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delta 9-Tetrahydrocannabinol (THC), one of the active compounds of marihuana, is known to induce drug dependence and tolerance, and its action is weaker than those of other abused drugs in humans and animals. Acute effects of THC, "high", "irritable" and "cognitive deficits" are more important than the drug dependence and tolerance. For this reason, we examined characteristics of abnormal behavior such as catalepsy-like immobilization, aggressive behavior including irritable aggression and muricide, and spatial cognition impairment induced by acute and chronic treatments of THC in rats. The catalepsy-like immobilization is related to a decrease in catecholaminergic and serotonergic neurons in the nucleus accumbens and amygdaloid nucleus and thus serves as a useful model for amotivational syndrome, one of cannabis psychoses. In aggressive behavior, muricide was determined by the housing condition. Muricide was induced if the rat was placed under an isolated housing condition within the period of the effect of single injection of THC. The behavioral change resembles exacerbation and flashback in humans. Spatial cognition is impaired by the interaction between cannabinoid (CB1) and 5-HT2 receptor in the dorsal raphe-hippocampal serotonergic neurons. Thus the abnormal behavior induced by THC can be a useful model for investigating mental function in humans and new drugs for the treatment of mental disorders.

The present study examined changes in angiotensin type-2(AT2) receptor mRNA level after global brain ischemia or during glutamate neurotoxicity in cultured cortical cells in rats. The AT2 mRNA level increased by three-fold in both the cortex and hippocampus, which are known to be sensitive to ischemic injury, 3 hr after ischemia. The day 10-14 cortical neurons were exposed to glutamate at a toxic concentration of 100 microM for 15 min. AT2 receptor mRNA was then increased 2-fold after exposure to glutamate, while the maximum increase was observed in a dose-dependent manner 3 hr after glutamate stimulation. AT2 receptor binding also increased 3-12 hr after glutamate exposure. The increase in the mRNA level was antagonized by N-nitro L-arginine methyl-ester, a nitric oxide synthase inhibitor. The hemoglobin, a nitric oxide trap, also inhibited the increase in the mRNA level. These results suggest that the increase in the mRNA level is associated with the nitric oxide synthesis by glutamate exposure. The viability of cortical cells after glutamate stimulation was partially restored by the antisense oligonucleotide for the AT2 receptor. The present results thus suggest the AT2 receptor may in some way be related to one of the processes in cell injury.

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.

Triazolam was 4 to 5 times as potent as diazepam in reducing hyperemotionality of either septal-lesioned or olfactory bulbectomized rats (O.B. rats), and in suppressing muricide in O.B. rats. This agent was equipotent with diazepam in inhibiting fighting behavior of long-term isolated mice, but was longer in duration of action. Triazolam was approximately 4 times more potent than diazepam in preventing pentetrazol convulsion, but was 10 times less potent in inhibiting maximal electroshock convulsion in mice. The muscle relaxant effect of triazolam as assessed by the inclined screen test was 34 times, and the effect on rotarod performance was 17 times more potent than that of diazepam in mice. Triazolam (0.2 approximately 0.5 mg/kg i.v.) changed the EEG to a drowsy pattern in unanesthetized rabbits with a chronic electrode implant, and suppressed the EEG arousal response to auditory stimulation and electrical stimulation given to either the mesencephalic reticular formation or posterior hypothalamus. The limbic afterdischarges induced by either hippocampal or amygdaloid stimulation were also markedly inhibited by triazolam. These EEG effects of triazolam were qualitatively similar to, but were 4 to 5 times more potent than those of diazepam. These results indicate that triazolam is a potent tranquilizer with a longer duration of action, and the muscle relaxant effect is considerable as compared with diazepam.

Behavioral and electroencephalographic effects of lormetazepam were investigated in rats, mice and rabbits, in comparison with those of diazepam, nitrazepam and flurazepam. Locomotor activity of mice in an open-field situation was decreased with large doses of lormetazepam and diazepam, while it was increased with nitrazepam and flurazepam. The anticonflict effect of lormetazepam in rats was much more potent than those of diazepam, nitrazepam and flurazepam. In suppressing the muricide of olfactory bulbectomized and raphe lesioned rats, lormetazepam was more potent than diazepam, nitrazepam and flurazepam. Lormetazepam, diazepam and flurazepam prevented both maximal electroshock and pentetrazol convulsions in mice, the effects on the latter being much more potent than those on the former. Lormetazepam was more potent than diazepam and flurazepam in potentiating thiopental-, ether- and ethanol anesthesia, impairing rotarod performance and in muscle relaxant activity. In conscious rabbits with chronically implanted electrodes, lormetazepam induced a drowsy EEG pattern and suppressed the EEG arousal responses not only to auditory stimulation but also to electrical stimulation of the midbrain reticular formation or hypothalamus. Lormetazepam also inhibited afterdischarges induced by electrical stimulation of the hippocampus and amygdala. These results indicate that lormetazepam has pharmacological properties characteristic of benzodiazepines and that the activity is more potent than those of diazepam, nitrazepam and flurazepam.

The effect of maprotiline (N-methyl-9, 10-ethanoanthracene-9 (10H)-propylamine) on animal behavior was investigated in mice and rats and compared with those of amitriptyline and imipramine. Maprotiline inhibited reserpine hypothermia in mice and tetrabenazine ptosis in rats, while it potentiated the effects of methamphetamine, L-DOPA and apomorphine in mice, in a similar manner to that of amitriptyline and imipramine. Maprotiline was more potent than anitriptyline and imipramine in antagonizing haloperidol-induced catalepsy as well as in suppressing muricide induced by either olfactory bulbectomy or delta-9-tetrahydrocannabinol in rats. Maprotiline potentiated anesthesia induced by thiopental or ether in mice to a lesser degree than did amitriptyline, and failed to counteract the lethal effect of physostigmine or oxotremorine tremor in mice, indicating that this drug has no central anti-cholinergic effect. Maprotiline markedly inhibited hyperemotionality of the rat with either septal lesions or olfactory bulb ablations, suggesting that it does have a tranquilizing effect. Inhibition of conditioned avoidance response of the rat in the shuttle box and reduction of methamphetamine group toxicity with maprotiline were similar to those with amitriptyline. Maprotiline exaggerated pentetrazol convulsion, decreased muscle tone and impaired coordinated motor activity in mice to a much lesser degree than amitriptyline and imipramine. LD50 of maprotiline was approximately twice that of imipramine and three times that of amitriptyline. These results indicate that maprotiline is a new type of antidepressant, has a low toxicity and shares both potent antidepressant and some tranquilizing effect, without possessing central anticholinergic action.

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 behavioral and electroencephalographic effects of Clozapine were investigated in mice, rats and rabbits, and compared with chlorpromazine and perphenazine. Clozapine showed in general the pharmacologic properties characteristic to neuroleptics, such as decrease in exploratory behavior, suppression of conditiond avoidance response, taming effects, anti-methamphetamine and so on. These effects were less potent and shoter in duration than those of chlorpromazine and perphenazine. Clozapine, however, lacked cataleptogenic propeties and depressed the EEG arousal responses induced not only by auditory but also by mesencephalic reticular stimulation, differently from chlorpromazine and perphenazine.