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Commercial preparations of essences of sage, hyssop, thuja, and cedar have caused human intoxication in eight cases, from which tonico-clonic convulsions were the major symptom. The experimental study of the toxic properties of commercialized essential oils of sage and hyssop has revealed that their convulsant action was of central nervous system origin in unanesthetized rats, as proven by electrocortical records. The toxicity of the hyssop oil seems to be more powerful than that of sage, since the dose limit from which the cortical events are only subclinical is 0.08 g/kg for hyssop oil and 0.3 g/kg for sage oil. Above 0.13 g/kg for hyssop oil and 0.50 g/kg for sage oil, the convulsions appeared and became lethal above 1.25 g/kg with hyssop oil and 3.2 g/kg with sage oil. The daily repeated injection of subclinical doses revealed the cumulative toxic effect of hyssop oil, since the same low dose induced electrocortical clonic seizures. The toxicity of each oil appeared to be related to the presence of terpenic ketones, camphor in sage commercial oil, camphor and thujone in sage Dalmatian oil, thujone in thuja and cedar oils, and pinocamphone in hyssop oil. The convulsant properties of camphor are well known. The neurotoxicity of thujone and pinocamphone is demonstrated in rats for the first time.

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It is known that in vivo excitatory amino acids (EAA) stimulate the hypothalamo-pituitary-adrenal axis. However their site of action is not fully understood. We investigated the possibility of a direct action of EAA on the secretion of the major adrenocorticotropin hormone (ACTH) secretagogue: corticotropin-releasing factor (CRF) from incubated rat hypothalamic slices. N-methyl-D-aspartic acid (NMDA) or L-glutamate (1 x 10(-7) to 1 x 10(-3) M) stimulated in a dose-dependent fashion CRF release. The maximal effect was obtained at a concentration of 1 x 10(-4) M for both drugs. The IC50 was 1.3 x 10(-5) M and 3.3 x 10(-5) M for NMDA and L-glutamate, respectively. Incubation with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist) or 2-amino-4-phosphonobutyrate (a metabotropic receptor antagonist) was without significant effect on basal CRF secretion and completely blocked the increase in CRF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M AMPA did not change basal CRF secretion. Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of kainate and AMPA receptor) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAA could stimulate directly CRF secretion, by an action through NMDA and metabotropic receptors, but not kainate or AMPA receptors. These findings may be relevant to the regulation of the hypothalamo-pituitary adrenal axis, both under basal conditions and during exposure to stress.

In order to better understand the mechanisms underlying the reduction in growth hormone (GH) secretion in diabetic rats, we studied hypothalamic somatostatin secretion both in vivo (into hypophysial portal blood) and in vitro (from hypothalamic fragments) 5,9 and 30 days after induction of diabetes. Experimental diabetes was induced by an intraperitoneal injection of streptozotocin (STZ) at a dose of 65 mg/kg. Basal plasma GH was significantly reduced in diabetic rats at all stages. Somatostatin levels in hypophysial portal blood was unaffected in 5-day STZ-diabetic rats and significantly increased 9 days after STZ administration. Chronic insulin replacement therapy in diabetic animals partly normalized somatostatin levels as well as plasma GH and glucose levels. A good correlation was observed between in vivo and in vitro experiments. Indeed, somatostatin release from hypothalamic fragments did not change 5 days after STZ-induced diabetes and significantly increased 9 and 30 days after STZ administration. The in vitro increase in hypothalamic somatostatin secretion was observed in 10 as well as in 33 mM glucose concentration in the incubation medium. In the same experiment, the in vitro hypothalamic corticotropin-releasing factor secretion was lowered 5 and 9 days after diabetes induction. We conclude that hypothalamic somatostatin release increases in diabetic rats. These changes may contribute to the reduction in GH secretion in these animals. However, since these changes occur after the onset of plasma GH decrease, a factor(s) other(s) than somatostatin may play a causal role in the reduction in GH secretion.

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Substance P (SP), a neurotransmitter localized to primary sensory neurons, is found in the vagus nerve, nodose ganglion, sympathetic chain, and phrenic nerve in various animal species. However, the changes in endogeneous SP concentration under various circumstances that involve the participation of cardiorespiratory afferent nerves are still unexplored. In the present study, attention was focused on the variations in SP content measured by radioimmunoassay (RIA) in respiratory afferent nerves (vagus nerve, cervical sympathetic chain, phrenic nerve) and respiratory muscles (diaphragm, intercostal muscles) during positive inspiratory pressure (PIP) breathing alone or PIP with an expiratory threshold load (ETL) in rabbits. SP was found in all sampled structures in spontaneously breathing control animals, prevailing in the nodose ganglion. Left-versus right-sided differences were noticed in nerves. As compared with that in control animals, the SP concentration was markedly higher in vagal and sympathetic nervous structures during PIP or PIP with ETL, and also in the phrenic nerve during ETL breathing. The SP content did not vary in respiratory muscles. These observations suggest that two very common circumstances of mechanical ventilation are associated with an increased SP concentration in nervous structures participating in the control of breathing.