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Methamphetamine (MAP) administered in doses of 0.5 to 5 mg/kg i.p. to rats anesthetized with pentobarbital produced a shortening of the duration of loss of righting reflex. This analeptic effect of MAP was blocked by atropine but not by atropine methylbromide, indicating the central cholinergic nature of the response. This effect was also blocked by the D1 and D2 dopamine antagonists SCH 23390 (0.2 mg/kg) and raclopride (2 mg/kg), respectively. Pentobarbital decreased sodium-dependent high-affinity choline uptake (HACU) in frontal cortex and hippocampus as measured in synaptosomes from treated rats. MAP given to pentobarbital-narcotized rats restored HACU activity to nonanesthetized levels, but this restorative effect of MAP was blocked by SCH 23390 or raclopride. These data suggest that in addition to a cholinergic mechanism, the analeptic effect of MAP involves the dopamine system. alpha-Methyl-p-tyrosine, but not reserpine, pretreatment completely blocked the MAP analeptic response. In reserpinzed rats, MAP produced a markedly enhanced analeptic response. Studies of the effects of repeated administration of MAP on its analeptic activity were also undertaken in view of the well known sensitization to the locomotor and stereotypic effects of the amphetamines that occur with repeated intermittent administration. Rats pretreated daily with MAP (5 mg/kg) for 5 or 12 days showed neither tolerance nor sensitization to the analeptic effect of subsequent MAP administrations. 3H-quinuclidinyl benzilate-binding studies also showed no changes in muscarinic binding characteristics of membranes prepared from cortex or hippocampus of rats pretreated chronically with MAP. These and our earlier studies suggest that the analeptic effect of MAP is mediated via a dopaminergic-cholinergic mechanism.

Thyrotropin releasing homone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 µg decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 µg produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.

A modified HPTLC technique was applied in investigating venous peripheral blood concentrations of PGE1, FGE2, FGF1, FGF2, PGA1 and PGAP2 in three subjects with occupational asthma, undergoing specific bronchial challenge test with chemical sensitizers, as well as in two control subjects, exposed to the same test. The findings obtained show that the technique employed in our study is quite suitable and could be Useful to acquire more information on some biochemical events occurring during asthmatic responses to bronchial challenge.

The prophylactic effectiveness of the phthalazinone derivative, azelastine was compared with ketotifen. A total of 111 patients, aged 18 – 65 years, from 10 centres was entered into this randomized, double-blind study. All patients had reversible asthma. After 1 week on placebo, patients were allocated to either 8 mg/day azelastine once or twice daily, or to 1 mg ketotifen, twice daily, for a further 12 weeks. Azelastine was more effective in improving respiratory function (forced expiratory flow in 1 s and peak expiratory flow rate) when given in the once daily regimen, whereas clinical measures (number of weekly asthma attacks) were most improved by twice daily dosing. There was no significant difference between the effectiveness of azelastine and that of ketotifen. Treatments were equally well tolerated and a low incidence of side-effects was reported. In conclusion, 8 mg/day azelastine, in either a single or twice daily dosage regimen may be regarded as providing effective prophylaxis against bronchial asthma.

In the present investigation, we examined the influence of both genetic background and sex factors in the rat hypothalamo-pituitary-adrenal (HPA) axis function under both basal and post adrenalectomy (ADX) conditions. For these purposes adult female and male rats, from Sprague-Dawley (S-D), Fischer (F344/N), Lewis (LEW/N) and Buffalo (BUF) strains, were decapitated in basal condition or several (2, 7 and 14) days after ADX. Plasma stress hormones levels and adrenal corticosterone (B) concentration as well as peptide (ACTH, CRH and vasopressin, AVP) content in different tissues (anterior pituitary, AP; medial basal hypothalamus, MBH), were then evaluated by specific assays. Our results indicate that: a) despite no sex- and strain-related differences in AP ACTH and MBH ACTH secretagogues in basal condition, there exits a clear sexual dimorphism in plasma ACTH levels as well as in both plasma and adrenal B concentrations, with values significantly higher in females than in males, regardless the strain; b) ADX abolished plasma B levels and increased AP ACTH output in a time-dependent fashion up to the 14th day post surgery; c) AP ACTH content decreased 2 days after ADX, except in BUF female rats, thereafter tending to either recover or increase sham values by two weeks post ADX; d) ADX decreased MBH CRH at all periods studied, except in BUF female animals on day 14; e) ADX clearly diminished MBH AVP only in S-D rats, and f) a sexual dimorphism was also found in AP ACTH in 7-day-ADX S-D rats and in 14-day-ADX S-D and F344/N animals; also, a dimorphic pattern in MBH CRH was found in 7-day-ADX S-D as well as in 14-day-ADX F344/N and LEW/N rats. Our findings further indicate that both sex- and genetic-factors are able to modulate the rat HPA axis function under both physiological and pathophysiological conditions.

Intracerebroventricular or intraseptal microinjection of adrenocorticotropic hormone1-24 (ACTH1-24) to pentobarbital-anesthetized rats and rabbits produced shortening of the duration of narcosis. This analeptic effect was blocked by atropine, indicating the central cholinergic nature of the response. ACTH1-24 also increased hippocampal sodium-dependent high affinity choline uptake activity that had been depressed by the barbiturate. Naloxone-pretreatment also blocked the analeptic and cholinergic activating properties of ACTH1-24. These results suggest that intraseptal ACTH1-24 produces its analeptic effect by activating a hippocampal cholinergic arousal system.

The effect of centrally administered thyrotropin-releasing hormone (TRH) (1, 10 or 100 micrograms) on transit of a charcoal marker placed in the proximal colon of anesthetized rabbits was determined. A dose-dependent stimulation of transit was produced, which, with the higher doses, was accompanied by a watery diarrhea. Pretreatment with atropine was ineffective against these effects. Hexamethonium or bilateral vagotomy attenuated these effects, whereas vagotomy + sacral cord transection completely abolished them. Several serotonin antagonists completely blocked, and fluoxetine markedly enhanced, the TRH-induced transit and diarrhea production. Measurement of portal blood demonstrated that TRH produced a dose-dependent elevation in serotonin levels. This response was blocked by pretreatment with hexamethonium or after bilateral vagotomy, but enhanced by fluoxetine. These observations indicate that centrally administered TRH activates colonic transit via a vagally mediated serotonergic mechanism. The release of serotonin is probably from the enterochromaffin cells and/or enteric serotonin neurons in the intestine.

In order to investigate the role of N-terminal proopiomelanocortin (N-POMC) in adrenal regeneration after bilateral adrenal enucleation (hereafter referred to as enucleation) rats 13 days after enucleation were injected (200 μl s.c. plus 200 μl i.p.) at 08.00 and 20.00 h with normal rabbit serum (NRS), an ACTH antiserum or an N-POMC antiserum. On the next day the animals were injected with colchicine, killed and mitotic figures in adrenal histological sections counted. The same treatment was given to rats 20 days after enucleation. Only the N-POMC antiserum significantly diminished adrenal mitotic activity 14 and 21 days after enucleation (P< 0·01 and 0·05 respectively) when compared with NRS-treated enucleated rats, whereas plasma corticosterone levels in rats 14 days after enucleation were significantly (P< 0·005) decreased only by treatment with ACTH antiserum. To determine whether the mitogenic N-POMC peptides involved in adrenal regeneration originated from the pituitary intermediate lobe, 0·9% (w/v) NaCl or ergocryptine (10 mg/kg body weight) was administered s.c. twice daily to rats between 7 and 13 days after enucleation. On day 14, adrenal mitotic activity and plasma levels of ACTH and N-POMC were not significantly different between ergocryptine and saline-treated enucleated rats, whereas α-MSH levels in ergocryptine-treated enucleated rats were significantly (P< 0·02) decreased.Increases in N-POMC content of the pituitary lobe accompanied those of ACTH in animals 7, 10, 14 and 21 days after enucleation (P< 0·01 compared with sham-treatment). Anterior lobes from rats 10 days after enucleation or from adrenalectomized rats showed raised ACTH and N-POMC levels compared with sham-treated animals, whereas α-MSH content in the anterior lobe of enucleated rats was significantly (P< 0·005) decreased. Adrenalectomized animals had raised (P< 0·005) amounts of α-MSH compared with sham-treated animals. Plasma levels of ACTH and N-POMC were significantly (P< 0·01) raised in rats 10 days after enucleation or in adrenalectomized rats compared with those in sham-treated animals, whereas α-MSH levels were raised (P< 0·005) only in adrenalectomized rats.Sephadex G-75 chromatography of anterior lobe extracts obtained 10 days after surgery from sham-treated, enucleated and adrenalectomized rats was performed. In sham-treated animals the main N-POMC-immunoreactive peaks were located at the elution positions of N-POMC(1–95) and N-POMC (1–74), whereas in enucleated rats the bulk of the N-POMC immunoreactivity was located in a third peak which eluted at the position of synthetic N-POMC (1–48). In adrenalectomized rats a peak coinciding with the N-POMC(1–48) standard could also be detected, but the bulk of the N-POMC immunoreactivity corresponded to the N-POMC(1–95) and N-POMC(1–74) peaks. Perfusates from dispersed rat anterior pituitary cells from rats 10 days after enucleation or sham-operation were also chromatographed. The profile of N-POMC immunoreactivity was essentially the same as that in the anterior lobe extract. Chromatography of plasma samples from ergocryptine-treated enucleated rats revealed a peak accounting for N-POMC (1–74) and a peak coinciding with N-POMC(1–48).It was concluded that N-POMC peptides are physiologically important in adrenal regeneration and that, in this condition, mitogenically active N-POMC peptides are generated from the anterior lobe and not from the intermediate lobe of the pituitary gland. This implies a change in the mode of anterior lobe N-POMC processing in adrenal regeneration.J. Endocr.(1988) 116,207–216

In order to demonstrate the mitogenic effects of N-terminal pro-opiomelanocortin (N-POMC) peptides on the adrenal glands further, female rats with bilateral adrenal enucleation (hereafter referred to as enucleation) were hypophysectomized 11 days after enucleation and injected twice daily with 5 μg purified human N-POMC(1–28), ACTH(1–24) or 0·9% (w/v) NaCl. On day 14 after enucleation, rats were injected with colchicine and, after killing, their adrenal glands weighed, fixed and mitotic counts in histological sections assessed. Plasma corticosterone was measured fluorometrically. In other experiments, rats 7 days after enucleation were hypophysectomized and implanted with osmotic minipumps delivering 5 μg purified N-POMC(1–28) per day. On day 14 after enucleation, animals were treated as above. Collagenase-dispersed adrenal cells were incubated with purified or synthetic N-POMC(1–28) or synthetic N-POMC (1–36) (1–300 nmol/l) and [3H]thymidine incorporation into DNA was determined. Intact female rats were implanted with osmotic minipumps delivering 8 μg purified or synthetic N-POMC(1–28)/day, 8 μg synthetic N-POMC(1–36)/day or saline alone. Mitotic counts were performed on histological sections.Both s.c. injection or continuous delivery from minipumps of purified N-POMC(1–28) partially prevented the atrophy of regenerating adrenal glands after hypophysectomy (s.c. injection of N-POMC: 2·29 ± 0·92 mitoses/section compared with 0·52 ± 0·39 for controls; minipump delivery: 5·02 ± 0·97 compared with 0·13 ± 0·05; P< 0·01 for both experiments). ACTH did not augment mitotic activity in enucleated– hypophysectomized rats but significantly increased plasma concentrations of corticosterone in s.c. injection experiments. Adrenal weights were not significantly changed. Both purified and synthetic N-POMC(1–28) increased thymidine incorporation in incubated adrenal cells, the synthetic peptide being less potent than the purified peptide. Whilst synthetic and purified N-POMC(1–28) significantly increased mitotic counts in histological sections of intact adrenal glands after chronic delivery from minipumps, N-POMC(1–36) had no significant effect.It was concluded that N-POMC(1–28) can partially reverse the adrenal atrophy in enucleated rats after hypophysectomy, whereas ACTH is mitotically inactive in the same situation. The low potency of the synthetic peptides compared with purified N-POMC(1–28) preparations reported in this study could be due to differences in secondary structure.J. Endocr.(1988) 116,201–206

Apomorphine (AP)-elicited stereotypic behavior and striatal 3H-spiroperidol binding sites were studied in rats given 3 weeks of chronic treatment with one of the following neuroleptic drugs: zotepine (10 or 20 mg/kg/day IP); thioridazine (10 or 20 mg/kg/day IP); haloperidol (2 or 5 mg/kg/day IP). On days 10–12 after the chronic neuroleptic treatment, enhancement of AP-elicited stereotypy was seen in the highand low-dose haloperidol-treated, as well as in the high-dose thioridazine and zotepine-treated rats when compared to that of saline-injected controls. No significant change in the response to AP was found in the low-dose thioridazine and zotepine-treated animals. Significant increases in the concentration of striatal 3H-spiroperidol binding sites were seen after treatment with all three neuroleptics, both high and low doses. A positive correlation was found between AP-elicited stereotypy and the concentration of striatal 3H-spiroperidol binding sites in the haloperidol-treated and control rats. However, no such correlation was seen after chronic thioridazine and zotepine treatments.