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In nonstressed rats, subcutaneous administration of haloperidol (HAL) and large doses of diazepam (DZ) increased plasma corticosterone (CS). Hypothalamic norepinephrine (NE) was lowered significantly by desmethylimipramine (DMI), HAL and, to a lesser extent by DZ and phenobarbital (PHB). In rats pretreated with either DZ, DMI, HAL or PHB the restraint-induced rise of CS was diminished, DZ being most potent. CPZ had a variable effect, slightly increasing or decreasing the CS response. Pretreatment (16 hr) with pargyline (PA) did not affect the CS rise to stress. The reduction of hypothalamic NE evoked by restrain was attenuated by DZ, and to a lesser extent, by PHB and HAL. Restraint of PA-treated rats did not lower the PA-elevated hypothalamic NE. The stress-induced increase in hypothalamic dopamine was prevented by CPZ and, partially, by PHB. It is emphasized that the net plasma CS and brain catecholamine changes in response to stress are dependent on the drug-induced neuroendocrine feedback state prevalent immediately before commencement of the stress procedure.

Restraint causes an increase in plasma renin activity (PRA) which is not affected by pretreatment with dl-propranolol (1 mg/kg IP) or sotalol (15 mg/kg IP). These doses of β-adrenergic blocking agents are effective in suppressing the stimulation of PRA by isoproterenol. Large doses of dl-propranolol (10 mg/kg IP) and d-propranolol (5 mg/kg IP) attenuate the restraint-induced PRA increase. Adrenal demedullectomy does not affect the PRA response to restraint. Renal denervation blunts the PRA rise due to restraint, but not to direct stimulation by the β-adrenergic agonist, isoproterenol. It is concluded that the increase in PRA during restraint stress in rats is not solely dependent on an intact renal sympathetic innervation. A significant portion of this stress-induced PRA increase appears to involve a non-adrenergic mechanism.

The injection of AT II in doses of 0.001 to 1.0 ug into the left vertebral artery caused an increase in spontaneous preganglionic cervical sympathetic nerve activity. This response showed tachyphylaxis and was independent of the vasopressor response. The enhancement of sympathetic discharges in response to hypothalamic stimulation was unaltered by AT II. It is concluded that one of the many different effects of AT II on the autonomic system involves a central sympathetic component.

Of several sympathetic responses elicited by electrical stimulation of the hypothalamus, diazepam (0.1–3 mg/kg i.v.) selectively attenuated the vasopressor response. In contrast, pentobarbital (1–10 mg/kg i.v.) in subanesthetic doses had a depressant effect on several evoked autonomic parameters. Chlorpromazine (0.1–1 mg/kg i.v.), in addition to its known peripheral α-adrenergic blocking action, also reduced preganglionic sympathetic outflow. The conclusion is reached that the central sympathetic system is not homogenous and may be selectively affected by different psychotropic agents.

The axodendritic response evoked by electrical stimulation of the cortical surface is diminished by intrapial injection of cholinergic agents. This effect is probably muscarinic in nature since it is blocked by atropine, and since administration of nicotine over a wide dose range does not diminish the axodendritic response. The diminution of the dendritic psp is not due to activation of inhibitory synapses because d -tubocurarine, strychnine and tetanus toxin, which are known blockers of inhibitory synaptic activity in spinal cord and brain, do not prevent the depressant effect of cholinergic agents. Since subcortical effects have been excluded by drug administration directly into the pial arteries, it is concluded that the muscarinic receptors involved are located within the cerebral cortex.

In the unanesthetized spinal cat i.v. injection of apomorphine depressed transmission of the monosynaptic reflex from extensor, flexor and dorsal root afferent sources. Polysynaptic discharges evoked from cutaneous afferents and from high threshold muscle afferents were effectively reduced as was the dorsal root reflex. Spontaneous and reflex activation of flexor efferents were initially depressed, then excited at higher concentrations of the drug. The effect of apomorphine is direct and not associated with the release of endogenous catecholamines since pretreatment with reserpine and a-methyl-p-tyrosine did not prevent its action. Haloperidol blocked the depressant effect of apomorphine whereas phenoxybenzamine, chlorpromazine and propranolol did not. It is concluded that apomorphine—claimed to act on central dopamine receptors—exerts distinct effects on spinal cord activity which are only in part similar to those of dopamine.

1. 1. It has been confirmed that low doses of reserpine phosphate produce spontaneous seizures and facilitate evoked seizures in the rhinecephalon without affecting thalamocortical recruiting responses and electrocortographic “arousal”. 2. 2. The occurrence of cortical low voltage fast activity after administration of large doses of reserpine phosphate can be blocked by atropine. Atropine does not interfere with evoked rhinecephalic seizure discharges. 3. 3. Activation of the reticular system of the brainstem by electrical stimulation of administration of central stimulants such as amphetamine, ibogaine, pipradol and methylphenidate exerts various graded effects according to stimulus intensity or dosage used: ◦ (a) “Low dose — low intensity” stimulation causes a cortical arousal reaction with little or sometimes no diminution of the thalamo-cortical recruiting response. Such stimuli do not influence the electrically evoked limbic paroxyms in either control or reserpine-treated animals. ◦ (b) “Higher dose — higher intensity” stimulation provokes not only cortical fast activity but also causes a considerable diminution of the thalamo-cortical recruiting response. It reduces the length of rhinencephalic seizures in control and reserpine-treated animals. 4. 4. The possible mechanisms involved in the interaction of reserpine and central stimulants are discussed in the light of the clinical potentiality of drug combinations of this type.

Desipramine in intravenous doses of 0.3 to 3 mg/kg in the cat enhances preganglionic cervical sympathetic nerve activity evoked by hypothalamic stimulation. This effect is dependent on the pulse frequency of stimulation. Spontaneous potentials are in general slightly diminished. Reflex excitation of preganglionic sympathetic outflow induced by sciatic nerve stimulation is not altered by desipramine. The described effects are interpreted as the result of a modulating influence of desipramine on central structures controlling sympathetic outflow.

In the chloralose-anaesthetized cat, stimulation of forelimb cutaneous afferent nerves evoked a response in the preganglionic splanchnic nerve, consisting of a short duration spinal reflex followed by a supraspinal component of longer duration. Diazepam (0·1–1·4 mg/kg, i.v.) markedly attenuated the supraspinal reflex but had a considerably lesser effect on the segmental response. On the other hand, diphenylhydantoin (10–40 mg/kg, i.v.) reduced predominantly the spinal component, whilst the supraspinal reflex was frequently enhanced after the initial dose of 10 mg/kg. This effect of diphenylhydantoin on the spinal reflex was direct, since it also occurred in the spinal cat. Phenobarbital (10–40 mg/kg, i.v.) was approximately equally potent in reducing both the spinal and supraspinal reflex. Visceromotor reflexes were markedly depressed by very small doses of diazephm (0·001 mg/kg, i.v.) and by larger doses of phenobarbital (10–20 mg/kg, i.v.). Diphenylhydantoin, although reducing this reflex, did not completely block it at the highest total dose tested (40 mg/kg, i.v.). The results indicate that the three CNS depressants differentially affect the spinal and supraspinal components of the somatosymphetic reflex. Furthermore, the three drugs also differ quantitatively from each other in depressing the spino-bulbo-spinal transmission of the viscerosomatic reflex.

Restraint stress of 30 min increases plasma CS and lowers hypothalamic NE. Restraints of longer durations are associated with an attenuation of these changes. Daily repetitive restraint enhances the CS response on the second day and progressively diminishes it on subsequent days. Whole brain NE increases on the first day and decreases on Day 2 to 5. The CS response to acute restraint is similar is similar in 5 different normotensive rat strains, but is enhanced in the genetically hypertensive SH rat, its normotensive backbreed WKY, and the DOCA hypertensive Sprague-Dawley rat. Comparison with other stressors (electric foot shock and novel environment) indicate that the responses to restraint are different at least in time course, if not qualitatively.

Electrical and cholinergic (physostigmine) stimulation of the mesencephalic reticular formation (MRF) blocks ciliary nerve activity. Pentobarbitone increases the spontaneous ciliary nerve potential and lowers the threshold to electrical MRF stimulation. Atropine has no significant effect on spontaneous activity, but diminishes the response to electrical MRF stimulation and blocks the physostigmine-induced inhibition. In contrast, electrical stimulation and physostigmine activation of the MRF generally increases vagal efferent discharges and tends to induce rhythmicity or increase the rate of pre-existing rhythmicity. Pentobarbitone depresses spontaneous activity and blocks effects induced by electrical MRF stimulation. Atropine, per se, may increase, decrease, or modify vagal efferent activity, suggesting selective effects on different neuronal aggregates of the vagal system. Physostigmine-induced alterations of vagal outflow are antagonized by atropine. From these results it is concluded that the differential effect of MRF stimulation, physostigmine, atropine and pentobarbitone on the upper (ciliary) and lower (vagal) parasympathetic outflow represents the consequence of a different organization of those substrates which govern the two parasympathetic activities.

In the spinalized cat the bradycardia evoked by activation of baroceptors is not blocked and is occasionally enhanced by diazepam. In contrast pentobarbital blocks this response. Diazepam also causes tachycardia due to central vagal inhibition. The effects of vagally mediated cardiac depressant reflexes are modulated by supramedullary influences. This is evidenced by the finding that diazepam-induced tachycardia and increased reflex bradycardia do not occur in cats spinalized at C1 and precollicularly decerebrated.

N-(4-pyridyl) substituted benzodioxan- and benziodioxepan carboxamides are central stimulants. The corresponding 3- or 2- pyridyls have less stimulant or depressant effects. Methylene-4-pyridyls and the 4-pyridyl substituted 3-phenylbenzodioxan-2-carboxamide also possess central depressant activity. The most active central stimulant, N-(4-pyridyl)-1, 4-benzodioxan-2-carboxamide (GPA 732) is a convulsant six to eleven times more potent and more toxic than pentylenetetrazol. Its action is of the mixed type, e.g., it precipitates convulsions by blocking inhibitions (strychnine-type) and facilitates excitatory synaptic mechanisms (pentylenetetrazol type). Diazepam is the most effective anticonvulsant against seizures induced by GPA 732.

A number of therapeutically unrelated agents diminish mast cell degranulation induced by BW 48/80; phenylbutazone, acetylsalicylic acid, chlorpromazine, morphine, meperidine and etonitazine. The mechanisms by which these agents act is unknown. Administration of hydrocortisone, cortisone and ACTH has no effect on mast cell disruption. Hypophysectomy induces a greater resistance of mast cells against the disrupting effect of BW 48/80.

Stimulation of hypogastric nerve contracts the urinary bladder. Exogenous norepinephrine and dopamine cause only an insignificant contraction or relaxation, whereas tyramine regularly contracts the bladder. Denervation or pharmacological sensitization by imipramine or cocaine does not alter the minor response to norepinephrine but the latter procedure enhances the effect of hypogastric stimulation. UML 491, a serotonin blocking agent, does not affect the hypogastric nerve-bladder response, whereas phentolamine has variable effects. Dihydroergotamine causes marked spontaneous contractions. Under certain conditions reserpine, syrosingopine and α-methylmetatyrosine diminish but never block the contraction induced by sympathetic stimulation. Choline-2,6-xylyl ether bromide markedly increases spontaneous contractions of the bladder, enhances the contractions to pelvic stimulation but irregularly diminishes those to hypogastric stimulation. Only guanethidine and bretylium block the hypogastric nerve-bladder response completely and selectively. Single pretreatment with syrosingopine (10 mg/kg i.V.), α-MMT (100 mg/kg i.v.) and guanethidine (15 mg/ kg i.v.) lowers the NE concentration of the bladder (18 hr) to approximately one third of that in controls, whereas the 5-HT content remains unchanged. The NE and 5-HT concentration in the untreated bladder is 1.13±0.48and0.20±0.03 μg/g respectively. Eserine augments and hexamethonium diminishes the sympathetically induced contraction.

Summary The spontaneous and hypothalamically evoked discharge patterns of the preganglionic cervical sympathetic, splanchnic and vagal nerves have been described and discussed as potential indicators of central “autonomic tone” in cat. Chlorpromazine and diazepam, in i.v. doses of 0·3-3 mg/kg, generally reduced slightly spontaneous evoked impulse traffic in cervical sympathetic fibers, but markedly attenuated the electrical activity in splanchnic nerves. Vagal efferent activity was more subtly affected by these two agents. Pentobarbital (3–10 mg/kg i.v.) depressed spontaneous and evoked potentials in the sympathetic and vagal nerves. In addition, it prevented the poststimulatory inhibition observed in sympathetic nerves.

The mechanism of action by which thalidomide exerts its teratogenic effects is still unknown. One of several possible approaches to the problem is to study the activity of compounds related to the structure of thalidomide. Misiti et al. (1) reported that d,1–3-phthalimidoglutarimide and N-phthalyl-d,1-aspartimide were teratogenic for the chick embryo and increased the incidence of fetal resorptions in rats. Simple substituted phthalimides, like N-butyl phthalimide, also increased fetal resorptions in rats (2). Since one of us (H.M.W.) has synthesized several thalidomide analogs, it was of interest to study some pharmacological properties and the teratogenic potential of two compounds which were available in sufficient quantities, namely 2-[hexahydrophthalimido] glutarimide (WU-320), m.p. 180–180.5°, and 2-phthalimido-N-methyl glutarimide (WU-313), m.p. 158.5–159°.

The dimethyl octyl ammonium ester of benzilic acid (AD-205) possesses marked anticholinergic properties on the bronchi of guinea pigs and on the gut and urinary bladder of intact, anesthetized dogs and cats. The mydriatic effect of AD-205 in mice is 50 times less than that of atropine after parenteral administration. The oral toxicity in mice, at 1150.0 mg/kg, is lower than that of atropine and adiphenine.

Single light flashes or electrical stimulation of the optic nerve evoke a bi- or triphasic potential in the short ciliary nerves. The central conduction and transmission time (from the optic nerve to the emergence of the preganglionic autonomic oculomotor fibers) is estimated to be about 12 msec. After prior conditioning stimuli, evoked responses to subsequent test shocks are inhibited when the interval is between 15 and 30 msec. Recovery takes 120 msec or longer. This inhibitory period is prolonged by pentobarbital. CPZ, which constricts the pupil in man, enhances optically evoked ciliary potentials, whereas diazepam and pentobarbital decrease them. The CPZ effect is interpreted as a diminution of inhibitory influences on the pupilloconstrictor outflow.

A miniature, three-channel high input and low output impedance preamplifier is described for extracellular unit recording in freely moving animals. A MOSFET and an integrated circuit operational amplifier provide the two stages of each of the three amplifiers. The overall gain is approximately 200, down 6db at 1.5 Hz and 5 kHz. The peak-to-peak broadband noise amplitude with a source resistance of 10 kΩ is 10μV.