Corticosterone Synthesis Inhibitor Research Articles

Putative mechanisms of buspirone-induced antinociception in the rat

Intraperitoneal administration of the serotonin 5-HT1A agonist, buspirone (1–5 mg/kg), produced dose- and time-related core hypothermia that was coincident with analgesia against a thermally noxious stimulus. Surface body temperature was not altered by buspirone. The 5-HT1A antagonist, NAN-190 (2 mg/kg, s.c.), blocked both hypothermic and analgesic effects, while systemic administration of the opioid antagonist, naloxone (1 mg/kg, s.c.), did not change the pattern of buspirone-induced hypothermia or analgesia. The apparent lack of opioid involvement and the documented role of the 5-HT1A receptor system in neuroendocrine substrates of thermoregulation and pain modulation prompted study of adrenal function in these buspirone-induced effects. Buspirone (5 mg/kg, i.p.) produced significant elevations in plasma epinephrine (EPI) and corticosterone (CST). Bilateral adrenalectomy reduced both control and buspirone-elevated EPI and CST levels and attenuated the antinociceptive, but not hypothermic, effects of buspirone (1–5 mg/kg, i.p.). Administration of the phenylethanolamine- N-methyltransferase (PNMT) inhibitor, dichloromethylbenzylamine (DCMB: 25 mg/kg, i.p.) reduced basal and buspirone-elevated plasma EPI, but not CST levels. This treatment did not affect buspirone-induced hypothermia, while significantly reducing buspirone antinociception. Pretreatment with the CST synthesis inhibitor, aminoglutethemide (AG: 2 × 25 mg/kg, i.p.), reduced plasma CST levels while not significantly affecting EPI. AG pretreatment did not alter the hypothermic effects of buspirone, but attenuated antinociception produced by the highest buspirone dose. The AG-induced reductions of buspirone antinociception were less than those effects produced by DCMB treatment. These data suggest that buspirone-induced antinociception may be a non-opioid, adrenally mediated co- and/or epi-phenomenon to core hypothermia evoked by 5-HT1A receptor agonism.

Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis

In a previous study, male rats showed behavioural deficits after a single restraint stress but not after 5 daily restraint periods (i.e. adaptation had developed): female rats although less affected by single restraint failed to adapt over the same time course. This sex difference was associated with the male but not the female rats showing enhanced behavioural responses to the 5-HT agonist5-methoxy- N,N-dimethyltryptamine (5-MeODMT) after 5 restraint periods. In the present study, the role of the greater increases of plasma corticosterone in stressed females in these sex differences was studied. The corticosterone synthesis inhibitor metyrapone (75 mg/kg i.p.) was given to attenuate the rise of corticosterone to a level typical of stressed males. This resulted in the behavioural deficits of the female rats being shifted in the direction of the male pattern. Thus, their deficits in open field activity and food intake after single and repeated stresses were potentiated and opposed respectively. The latter effect was associated with increased responses to 5-MeODMT. Metyrapone alone was without significant effect. Brain regional 5-HT metabolism was unaffected. The results are consistent with corticosterone facilitating adaptation to single restraint but impairing adaptation to repeated restraint. As failure to adapt repeated stress is an animal model of depression, results as a whole suggest that increased corticoid levels and decreased 5-HT functional activity may have a role in the development of the illness and its greater incidence in women.

Central serotonergic responses and behavioural adaptation to repeated immobilisation: The effect of the corticosterone synthesis inhibitor metyrapone

Rats were immobilised for 2 h/day. Twenty four hours after the 1, 3 or 7 immobilisation periods they were injected with the 5HT agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT; 5 mg/kg i.p.) and behavioural responses (i.e. hind limb abduction, forepaw treading, head weaving, trenor, Straub tail) compared with those of a control group. As we have previously observed after 7 (but not after 1 or 3 immobilisations) forepaw treading and tremor were enhanced and the other responses unaffected. Pretreatment with metyrapone (a corticosterone synthesis inhibitor 150 mg/kg i.p., 3 h before each immobilisation) did not affect the above responses to 1 immobilisation, increased tremor after 3 immpbilisations and also increased forepaw treading, hind limb abduction and Straub tail after 7 immobilisations but decreased head weaving under the latter conditions. Metyrapone without immobilisation had no effect on responses to 5MeODMT. Twenty four hours after 1 or 3 (but not 7) immobilisation periods, rats placed for the first time in an open field showed less locomotion and rearing and more defaecation than control animals. Rats also given metyrapone exhibited normal open field behaviour after only 3 immobilisations. The drug also accelerated the return to normal on repeated immobilisation of the impairment of food intake and growth rate which occurred after a single immobilisation. The results as a whole suggest that metyrapone promotes behavioural adaptation to repeated immobilisation and that this is associated with enhanced postsynaptic responses to 5HT. These findings suggest that immobilisation stress-induced changes might be relevant as an animal model for depression which incorporates reported biochemical abnormalities in the illness and is of relevance to proposals concerning its precipitation by stress.

Corticosterone prevents the increase in noradrenaline-stimulated adenyl cyclase activity in rat hippocampus following adrenalectomy or metopirone

Corticosterone modulation of the noradrenaline-responsive cyclic AMP generating system was examined in rat hippocampus. Adrenalectomy was found to produce a small but significant elevation in the rate of cyclic AMP formation in response to noradrenaline. Implantation of corticosterone pellets 5 days prior to sacrifice prevented this adrenalectomy-induced increase. Metopirone, an inhibitor of corticosterone synthesis, was also observed to increase cyclic AMP formation. This elevation was seen 2 h following a 50 mg/kg i.p. injection and was completely prevented by corticosterone pellet implantation. Metopirone had no significant effect on cyclic AMP production after 1 h, while a slight but statistically non-significant elevation remained at 4 h. These observation parallel the inhibitory effect of Metopirone on corticosterone synthesis as determined by serum corticosterone levels.

Modification of High Temperature and ACTH Induced Immunodepression by Metyrapone ,

High environmental temperature and ACTH caused depression of developing, as well as established, hemagglutinins in young chickens. Metyrapone, an inhibitor of adrenal corticosterone synthesis, modified the immunodepressive effects of heat and ACTH when given in combination with these treatments; however, consistent changes in serum cholesterol and corticorticosterone were not observed. Sire-family differences in birds known to respond differently to ACTH appeared to be related to immunological responsiveness.

Ultrastructural localisation of adrenal cholesterol by autoradiography and digitonin reaction after cycloheximide-induced inhibition of corticosterone synthesis.

In rats given cycloheximide to prevent ACTH from stimulating corticosterone biosynthesis, the lipid droplets in the zona fasciculata were found to have turned polymorphic, grown larger, and increased in number. In the absence of eorticosterone production 3H-cholesterol accumulated in the lipid droplets. The digitonin reaction was used to identify free cholesterol for electron microscopy.

Adrenal Glands in Vitamin E Deficiency: in vitro Corticoid Synthesis by Quartered Adrenal Glands of Rats deprived of Vitamin E

RECENT investigations in this laboratory have indicated an inhibition of corticosterone synthesis in quartered adrenal glands from vitamin E-deficient rats1. It was also found that adrenal homogenates of the deficient rats, when properly diluted, undergo in vitro lipid peroxidation and formation of malonaldehyde, as determined by the thiobarbituric acid (TBA) test, more readily than any other organ tested1,2. However, when incubated adrenal quarters instead of homogenates were assayed for lipid peroxidation by the TBA method, there was very little net production of malonaldehyde, but significant inhibition in corticoid synthesis occurred in the quartered adrenals of vitamin E-deficient rats. This is in contrast to other enzymatic inhibitions which have been demonstrated in vitamin E-deficient rats and shown to be associated with the process of in vitro lipid peroxidation3,4. The various investigations and aspects of in vitro lipid peroxidation in adrenal homogenates of vitamin E-deficient rats will be reported separately. This communication reports preliminary data obtained on corticoid synthesis by the quartered adrenal glands of vitamin E-deficient and sufficient rats.