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3-Dimethylamino-1,2,3,4-tetrahydrocarbazole, a structurally modified tryptamine, prevented amphetamine-induced stereotyped behavior in rats and prevented reserpine-induced ptosis in mice. Further study of this compound and a number of substituted derivatives indicated that either imipramine-like or chlorpromazine-like profiles were obtainable by changing substituents and their positions.
This study characterized the neuroprotective and behavioral effects of (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), a novel, selective and systemically active metabotropic glutamate (mGlu)(1) receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40-50% at 0.01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); whereas in the middle cerebral artery occlusion model, a trend for a neuroprotective effect was obtained after triple i.v. bolus application of 0.03-3 mg/kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those at which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. BAY 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse (MED: 10 mg/kg, i.v.). As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801). Thus, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulation behavior. Although behavioral stereotypies and disruption of sensorimotor gating induced by amphetamine or apomorphine were not affected by BAY 36-7620, the compound attenuated some behavioral effects of iGlu receptor antagonists, such as excessive grooming or licking, and their facilitation of intracranial self-stimulation behavior. It is concluded that mGlu(1) receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resulting from antagonism of iGlu receptors.
Several independent genome scans have revealed excess allele sharing in an overlapping 40 cM region of 7q21-34 in autism. DLX6 and Piccolo (PCLO) at 7q21-q22 are two positional and functional candidate genes in autism. We have investigated a single nucleotide polymorphism (SNP) in exon 4 of the PCLO gene and a SNP in intron 1 of the DLX6 gene for linkage and association in autistic disorder using both qualitative and quantitative analyses. One hundred ninety-six multiplex autistic disorder families were tested using transmission disequilibrium and two-point affected sib pair linkage analysis. We found no evidence of association or linkage with the two intragenic markers. In addition, there was also no linkage or association between language and stereotypic behavior quantitative traits in autism and the SNPs. In conclusion, our studies suggest that these two SNPs in DLX6 and PCLO genes are not in linkage disequilibrium with autism.
Though quipazine is widely regarded as a relatively pure serotonergic (5-HT) agonist and has been reported to have no dopamine (DA) agonist properties, it has produced stereotyped behavior (SB) associated with DA agonist arousal of striatal DA mechanisms. Since we observed a dose-related inhibition of quipazine induced stereotypy (QISB) by a centrally acting DA antagonist (haloperidol) that could not be mimicked by a central 5-HT receptor blocking agent (methysergide), it appeared likely that QISB is mediated by striatal DA mechanisms. This was further supported by our observing that QISB could be potentiated by a subthreshold dose of the central DA agonist apomorphine. In light of this, and the presence of abnormal movements seen concomitantly with QISB that are typically produced by intrastriatal injections of 5-HT agonists, it appears that QISB is a complex phenomenon. While QISB seems to be primarily due to the stimulation of DA mechanisms, the effect of quipazine on behavior appears to be a combined result of its effects on both DA and 5-HT mechanisms. Specifically, central striatal DA receptors appear to mediate QISB per se, while serotonergic mechanisms stimulated by quipazine inhibit its further development and produce extrapyramidal-like abnormal movements.
Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity.
Clonazepam at two doses of 1 mg/kg i.p. significantly decreased 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents in the rat caudatus and cortex but not so in the olfactory tubercle, septum and hypothalamus. The drug decreased dopamine (DA) turnover rate in the caudatus, but did not inhibit tyrosine hydroxylase activity. The drug significantly enhanced stereotyped behavior induced by apomorphine and d-methamphetamine. Clonazepam enhanced apomorphine-induced decrease in striatal HVA, and cortical DOPAC and HVA contents, and d-methamphetamine-induced decrease in cortical DOPAC content. Reserpine pretreatment did not affect apomorphine-induced stereotypy and its enhancement with clonazepam. The drug did not activate adenylate cyclase nor DA-sensitive adenylate cyclase in the striatal homogenates and did not change cyclic AMP content in the caudatus. The drug inhibited phosphodiesterase activity in caudate and cortical homogenates but not in vivo. Clonazepam did not alter ChAc and AChE activities in the caudatus, 6 other cerebral regions and the spinal area. Clonazepam also decreased NE turnover in the caudatus and 5-HIAA contents in the brainstem area. These neurochemical and behavioral effects of clonazepam indicate probable postjunctional DA stimulation in the striatum and cortex of the type not linked with adenylate cyclase and phosphodiesterase but probably due to activation of inhibitory gamma-amino butyric acid (GABA) neurons on the strio-nigral pathway.
Molindone was compared with haloperidol in animal models of tardive dyskinesia. Treatment with molindone for 14 days at 3, 6, 20 and 40 mg/kg, enhanced the stereotyped behavioral response induced by apomorphine and increased the numbered of D-2 dopamine receptors in the striatum (Bmax) labelled by high affinity (Kd = 40 pmol) binding or [3H] spiroperidol in the guinea-pig. Molindone at 1 mg/kg, caused no behavioral supersensitivity or change in the binding of dopamine receptors. Chronic administration of haloperidol (0.1, 0.5 and 5.0 mg/kg) also increased both the behavioral response to apomorphine and the number of dopamine receptors. Haloperidol, at 0.02 and 0.004 mg/kg, had no effect. Molindone potentiated dopaminergic activity in animal models in a similar way to other neuroleptics, suggesting that its use may also result in tardive dyskinesia.
Four experiments were conducted using male rats to determine whether testosterone (T), or its neural metabolites estradiol (E2) and 5 alpha-dihydrotestosterone (DHT), influence the expression of locomotor activity, which is thought to depend in part on the activation of mesolimbic dopaminergic neurons. Subcutaneous implantation of silastic capsules containing E2, but not T or DHT, caused a significant increase in the amount of activity displayed by castrated rats which had been habituated to infrared photobeam activity cages prior to receiving an i.p. injection of D-amphetamine sulfate (1.5 mg/kg). Administration of E2, but not T or DHT, also significantly increased the amount of activity which other groups of castrated rats displayed when they were first placed in the photobeam cages. Likewise, administration of E2 but not T or DHT, to castrated rats which had previously received bilateral injections of 6-hydroxydopamine into the nucleus accumbens septi, caused a significant increase in the activity displayed in response to an i.p. injection of apomorphine HCl (1.0 mg/kg). However, administration of estrogen or androgen to castrated rats which were neurologically intact had no effect on the amount of stereotyped behavior displayed in response to increasing doses (1.0, 2.0 and 4.0 mg/kg) of apomorphine. It is suggested that the selective, facilitatory effect of E2 on drug- and novelty-induced locomotor activity resulted from increased postsynaptic receptor activation at dopaminergic synapses in the nucleus accumbens septi.
6-Nor-9,10-dihydrolysergic acid methyl ester (IV) was prepared by demethylation of 9,10-dihydrolysergic acid methyl ester (II) with 2,2,2-trichloroethyl chloroformate, followed by reduction of the intermediate carbamate (III) with zinc in acetic acid. The 6-ethyl-V and 6-n-propyl-VI derivatives were prepared by alkylation of IV with the appropriate halide. All of the ergoline derivatives were evaluated for stereotyped behavior in rats, with 6-nor-6-ethyl-9,10-dihydrolysergic acid methyl ester (V) being active but much less potent than apomorphine. Compound VI was evaluated for its effect on blood pressure; at a dose of 30 mg/kg ip, it significantly lowered, diastolic pressure in normotensive rats.
Administration of B-HT 920 alone produced weak stereotypy in a small percentage (4-8%) of rats. In contrast, after combined administration of idazoxane and B-HT 920, stereotyped behaviors (sniffing and licking) were consistently produced in all rats. The appearance of stereotypy after combined treatment with yohimbine and B-HT 920 was inversely related to the dose of yohimbine. These data suggest that the alpha 2-adrenoceptor agonist effects of B-HT 920 can mask it's postsynaptic dopamine agonist effects.
Microdialysis technique was used to compare the effects of four repeated intraperitoneal administrations of two psychostimulant drugs, D-amphetamine and sydnocarb, at the equimolar doses 5 and 23.8 mg/kg, respectively, on the extracellular level of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and hydroxyl radicals (.OH) in the dorsal striatum of freely moving 3-month-old male Wistar rats 250-300 g in weight. D-amphetamine caused immediate increase of DA concentration up to 950% with quick decline towards baseline values thereafter, followed by much less increase after further injections. Sydnocarb elicited moderate elevation in DA level achieving 400% after the fourth injection. D-amphetamine induced deep decrease in DOPAC concentration, while sydnocarb caused its increase after the first and second dosing. Both drugs enhanced generation of .OH, the effect of D-amphetamine was more pronounced. D-Amphetamine induced more intensive stereotyped behavior in rats compare to sydnocarb. It is concluded that the psychostimulant action of sydnocarb is accompanied by facilitation of the central dopaminergic transmission in rat neostriatum and followed by less pronounced neurotoxic effect than that of D-amphetamine.
Adult cats were implanted with standard electrodes to record EEG, EOG, and EMG. After 15 days, morphine sulphate or saline placebo was given IP at 0.5, 1.0, 2.0, 3.0 mg/kg, at least 15 days apart. Cats were continuously recorded for 72 hr postinjection. Wakefulness, drowsiness, NREM and REM sleep percentages were scored from polygraphic features and statistically analysed. There was a dose-dependent suppression of NREM and REM sleep for at least 6 hours postmorphine, with a progressive sleep recovery thereafter. During the insomnia period there was an EEG/behavioral dissociation where bursts of high-voltage waves were seen over a background of desynchrony; meanwhile the animal was first aroused although quiet and later showed stereotypic behavior. There was a prolonged NREM sleep rebound which started later at the higher doses. A significant, relatively brief REM sleep rebound was seen only at the lowest dose. The latency for NREM and REM sleep onset was also dose-dependent. Possible brain sites of morphine actions and similarities with effects in other species are discussed.
The novel neuropsychotropic agent milacemide hydrochloride (2-n-pentylaminoacetamide HCl) is a highly selective substrate of the B form of monoamine oxidase (EC 1.4.3.4; MAO). Under the in vitro conditions used in the present study, milacemide acts as an enzyme-activated, partially reversible inhibitor of MAO-B. A reversible inhibition of MAO-A activity is also observed at high concentrations. The inhibitory activity of milacemide is significantly greater for MAO-B. In vivo, after single or repeated oral administration, a specific inhibition of MAO-B is apparent in brain and liver, with a lack of inhibition of the MAO-A activity. In contrast to the irreversible inhibitory action of L-deprenyl, the recovery of MAO-B activity in vivo after milacemide administration is significantly faster, a result suggesting that it is a partially reversible inhibitor. The selective inhibitory effect of milacemide for MAO-B in vivo is confirmed by its potentiation of phenylethylamine-induced stereotyped behavior, whereas vasopressor responses to tyramine were not affected. These observations suggest that milacemide could enhance dopaminergic activity in the brain and could be used as therapy for Parkinson's disease in association with L-3,4-dihydroxyphenylalanine.
Amphetamine-induced stereotyped behavior is a nonsteady oscillatory process with minute fluctuations rate of head turnings. After acute amphetamine stereotypy have lower amplitude and limited rhythmicity in pinealectomized rats as compared with intact animals. Pinealectomy also delayed tolerance after chronic administration of amphetamine (5 mg/kg/day, 14 days) without usual decrease number of short period (2-3 min) fluctuations in time course of stereotypy.
REM sleep deprivation (REMSD) induces augmented responses to dopaminergic agonists. Prolonged administration of neuroleptics induces a similar state, probably by the production of supersensitivity of dopaminergic receptors. Such a supersensitive state could be induced by REMSD as a result of impairment of dopamine neurotransmission. In order to test this hypothesis, bromocriptine, nomifensine, amphetamine, L-dopa, imipramine and electroconvulsive shock (ECS) were administered to rats during REMSD, and aggressive and stereotyped behaviors were measured. Amphetamine and L-dopa pretreatment attenuated the increases in apomorphine-induced stereotypy and aggression in REMSD rats, but ECS selectively reduced apomorphine-induced aggression. The other drugs tested were ineffective on both behavioral tests. Such a selective action may reflect different effects of ECS on different dopaminergic systems such as those involved with stereotypy and aggression. The results suggest that REMSD induces an increase in dopaminergic sensitivity which may be reversed by pretreatment with some dopaminergic agonists.
Two strains of mice (NMRI and C57B1/ 6) were treated with MPTP (within 8 h 4 x 30 mg/kg MPTP, IP) and motility was monitored 10 days later. An acute administration of amphetamine (2.5 mg/kg or 10.0 mg/kg) or apomorphine (0.5 mg/kg or 5.0 mg/kg) led to hypermotility and a dose-dependent increase of stereotyped behavior. Immunocytochemical investigations indicated a substantial loss of tyrosine-hydroxylase immunoreactivity in the basal ganglia which was accompanied by a 15% increase of 3H-spiroperidol binding to a striatal membrane preparation. No difference was found in biochemical and behavioral measures between both mice strains. Thus, MPTP-induced lesions in mice are probably followed by a denervation-like supersensitivity of the dopaminergic system, which might account for the finding that despite a severe degeneration of dopaminergic terminals amphetamine induces hypermotility.
Insect ecdysis is a hormonally programmed physiological sequence that enables insects to escape their old cuticle at the end of each developmental stage. The immediate events leading to ecdysis, which are initiated upon release of ecdysis-triggering hormones (ETH) into the bloodstream, include respiratory inflation and sequential stereotypic behaviors that facilitate shedding of the cuticle. Here we report that the Drosophila gene CG5911 encodes two functionally distinct subtypes of G protein-coupled receptors through alternative splicing (CG5911a and CG5911b) that respond preferentially to ecdysis-triggering hormones of flies and moths. These subtypes show differences in ligand sensitivity and specificity, suggesting that they may play separate roles in ETH signaling. At significantly higher concentrations (>100-fold), certain insect and vertebrate peptides also activate these receptors, providing evidence that CG5911 is evolutionarily related to the thyrotropin-releasing hormone and neuromedin U receptors. The ETH signaling system in insects is a vital system that provides opportunities for the construction of models for the molecular basis of stereotypic animal behavior as well as a target for the design of more sophisticated insect-selective pest control strategies.
FH-510 (5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol) is a potent ligand for sigma ligand binding sites in rat brain membranes and has an IC50 value of 4.8 +/- 1.0 nM, which is comparable to that of haloperidol (2.2 +/- 0.2 nM). The high selectivity of FH-510 for sigma binding sites was evaluated by its lack of significant affinity for other binding sites, including those for dopamine D2 and phencyclidine. When administered to mice orally, FH-510 suppressed (+)-N-allylnormetazocine ((+)-SKF10,047)-induced stereotyped behavior with an ED25 value of 0.54 mg/kg, which is 14-fold more potent than that for (+)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol ((+)-BMY14802) (7.6 mg/kg). These results suggest that FH-510 may be a potent and selective sigma ligand.