Electroencephalographic and behavioral alterations produced by delta-1-tetrahydrocannabinol.

The administration of small doses of Delta(l)-tetrahydrocannabinol to cats with indwelling electrodes produced a disruption of both the electroencephalogram and behavior. Some of these alterations, including the appearance of a high-voltage slow wave electroencephalogram in the awake and moving animal, have been observed in cats that had been administered other drugs known to cause hallucinogenic states in man.

Electroencephalographic tolerance and abstinence phenomena during repeated alcohol ingestion by nonalcoholics.

Certain measures of the auditory average evoked response are sensitive to alcohol and provide evidence for abstinence and tolerance during and after 10 days of alcohol consumption by nonalcoholics. Electroencephalographic techniques provide a single sensitive measure for the study of the etiology of tolerance and abstinence with particular reference to a new area of investigation with nonaddicted humans.

Male rats with inherited insensitivity to androgen show reduced sexual behavior.

Pseudohermaphroditic Stanley-Gumbreck male rats showed infrequent and incomplete copulatory responses to receptive females. Administration of testosterone propionate produced no increase in this behavior. Injections of estradiol and progesterone induced the pseudohermaphrodites to exhibit lordosis when mounted by stimulus males, but feminine responses were no more frequent than those of normal males given the same hormonal treatment. The hypothesis is suggested that early in development sufficient endogenous testis hormone is produced to cause normal desensitization of feminine behavioral mechanisms to estradiol, but that mechanisms for male behavior are not normally sensitized to testosterone.

Timid singly-housed mice: their value in prediction of psychotropic activity of drugs.

1 About 45% of singly-housed male mice showed timidity (alert postures, running away, defensive postures) instead of aggression on interactions in pairs with group-housed male mice, though their partners did not show any aggression. The isolation-induced timidity was stable in repeated interactions. Timid mice also showed locomotion (walking across cage and rearing) and a small amount of sociable activity (sniffing, following partners and climbing over them). 2 Diazepam (5 mg/kg), chlordiazepoxide (20 mg/kg), chlorpromazine (7.5 mg/kg) and barbitone (60 mg/kg) given orally inhibited the isolation-induced timidity without reducing other motor activities in the timid mice. Imipramine lessened timidith only in a dose (80 mg/kg) which also decreased other components of behaviour in the timid isolates. (+)-Amphetamine and lysergic acid diethylamide (LSD) increased the timid response. 3 Comparison of the inhibition of timid activities with changes in other behaviour occurring at the same time seems a better measure of selective timidity-reducing effects of drugs than the rota-rod test. 4 Diazepam (5 mg/kg) increased sociable and locomotor activities. Barbitone (20 and 60 mg/kg) increased sociable activities; however, the higher dose also evoked some aggression in timid mice. 5 Behaviour of timid singly housed male mice seems to be a good measure for prediction of activity of drugs in relieving anxiety as well as for detection of aggression-evoking and sociability-increasing effects of drugs.

Pharmacological properties of centrally administered ouabain and their modification by other drugs.

1. Ouabain given by intracerebroventricular injection to mice in small doses (0.1-0.4 mug) produced a dose related depression of central nervous activity, characterized by a reduction in spontaneous locomotor activity, hypothermia, catalepsy and ptosis, lowered body posture and lack of response to external stimuli. Doses above 0.4 mug were excitatory, convulsant and lethal.2. The depressant effects could be antagonized by (+)-amphetamine, desmethylimipramine, dibutyryl cyclic 3'5'-adenosine monophosphate and caffeine.3. The MAO inhibitor nialamide produced only a small antagonism of ouabain, resulting in a greater rate of recovery from the depressant effects of ouabain.4. The depressant effects were associated with a marked elevation of whole-brain dopamine levels with little change in noradrenaline or 5-hydroxytryptamine.5. The dopamine-beta-hydroxylase inhibitor sodium diethyldithiocarbamate, administered by intracerebroventricular injection, produced effects qualitatively similar to those seen after ouabain.6. An interference with central transmitter function is postulated as a possible mode of action of intracerebroventricularly injected ouabain.

A sexually dimorphic rhythm in oestradiol-activated lordosis behaviour in the rat.

Ovariectomized rats exposed to constant plasma levels of oestradiol showed a daily rhythm in lordosis behaviour, with high levels of lordosis occurring during the dark portion of the daily light: darkness cycle and low levels during the light period. Similarly treated male rats failed to show a rhythm in lordosis behaviour. However, neonatal castration permitted the expression of the lordosis rhythm in male rats; conversely, an injection of 1.25 mg testosterone propionate on day 4 of life abolished the rhythm in female rats. Pinealectomy, adrenalectomy or depletion of brain 5-hydroxytryptamine levels did not affect the periodicity in lordosis behaviour but lesions in the suprachiasmatic nuclei of the hypothalamus disrupted the rhythm. It is suggested that the daily rhythm in lordosis behaviour participates in the control of the termination of heat in the female rat and that the perinatal hormone milieu may exert permanent effects on periodic functions.

Forelimb placing and hopping reflexes in haloperidol- and morphine-treated cataleptic rats.

Although both haloperidol and morphine produce catalepsy, there are fundamental differences in their neurological effects (De Ryck, Schallert, & Teitelbaum, 1980). Haloperidol-treated rats show brisk righting, bracing, and clinging reflexes, effects suggesting that motor subsystems subserving static postural support are dominant over those involved in more phasic locomotor and orienting movements. In contrast, morphine-treated rats show impaired righting, bracing, and clinging, effects suggesting that postural support mechanisms are suppressed. In order to determine whether phasic postural reactions other than righting are also differentially affected by these drugs, forelimb placing and hopping reflexes were evaluated in rats given either haloperidol (0, 0.25, 0.5, 1, and 5 mg/kg) or morphine sulfate (0, 10, 20, and 40 mg/kg). Morphine produced a dose-dependent impairment in all tests. In contrast, haloperidol did not impair contact placing to dorsal stimulation of the limb or chin placing. Hopping and contact placing to lateral stimulation of the limb were impaired by haloperidol, perhaps because stimulation induced a competing tendency to brace. These results provide additional evidence that morphine and haloperidol produce functionally different neurological states.

Effects of ethyl alcohol on behaviour in nursing female mice.

Effects of administering 10% ethyl alcohol as drinking fluid to mice during pregnancy and lactation have been examined by ethological analysis of behaviour of nursing females in their home cages at 1 day, 5--7 days, and 12--14 days postpartum. The treatment with alcohol did not affect gestation period or litter size, and fluid intake of treated mice remained similar to that of controls, the average intake of alcohol amounting to 29 mg/g body weight during lactation. Increase in frequency of exploration at 1 day postpartum was the only significant behavioural effect of alcohol on the nursing female mice. Duration of Non-Social Behaviour was unaltered, and no effects of the treatment on Maternal Behaviour or on Social and Sexual Investigation of male partners could be demonstrated. Behaviour of nursing females changed with increase in age of their pups. This occurred to a similar extent in treated and control animals. Maternal and Non-Social Behaviours declined in frequency as the pups became older although the time spent in these behaviours remained fairly constant. Social Investigation of the male partner declined both in frequency and duration while females were nursing their pups.

Studies in vivo with ICI 174864 and [D-Pen2, D-Pen5]enkephalin.

We studied the in vivo pharmacology of a selective agonist (DPDPE) and a selective antagonist (ICI 174864) at delta opioid receptors. ICI 174864 (10 micrograms icv) caused postural abnormalities, barrel rotation and hypothermia in rats. DPDPE induced behavioural arousal (at 75 micrograms icv) and barrel rotation (at 125 micrograms) in rats. ICI 174864 (10 micrograms icv) attenuated acetic acid induced writhing in mice. This action was antagonized by naloxone (10 but not 2 mg/kg s.c.). A lower, non-agonist dose of ICI 174864 (5 micrograms) antagonized DPDPE (3 micrograms icv) in this test without affecting DAGO (0.0006 micrograms icv), a selective agonist at mu receptors. In the mouse tail flick test, ICI 174864 (10-50 micrograms icv) did not significantly antagonize the agonist actions of DPDPE (40 micrograms icv) or DAGO (0.3 micrograms icv). At 10-50 micrograms icv, ICI 174864 had no marked effect on gastrointestinal transit in mice. ICI 174864 (25 micrograms icv or 20 mg/kg s.c.) did not interact with mu opioid receptors in mice rendered physically dependent on morphine.

Prenatal testosterone causes shift of asymmetry in neonatal tail posture of the rat.

Neonatal tail posture is a sexually dimorphic behavior with females more biased leftwards than males. Prenatal exposure of female pups to testosterone propionate (TP) but not dihydrotestosterone propionate (DHTP) shifts the population pattern of tail posture to the right. No effects were found with male pups. Since TP is aromatizable and DHTP is not, it is concluded that TP exerts its effects on tail posture via the CNS.

Intranigral kainic acid: evidence for nigral non-dopaminergic neurons controlling posture and behavior in a manner opposite to the dopaminergic ones.

The unilateral, intranigral administration of kainic acid (k.a.) produced a syndrome characterized by early sequelae of contra- and ipsilateral circling and by a chronic contralateral turning associated with moderate loss of neurons in the pars reticulata. The acute contralateral circling seems to be related to dopaminergic nigro-neostriatal neuron stimulation, since it was prevented by previous intranigral injections of 6-OHDA. The acute ipsilateral circling and the chronic contralateral turning, on the other hand, seem to be independent of the integrity of the dopaminergic system and may be due to an initial stimulation, followed by destruction, of a nigral neuronal system which mediates turning behavior in a manner opposite to that of nigro-striatal dopamine. Treatment with D-amphetamine or apomorphine changed the contralateral into ipsilateral turning, while haloperidol potentiated the contralateral turning. Bilateral injection of k.a. into the nigra resulted in chronic stereotyped sniffing and gnawing, which were not inhibited by haloperidol. Moreover, haloperidol did not produce catalepsy in these animals. It is suggested that the intranigral k.a. injection destroyed a neuronal system antagonistic to dopamine and resulted in a reduction of the response to DA-receptor stimulation of the c. striatum.

[An experimental study of the psychostimulant action of amantadine]. / Etude expérimentale de l'action psycho-stimulante de l'amantadine

According to previous experimental and clinical data, we have tested the hypothetic psycho-stimulating activity of amantadine on experimental sensitized models. We obtained a strong action on the spontaneous sleep of rats at a dose of 10 mg/kg and a less striking action in diminishing the effects of barbitol on the righting reflex of mice and in reducing the narcosis of rats induced by mebubarbital. This action does not seem to be due to a release of catecholamine because the lesions produced by electrocoagulation in the ascending aminergic pathways or pretreatment by alpha-methylparatyrosine (AMPT) do not block it. It is suggested that there may be a non-aminergic receptor of amantadine which is different from the amphetamine receptor.

Induction of turning by direct intrastriatal injection of dopaminomimetic drugs in mice: pharmacological analysis of a simple screening model.

A new simple model designed for the screening of dopaminomimetic drugs in mice is presented. When injected directly into the right striatum of conscious mice, the dopamine (DA) receptor agonists apomorphine, SKF 38393 and bromocryptine, the indirect DAmimetic drugs (+)-amphetamine and nomifensine, the atypical DAergic antidepressant drug minaprine, induced contralateral rotations. Rotations induced by DA mimetics were antagonized by i.p. injected haloperidol. A pretreatment with the D1 antagonist SCH 23390 (s.c.) antagonized the turning induced by apomorphine or by the D1 agonist SKF 38393, and, to a lesser extent, that induced by the D2 agonist bromocryptine. In contrast, the D2 antagonist (-)-sulpiride (i.p.) blocked the effects of the 3 agonists to the same extent. A pretreatment with alpha-methylparatyrosine (i.p.) antagonized rotations induced by bromocryptine, (+)-amphetamine and minaprine, but not those induced by nomifensine or apomorphine. The results suggest that this model could represent a useful screening tool for the search of new DAmimetic drugs, and for the assessment of DA receptor blockade.

Prenatal benzodiazepine effects in mice: postnatal behavioral development, response to drug challenges, and adult discrimination learning.

Oxazepam treatment of primiparous mouse dams on days 12-16 of pregnancy (15 mg/kg p.o. twice daily) produced a transient retardation of postnatal body growth and neurobehavioral development, a reduction of the hyperactivity response to amphetamine in open-field tests on postnatal days 14-16, and a selective impairment of adult active avoidance in four go-no go discrimination tasks. Equally important for understanding the nature of the prenatal benzodiazepine syndrome were several negative results, namely, the absence of changes in homing performance on postnatal day 10, an intact hyperactivity response to scopolamine on postnatal days 21-23, a lack of effects on adult activity, and a normal passive avoidance performance in the go-no go tasks. A modification in monoaminergic regulatory functions may account for the overall profile of prenatal drug effects. Based on the results of this experiment, of a preliminary multidose study (0-50 mg/kg), and of an additional cross-fostering experiment, several methodological issues are addressed. These include the choice of appropriate treatment schedules and of testing procedures adequate for each developmental stage, and the control for various confounding variables such as litter effects, postnatal maternal influences, and developmental history.

Intracerebral implantation of the anti-estrogen CN-69, 725-27: Effects on female sexual behavior in rats.

Ovariectomized adult female rats were stereotaxically implanted with double walled cannulas (22 ga outer and 27 ga inner) and tested for sexual receptivity (lordosis behavior) following SC estradiol benzoate and progesterone priming. Implantation of the anti-estrogen CN-69,725-27 (c. 65 mug) immediately after the first of 3 daily estrogen injections produced a dramatic inhibition of sexual receptivity when these implants were placed in the preoptic and anterior hypothalamic areas. CN-69,725-27 implants had no effect on receptivity when implanted in the middle hypothalamus, mesencephalon or frontal cortex. All inhibitory effects of the anti-estrogen were reversible within one day after removal of the CN-69,725-27 cannula from the brain.

Functional development of dopamine receptors in the rat forebrain.

Dopamine (DA) was injected unilaterally into the dorsal caudate-putamen (D-CPU), ventral caudate-putamen (V-CPU), piriform cortex (PIR), olfactory tubercle (OTU) and frontal cortex (FC) of two day old rats and rotational behavior observed. Injection of DA into D-CPU, PIR, and OTU produced a contralateral postural deviation which differed significantly from the ipsilateral deviation produced by control injections. Only DA injections into PIR and OTU produced contralateral turning differing significantly from the effects of control injections. These results suggest that the DA receptors in C-CPU, PIR, and OTU involved in rotational behavior are functionally mature at two days of age and that the two components of rotation, postural deviation (direction) and turning (locomotion), involve different neural systems at this age. The developing rat is suggested as a valuable tool for understanding the neural circuitry and pharmacology of rotational behavior.

Effects of ovariectomy and estrogen replacement on intrastriatal dopamine-elicited postural deviation.

The effects of ovariectomy, sham ovariectomy, and estradiol benzoate replacement on unilateral intrastriatal dopamine-induced postural deviation were studied in rats. Animals were tested prior to surgery, and at both two and seven days after surgery. Relative to the pre-surgery test, ovariectomized rats greatly increased this behavioral response two days after surgery while sham ovariectomy resulted in no significant change. Estradiol benzoate treatment in ovariectomized animals not only prevented this increase but significantly suppressed it at both two and seven days after surgery relative to pre-surgery levels. Thus, removal of endogenous estrogen in female rats resulted in an acute increase in a striatal DA-mediated behavior which could be prevented by hormone replacement. These results are consistent with the hypothesis that estrogen suppresses some striatal DA-mediated behaviors.

Rotation and postural deviation elicited by microinjections of dopamine into medial and lateral regions of dorsal striatum.

Unilateral microinjections of DA (25 micrograms/0.25 microliter) into several medial to lateral regions of the dorsal striatum of female rats produced both contralateral postural deviation and rotation. However, injections of DA into the medial striatum were more effective in producing rotation than postural deviation, whereas the opposite was the case for lateral striatal injections.

Lisuride inhibits temporarily sexual behavior in female rats.

The effect of lisuride (0.1 and 0.2 mg/kg IP) on the sexual behavior was studied in the adult, ovariectomized and chronically estradiol-primed female rats. The behavioral tests were done under dyadic interaction with males 60 min before and 30, 120 and 360 min after lisuride or saline injection. Lisuride induced a prompt, short-termed and dose-dependent loss of the precopulatory patterns (darting, hopping, presenting posture) while the effect on the copulatory (lordosis) behavior was weaker. A partial restoration of the precopulatory behavior was observed in the 120th min, the full restoration of the original precopulatory states was found in the 360th min. The inhibitory effect of lisuride on feminine sexual behavior is in contrast with its facilitatory effect on masculine sexual behavior in rats. The results suggest that the serotonergic system participates in the mediation of both copulatory (receptive) behavior and precopulatory (proceptive) behavioral patterns.

Atonia after carbachol microinjections near the locus coeruleus in cats.

The effect of microinjections of carbachol into the dorsolateral pontine tegmentum on the behaviour of cats is investigated. Injections of small amounts (50 and 500ng) of carbachol into the pontine reticular formation induced muscular atonia in otherwise awake animals. The atonia is not due to cholinergic stimulation of the noradrenergic cells of the locus coeruleus or the dorsolateral pons, since the most effective sites were situated ventrally to the locus coeruleus and alpha- and beta-adrenergic blocking agents did not affect the antonia. The results are discussed in view of the postulated role of the locus coeruleus in paradoxical sleep.