Comparative study of aggressive behaviour after injection of cholinomimetics,anticholinesterases, nicotinic,and muscarinic ganglionic stimulants into the cerebral ventricles of conscious cats: Failure of nicotinic drugs to evoke aggression

Emotional behaviour, especially aggression, evoked by cholinomimetics, anticholinesterases, nicotinic, and muscarinic ganglionic stimulants injected into the cerebral ventricles of unanesthetized cats was studied and compared. Aggressive behaviour was obtained after intraventricular carbachol, muscarine, arecoline, eserine, neostigmine, and 4-m-chlorophenylcarbamoyloxy-2-butynyl-trimethylammonium chloride (McN-A-343). The aggressive behaviour and the autonomic and motor phenomena of various single doses of cholinomimetics and anticholinesterases were dose-dependent and long-lasting. Neostigmine produced aggressive behaviour only in about one-fourth of the experiments, while arecoline and McN-A-343 induced aggression of slightest intensity. The type of aggressive behaviour caused by carbachol, arecoline, eserine, neostigmine, and McN-A-343 was classified as irritable-type aggressive behaviour, while muscarine induced fear-type aggressive behaviour. Intraventricular administration of nicotine, dimethylphenylpiperazinium, tetramethylammonium, and N-benzyl-3-pyrrolidyl acetate methobromide (AHR-602) did not evoke aggressive behaviour, but they induced fleeting autonomic and motor phenomena. The ability of single intraventricular injections of cholinomimetics and anticholinesterases to trigger and to maintain long-lasting aggressive behavioural phenomena cannot be ascribed to a rapid detonator transmission, but rather to an action that differs from the conventional transmitter function. In addition, we advance a hypothesis that the cholinoceptive neurons sensitive to cholinomimetics and anticholinesterases behave as a biologic generator that when activated produces long-lasting aggression with autonomic and motor phenomena.     

Effects of parachlorophenylalanine and 5,6-dihydroxytryptamine on aggressive behaviour evoked by cholinomimetics and anticholinesterases injected into the cerebral ventricles of conscious cats.

Carbachol, muscarine, eserine and neostigmine injected into the cerebral ventricles of conscious cats, evoked emotional behaviour with aggression and autonomic and motor phenomena with clonic-tonic convulsions. The main and the most impressive feature of the gross behavioural effects of intraventricular cholinomimetics and anticholinesterases was an affective type of aggression. After 5,6-dihydroxytryptamine and parachlorophenylalanine, intraventricular carbachol, muscarine, eserine and neostigmine elicited aggression and autonomic and motor phenomena with clonic-tonic convulsions. The affective type of aggressive behaviour was modified with biting attack predominant, while hissing and snarling (i.e. vocalization) were depressed or absent. The manifestations of affective aggressive behaviour caused by muscarine were most resistent to 5,6-dihydroxytryptamine and parachlorophenylalanine. When 5-hydroxytryptophan was given to parachlorophenylalanine treated-cats, intraventricular carbachol, muscarine and eserine evoked emotional behaviour with aggression and autonomie and motor phenomena with clonic-tonic convulsions. Hissing and snarling reappeared, but they were less intense and shorter in duration than in control animals. Based on these experiments, it is concluded that an intact central 5-hydroxytryptamine network is required for the expression of emotional behavioural phenomena, especially vocalization in the appearance of the affective type of aggression. On the other hand, intact central 5-hydroxytryptamine pathways are not essential for the performance of the motor act for the attack and biting.     

The pharmacology of gross behavioural effects of cholinomimetic substances injected into the cerebral ventricles of unanaesthetized cats: Evidence for central muscarinic mediation

Choline esters (acetylcholine, methacholine and carbachol) as well as substances with a peripheral muscarinic type of action, such as pilocarpine and arecoline, injected intraventricularly to unanaesthetized cats. evoked emotional behaviour, autonomic changes, motor phenomena and clonic-tonic convulsions. The gross behavioural effects of various single doses of these agents were dose-dependent. Of choline esters and substances with peripheral muscarinic type of actions that were administered, carbachol was the most potent. The emotional behaviour effects after pilocarpine were slight and a few in number in comparison with those produced by choline esters. Arecoline caused only miaowing.

Atropine and scopolamine, injected intraventricularly, abolished the emotional behaviour, autonomie changes, motor phenomena and clonic-tonic convulsions of intraventricularly injected choline esters, while only scopolamine antagonized the gross behavioural effects of pilocarpine and arecoline. On the other hand, the excitant behavioural changes of choline esters, pilocarpine and arecoline were resistant to intraventricular administration of ganglionic (tetraethylammonium, hexamethonium. nicotine and dimethylphenylpiperazinium) or neuromuscular ( + )-tubocurarine and gallamine) blocking agents. In fact, ganglionic and neuromuscular blocking agents potentiated the behavioural effects of choline esters, pilocarpine and arecoline.

It is concluded that choline esters, applied intraventricularly to unanaesthetized cats, elicit excitant behavioural phenomena by an action on central muscarinic cholinoceptive sites.     

Hyperthermic effect of palmitate sodium, stearate sodium and oleate sodium injected into the cerebral ventricles of conscious cats

Palmitate sodium, stearate sodium and oleate sodium injected into the cerebral ventricles of conscious cats produced hyperthermia. Threshold effects were obtained with as little as 2.0–5.0 μg of palmitate sodium and stearate sodium or 20.0 μg of oleate sodium. The hyperthermic effect of these fatty acids reached its maximum 2–3 hr after administration and lasted for more than 12 hr. The rise in temperature was always associated with sedation. The temperature was not affected by an i.p. injection of palmitate sodium (1.2–6.0 mg/kg), stéarate sodium (1.2–6.0 mg/kg) or oleate sodium (1.2–6.0 mg/kg).     

Changes in body temperature produced by cholinomimetic substances injected into the cerebral ventricles of unanaesthetized cats

1. The effects on body temperature of a number of substances injected into a lateral cerebral ventricle were examined in the unanaesthetized cat.2. Nicotine (50 and 100 mug) caused a fall in body temperature ranging from 0.95-2.1 degrees C associated with skin vasodilatation, tachypnoea and panting. These responses were prevented by the intraventricular injection of hexamethonium or mecamylamine, but not of atropine or phentolamine.3. Carbachol (5 mug) caused a rise in temperature associated with skin vasoconstriction, piloerection and severe shivering. These effects were prevented by the intraventricular injection of atropine, but not of hexamethonium or mecamylamine.4. An acetylcholine/eserine mixture (10 mug of each) had no reproducible effect on body temperature. Because of the variability in the response, interaction studies with antagonist drugs were not performed.5. Hexamethonium (100 mug) or mecamylamine (100 mug) caused a prolonged rise in temperature, together with skin vasoconstriction, piloerection and intense shivering. Atropine (200 mug) was without effect on body temperature.6. Noradrenaline (100 mug) caused a fall in temperature with skin vasodilatation. The fall was converted to a rise with skin vasoconstriction, piloerection and vigorous shivering following an intraventricular injection of phentolamine (100 mug).7. These observations suggest the existence of cholinergic heat loss and heat gain mechanisms in the hypothalamic thermoregulatory pathways of the cat and the interaction studies with hexamethonium, mecamylamine and atropine, support the involvement of ;nicotinic' and ;muscarinic' receptors within the cholinergic thermoregulatory system.     

Antidiuresis induced by infusions of histamine into the brain ventricles of conscious hydrated goats.

Histamine was infused into the third or lateral ventricle of conscious hydrated goats, and urine samples were analyzed for volume, osmolality and electrolytes. Doses of 10--1000 microgram of histamine induced dose-dependent antidiuretic responses both as to the maximum osmolality and the duration of the osmolality increase. Urine osmolality began to rise within a few minutes, reached its maximum within 0.5--2 h and was elevated for 1.5--4 h, depending on the dose. Thereafter a second increase in osmolality often occurred, which lengthened the effect of histamine dose-dependently up to about 10 h with the largest dose of histamine. Histamine (50--300 microgram) and the control solution given into the lateral ventricle increased the excretion of Na+ into the urine. After the largest dose of histamine (1000 microgram), however, the excretion of Na+ was significantly lower than in the control experiments. After the larger doses of histamine, effects on motor or autonomic functions were seen. These included decreased spontaneous motor activity, increased respiratory rate, defecation and miosis. It is suggested that the site of action of histamine is central, and that the release of vasopressin through the activation of the neurosecretory system is probably involved. In addition the changes in electrolytes may suggest an involvement of the release of other factors such as prolactin.     

Long lasting stimulation of locomotor activity produced by the intraventricular injection of a cyclic analogue of dopamine into conscious mice

The cyclic analogue of dopamine, 2-amino-6,7-dihyroxy-1,2,34-tetrahydronaphthalene (ADTN) was injected intraventricularly into conscious mice. ADTN was found to cause a strong stimulation of locomotor activity which lasted for 18 hr. The locomotor-stimulant action of ADTN was blocked by haloperidol, but was not reduced by α-methyl-p-tyrosine, p-chlorophenylalanine or reserpine. ADTN was shown to have a dopamine-like action on the blood pressure of the anaesthetised guinea pig. The dimethyl ether of ADTN, which has no effect on guinea pig blood pressure, had no locomotor stimulant action. The possibility that the central action of ADTN is due to a direct action on dopamine receptors in discussed.     

Further studies on the pharmacological effects of pentobarbitone and 2,4-dinitrophenol injected into the cerebral ventricles of the mouse and rat

N.S. DOGGETT and P.S.J. SPENCER, Further studies on the pharmacological effects of pentobarbitone and 2.4-dinitrophenol injected into the cerebral ventricles of the mouse and rat, Europcan J. Pharmacol. 22 (1973) 150–155.A comparison of some pharmacological effects of pentobarbitonc and 2,4-dinitrophenol (DNP) was made after intracerebroventricular (i.c.v.) injection in the conscious mouse and rat. Both compounds produced marked hypothermia after injection by this route. They differed, however, in that sub-hypnotic doses of DNP reduced conditioned avoidance responses (C.A.R.) with no effect on unconditioned responses (U.R.) in trained rats, whereas sub-hypnotic doses of pentobarbitone reduced both C.A.R. and U.R. Determinations of whole-brain amine levels showed that pentobarbitone increased dopamine with no effect on noradrenaline, whereas DNP had no effect on dopaminc but reduced noradrenalinc. 5-Hydroxytryptamine levels were reduced by both compounds. Finally, it was demonstrated that i.c.v. DNP potentiates the hypnotic activity of peripherally-administered pentobarbitone. Although both compounds may share a common mechanism in the production of hypothermia, the present experiments provide further evidence of dissimilarities in the mechanisms involved in the production of their central depressant activity.