myoclonus associated with long-term administration of neuroleptics was demonstrated in schizophrenic patients. Sixty patients who had been taking neuroleptics for more than 3 months were investigated for myoclonus and the relationships between postural myoclonus and age, duration of illness, duration of medication, current daily dose, cumulative dose, occurrence of abnormal finger movement, parkinsonism, and tardive dyskinesia were evaluated. Twenty-three patients (38%) showed postural myoclonus when holding the hands forward with the elbow joints flexed at about 90%. Male patients showed a higher incidence of myoclonus than female patients. Patients with myoclonus had been given significantly higher doses of neuroleptics than those without myoclonus. There was a significant correlation between the occurrence of myoclonus and abnormal finger movement. Electromyographic recordings in 7 patients with prominent myoclonus revealed that arrhythmic jerks occurred in the extensor carpi radialis and posterior deltoid muscles and that the jerks on the left and right side were not synchronized. Clonazepam reduced the frequency of the myoclonic activity.

We investigated whether chronic administration of guanidinoethane sulfonate, an inhibitor of taurine uptake, could modify the antiepileptic actions of phenobarbital and phenytoin on maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate decreased the taurine concentration in the brain to 76% of the control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. However, treatment with guanidinoethane sulfonate lessened the antiepileptic actions of phenobarbital and phenytoin on electroshock seizures. The brain concentrations of phenobarbital and phenytoin were unaltered by administration of guanidinoethane sulfonate. The brain concentrations of guanidinoethane sulfonate and total guanidino compounds were unchanged by the injection of either phenobarbital or phenytoin. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may have been related to the decrease in taurine concentration produced by guanidinoethane sulfonate.

Tremor induced by TRH and oxotremorine was recorded by a capacitance transducer, and its intensity and frequency were evaluated using power arrays. In mice treated with TRH (20 mg/kg, i.p.), the latency of tremor was 17.1 +/- 1.7 min (mean +/- S.E.) and the duration was 20.4 +/- 2.2 min, while the frequency was 13.7 +/- 0.3 Hz. In animals with oxotremorine (0.5 mg/kg, i.p.), the latency was 4.3 +/- 0.4 min and the duration was 18 +/- 2.2 min, while the frequency was 12.7 +/- 0.3 Hz. The latter frequency, however, was significantly shifted to a lower frequency as a function of time. In TRH-induced tremor, vertical movements appeared in the same degree as horizontal movements. In oxotremorine-induced tremor, the vertical movements were few, whereas the horizontal movements were observed in a degree similar to those of TRH. The TRH tremor was suppressed by haloperidol and propranolol, but not by atropine. On the contrary, the oxotremorine tremor was inhibited by atropine, but not by haloperidol or propranolol. These results suggest that mechanisms of tremor induced by TRH differ qualitatively from those by oxotremorine; dopaminergic and beta-adrenergic receptor mediated functions may be linked to the developments of tremor caused by TRH, while cholinergic systems have a little effect in mice. The apparatus used in this study and power spectral analysis with power arrays may provide a useful method for simultaneous evaluation of the latency, duration, intensity and frequency of tremors.

The effects of taurine on wet-dog shakes produced by [D-Ala2,Met5]enkephalinamide (DAME) were investigated in rats. Wet-dog shakes and epileptic discharges in the hippocampus were produced by intraventricular administration of 50 micrograms of DAME. Pretreatment with 10 microliter of taurine, given intraventricularly in a dose of 0.95 mumol, inhibited wet-dog shakes and epileptic discharges in the hippocampus. While the same dose of gamma-aminobutyric acid (GABA) also inhibited the wet-dog shakes, the same dose of L-leucine did not suppress them. These observations indicate that the inhibition of DAME-induced wet-dog shakes by taurine is associated with the suppression of seizure activities in the hippocampus. The possibility that taurine possesses an antagonistic action on opioid peptides is discussed.

We demonstrated that stereotyped behavior and tremor induced by methamphetamine (MA) were potentiated by pretreatment with phenytoin (PNT) in mice. Similar enhancing effects were obtained by pretreatment with carbamazepine. Gas chromatographic study demonstrated that pretreatment with PNT increased MA concentrations in the brain to approximately 2.5 times of control level. The increased MA concentrations were thought to be a major factor for the observed potentiation of MA-induced behavior by PNT. However, all MA-induced behavior were not equally potentiated; tremor was enhanced more than stereotypy. These results suggest that central neuronal mechanisms may also be involved in PNT-potentiated MA-induced behavior in mice.

Wet dog shakes (WDS) are paroxysmal shudders of head, neck and trunk. This behavior has been observed when dipping animals into cold water (41), application of xylene to the fur (39) and tactile stimulation around ears (1). Pharmacological studies revealed that WDS can be produced by administration of thyrotropin-releasing hormone (9,24,29,41,42), 5-Hydroxytryptamine (3,12), or kainic acid (5,25). WDS are also known as a classical sign of morphine abstinence in rats (40,43). In 1976, Bloom et al. first reported that this shaking behavior was elicited by acute administration of β-endorphln into the lateral ventricle in rats. Similar observations were made in rats with enkephalin (15). In addition, it was found that epileptic discharges were provoked by the intraventricular (icv) injection of opioid peptides and WDS always accompanied the onset of seizure discharges (15,16,37). These findings suggest that there may be an association between electrical seizure activities and WDS.

We investigated the antinociceptive effects produced by peripheral electric stimulation (PES) in mice and the influence of administration of l -5-hydroxytryptophan (5-HTP), methysergide and naloxone on the antinociceptive effects of the PES. Administration of 5-HTP enhanced antinociceptive effects induced by PES, while methysergide and naloxone abolished this antinociception. The mechanisms of analgesia produced by PES involve both endogenous opiate systems and central serotonergic mechanisms.

Guanidinoethane sulfonate is a compound which has been recently found to inhibit competitively taurine uptake and thereby decrease the concentration of this amino acid in various organs including the brain in rats1 and mice2,3. Taurine, or 2-aminoethane sulfonate, is an inhibitory amino acid like γ-aminobutyric acid (GABA), glycine or β-alanine in the central nervous system (CNS) and is known to possess antiepileptic properties against various types of experimentally-induced seizures in mammals (for review see Barbeau and Huxtable4, Huxtable5, Durelli and Mutani6). Interference with GABA or glycine system in the CNS by specific receptor blockers such as bicuculline or strychnine causes convulsions7. Decreased GABA content of the brain caused by inhibiting glutamic acid decarboxylase activity also produces convulsions.In this study we investigate whether a selective decrease in the taurine concentration in the brain produced by guanidinoethane sulfonate can increase the susceptibility to electroshock seizures or modify the anticonvulsive action of phenobarbital or phenytoin against maximal electroshock seizures in mice.

Tardive dyskinesia seems to occur as a result of diminished cholinergic and enhanced dopaminergic activity in the striatum. Meclofenoxate has been shown to increase cerebral cholinergic activity. To ameliorate the tardive dyskinesia, meclofenoxate was given orally, 600–1200 mg/day, for 6–12 weeks. The effects of the drug were evaluated by scoring the degree of involuntary movement. Among 11 subjects with tardive dyskinesia or dystonia, 4 improved markedly, 1 moderately, 2 slightly, and there was no improvement in 4. One patient with subacute oral dyskinesia, induced by administration of neuroleptics for 1 month, improved markedly. The possibility that meclofenoxate may be effective in dealing with dyskinesias that are induced by neuroleptics warrants further attention.

Oral administration of isofloxythepin (0.5-8.0 mg/kg) inhibited decapitation convulsions in a dose-dependent manner as shown by decreasing the incidence and shortening the convulsion's duration, the effects continuing until 24 hr after administration. Zotepine (8, 16 mg/kg, SC) also decreased the duration but not the incidence of the convulsion. However, the other neuroleptics such as haloperidol, spiperone, perphenazine, trifluoperazine, pimozide and sulpiride failed to affect decapitation convulsions. Reserpine (8 mg/kg, SC) inhibited decapitation convulsions, accompanied by decreasing levels of norepinephrine, dopamine and serotonin in the spinal cord. Isofloxythepin at doses of 4 and 8 mg/kg, PO which completely abolished decapitation convulsions, failed to change norepinephrine and dopamine levels but increased serotonin levels in the spinal cord. Isofloxythepin (0.5-8.0 mg/kg) increased serum prolactin levels in a dose-dependent manner and zotepine (16 mg/kg), haloperidol (1 mg/kg) and reserpine (8 mg/kg) also elevated the levels. The results imply that both isofloxythepin and zotepine, but not the other neuroleptics, inhibit convulsions without decreasing spinal levels of norepinephrine which appears to be the amine most directly involved in the occurrence of decapitation convulsions, although these neuroleptics enhance prolactin secretion by blocking dopamine receptors in the pituitary.

Doxepin was compared with amitriptyline and imipramine in respect to behavioral pharmacology with rats and mice. Doxepin antagonized reserpine hypothermia and tetrabenazine ptosis and potentiated amphetamine stereotypy and methamphetamine hyperactivity. In this respect doxepin and amitriptyline were equipotent but doxepin was more potent than amitriptyline and imipramine regarding major or minor tranquilizing-like effects, such as reduction of locomotor activity in open-field test, inhibition of conditioned avoidance response, suppression of experimentally induced hyperemotionality, anticonvulsant activity and potentiation of hypnotics and anesthetics. Doxepin is, therefore, characterized as an antidepressant drug having marked tranquilizing activities.

We investigated effects of various drugs affecting noradrenergic, serotonergic and cholinergic activities upon potentiating action of Phenytoin (PNT) for methamphetamine (MA)-induced behavior in mice. Five min after pretreatment with PNT (10 mg/kg), male adult mice were injected with propranolol, methysergide or atropine or saline 5 min prior to an injection of MA (10 mg/kg). All solutions were administered i.p. Stereotypy and tremor produced by this combination of MA plus PNT were approximately 1.5 and 2.0 times potent, respectively, as compared with those induced by a single injection of MA. MA-induced behavioral responses were individually observed and scored in a photocell chamber allowing simultaneous recording of locomotor activity. Methysergide reduced the scores for stereotypy induced by MA plus PNT only with the highest dose (15 mg/kg), while this serotonin-receptor blocker did not affect the scores for tremor. Atropine (5 mg/kg) did not influence behavior caused by MA plus PNT. Propranolol (1-10 mg/kg) decreased dose-dependently the scores for tremor and stereotypy produced by MA plus PNT. Even with the smallest dose, stereotypy was suppressed significantly. The effects of propranolol accompanied alteration of locomotor activity: the activity did not decrease with time to the same extent as that in control animals probably because stereotypy and tremor were suppressed. Since propranolol (1 mg/kg) was found not to alter the behavioral responses induced by MA alone in separate experiments, the suppressive actions of the μ-adrenoceptor blocker against tremor and stereotypy produced by MA plus PNT may be due to an interaction with PNT in the central nervous system.

In previous studies, we demonstrated that clonic seizures caused by either maximal electroshock or decapitation in mice were suppressed by intraspinal injection of 6-OHDA, suggesting that the induction of clonic seizures may be associated with spinal noradrenergic mechanisms. In the present study, we investigated whether clonic phase of maximal electroshock seizures (MES) and decapitation convulsions (DC) are also involved by drugs affecting cholinergic activity. Male adult mice (ddY) were used. MES were elicited with a current intensity through corneal electrodes (50 mA for 0.2 sec). Intensity of clonic seizures caused by a maximal electroshock and decapitation was recorded by an apparatus with an accelerometer. All drugs except bethanechol, carbachol and 6-OHDA were injected i.p.. Bethanechol, carbachol and 6-OHDA were administered into intrathecal space at Th8-L2 with a volume of 1 μl. The intensity of clonic seizures of MES and DC was suppressed by oxotremorine, physostigmine and bethanechol. Similarly, the clonic intensity of DC was reduced by carbachol, whereas it was enhanced by atropine and scopolamine. As previously shown, Phenytoin (PNT) increased the seizure intensity. Potentiating effects of PNT on clonic seizures of MES and DC were reduced by oxotremorine. The clonic intensity of MES was increased by methamphetamine and procaine. This increased intensity by these drugs was also reduced by oxotremorine. On the other hand, clonic seizure activity of DC which had been inhibited by 6-OHDA reappeared by atropine. These results suggest that cholinergic as well as noradrenergic neuronal activity in the spinal cord may play a role in causing clonic seizures of MES and DC in mice.

It is well known that edema occurs rapidly after spinal cord injury. However, the mechanisms of the formation of edema remains unresolved. In the present study, we investigated relationship between edema formation and enhancement of vascular permeability. Edema was produced by a compression method by which the spinal cord of adult rabbits (1.6-2.5 kg of body weight) was injured at the Th8 cord level. Degree of edema was estimated by measurement of water content of the injured segment of the spinal cord. The vascular permeability was evaluated with time by measuring fluorometrically levels of fluor-escein-Na (Flu) that was administered i.v. at a dose of 50 mg/kg 10 min prior to sacrifice. Rabbits which had suffered from mild injury in the spinal cord with a plumb of 50 g for 1 min showed progressive formation of edema until 6 hours after compression. In these cases the levels of Flu which had been injected 10 min before sacrifice was high 1 hour after the trauma as in animals with severe injury caused by compression with a 100 g plumb for 10 min. However, these high values of Flu in the mild cases were restored to the control levels 3 hours after the injury, while they continued till 6 hours in the severe trauma. Thus, there appeared to be dissociation in the degree between edema formation and extravasation in the mildly injured spinal cord caused by compression.