Attenuation of the plasma prolactin response to restraint stress after acute and chronic administration of nicotine to rats

We have previously shown that a single dose of nicotine elevates plasma adrenocorticotropin (ACTH) levels in rats and has a biphasic effect on plasma prolactin (PRL). The stimulatory effect of nicotine on these stress responsive hormones desensitizes after a single injection of nicotine. Continuous exposure to nicotine also induces tolerance to its locomotor depressive and hypothermic effects, which have been associated with an increase of central [3H]nicotine binding. Thus, the acute and chronic administration of nicotine might induce changes in central nicotinic cholinergic circuits that affect the ACTH and PRL responses to stress. In the present study, a single dose of nicotine (0.75-3.0 mg/kg b.wt.) significantly inhibited the elevation of plasma PRL due to restraint stress initiated 60 min afterward. Five injections of nicotine during 1 day produced a similar attenuation of the PRL response to restraint stress but neither of these paradigms affected ACTH. In contrast, intermittent delivery of nicotine for 7 days failed to affect the PRL response to restraint stress; however, after withholding nicotine for 14 hr, high dose nicotine attenuated the PRL response to stress, whereas low dose nicotine remained ineffective. On the other hand, administration of the same schedule of low dose nicotine did significantly diminish the expected release of PRL in response to a final injection of nicotine (0.5-2.0 mg/kg b.wt.) in unstressed animals. In summary, a single dose or 5 doses of nicotine in 1 day attenuated the PRL response to restraint stress, whereas, after chronic administration, this effect was lost.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of nicotine on prolactin release in the rat: agonist and antagonist effects of a single injection of nicotine

The effects of nicotine on prolactin release were studied in conscious, unrestrained rats in which an indwelling jugular cannula allowed multiple samplings of blood after i.v. administration of nicotine. Intravenous administration of nicotine bitartrate dihydrate increases plasma prolactin concentrations in a dose-dependent manner with an ED50 of approximately 100 micrograms/kg (200 nmol/kg) and this effect is blocked completely by pretreatment with mecamylamine, indicating that it is mediated by a nicotinic cholinergic receptor. Intracerebral ventricular injection of 1 microgram of nicotine also increases plasma prolactin levels, but i.v. injection of this same amount of nicotine has no effect, indicating that nicotine acts within the brain to release prolactin. A single i.v. injection of nicotine resulted in desensitization of the prolactin response to a subsequent injection of nicotine given 1 to 2 hr later, thus confirming a previous report by Sharp and Beyer (J. Pharmacol. Exp. Ther. 238: 486-491, 1986). The prolactin response to nicotine was restored within 24 hr after a single injection. The acute desensitization after a single injection of nicotine appears to be specific to release of prolactin by nicotine because the prolactin response to morphine was unaffected 1 hr after injection of nicotine. A single injection of nicotine appears to desensitize the prolactin response to a subsequent injection of nicotine with an ED50 of approximately 20 micrograms/kg (40 nmol/kg), indicating that nicotine is even more potent in stimulating desensitization of nicotinic cholinergic receptors than in stimulating prolactin release. These results support the concept that nicotine acts as a time-averaged antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of the fourth cerebroventricle in mediating rat plasma ACTH responses to intravenous nicotine

Peripherally administered nicotine elevates rat plasma adrenocorticotropic hormone (ACTH) levels, acting at brain regions adjacent to or downstream from the third cerebroventricle. Studies evaluated whether the paraventricular nucleus (PVN) mediates directly the ACTH response to nicotine administered i.v. and if regions adjacent to the fourth ventricle (IV) are involved. Direct involvement of the PVN in the release of ACTH in response to i.v. nicotine (0.03 or 0.01 mg/kg b.wt.) was refuted by studies in which the administration of the nicotinic cholinergic antagonist, mecamylamine (20 or 40 micrograms bilaterally adjacent to the PVN), failed to block ACTH secretion. To activate sites distal to the third ventricle, nicotine (0.25, 0.5, 2.5 or 5.0 micrograms) was injected into the IV; ACTH levels peaked between 3 and 7 min. Nicotine 0.25 micrograms injected into the IV elevated ACTH to levels within the range of those produced by i.v. nicotine (0.03 mg/kg b.wt.). To confirm that sites accessible from the IV are involved, mecamylamine was administered i.v. (0.5 or 1.0 mg/kg b.wt.) or into the IV (4 or 40 micrograms) and nicotine was delivered by the opposite route. Intravenous mecamylamine reduced the plasma ACTH response to 0.25 micrograms of nicotine in the IV. Mecamylamine, administered into the IV before i.v. nicotine (0.03 mg/kg b.wt.) antagonized the effect of nicotine. These results indicate that stimulation of ACTH secretion by nicotine delivered i.v. occurs via structures accessible from the IV. In contrast to prevailing ideas, the PVN does not appear to be the direct site of action of nicotine.     

Nicotine elevates rat plasma ACTH by a central mechanism

Nicotine is a potent secretagogue for the release of adrenocorticotropin (ACTH) from the anterior pituitary in vivo. However, the location of its action is unknown; knowledge of this is essential for elucidating its mechanism. Our studies show that cytisine, a peripherally acting nicotinic cholinergic agonist, given i.v. at doses equimolar or greater than nicotine, failed to elevate plasma ACTH levels, whereas nicotine (0.01 and 0.03 mg/kg b.wt.) had significant effects. Nicotine (10(-7)-10(-4) M) had no effect on the secretion of beta-endorphin by anterior pituicytes in vitro, nor did it potentiate the action of corticotropin-releasing factor (10(-9) or 10(-8) M). Intracerebroventricular injection of nicotine (1-20 micrograms) significantly elevated ACTH levels. Moreover, ACTH responses to nicotine delivered into the hypothalamic region of the third ventricle were significantly greater than those elicited by injection into the upper region. Additional studies were conducted to determine the earliest age at which nicotine stimulates ACTH. The response to i.p. nicotine (1 or 2 mg/kg b.wt.) was present but diminished during the postnatal period, whereas maximal responses comparable to mature rats were attained by day 15. To establish whether nicotine has a central effect in younger animals, nicotinic antagonists were tested. Hexamethonium (2 mg/kg b.wt.), a peripherally acting antagonist, was ineffective against nicotine (0.025 and 2.0 mg/kg b.wt.), whereas mecamylamine (2 mg/kg b.wt.), inhibitory at both peripheral and central sites, blocked the ACTH response. Thus, whether administered peripherally or centrally, nicotine activates central mechanisms mediating the release of ACTH; it appears that the target(s) for nicotine are within the hypothalamus or brainstem.     

Changes in the ambulatory activity and discriminative stimulus effects of psychostimulant drugs in rats chronically exposed to caffeine: effect of caffeine dose

Caffeine is a common psychoactive constituent of coffee, carbonated beverages, and over-the-counter medications. This study examined the effects of chronic caffeine exposure on the behavioral response to acute administrations of psychostimulant drugs on ambulatory activity and on the pharmacological characteristics of nicotine discrimination in rats. Rats were maintained continuously on caffeine added to the drinking water at a concentration of 0.25 or 1. 0 mg/ml that resulted in plasma caffeine concentrations ranging from 0.37 to 5.95 microg/ml. Rats maintained on tap water served as control groups. Exposure to the lower caffeine concentration (0.25 mg/ml) potentiated stimulatory effects of nicotine, amphetamine, and cocaine on ambulatory activity and failed to produce tolerance to the acute stimulatory effects of caffeine. In contrast, exposure to the higher caffeine concentration (1.0 mg/ml) did not alter the effects of the psychomotor stimulants on ambulatory behaviors but resulted in the development of complete, insurmountable tolerance to the acute stimulatory effects of caffeine. In the nicotine discrimination paradigm (0.4 mg/kg, training dose, a fixed-ratio 10 schedule of food delivery in a two-lever choice paradigm), rats exposed to the lower, but not to the higher, caffeine concentration acquired the nicotine discrimination significantly faster and were more sensitive to the effects of amphetamine and cocaine in substitution tests than water-drinking rats. Caffeine exposure did not change pharmacokinetic properties of nicotine (i.e., plasma levels, metabolism). In summary, exposure to two different caffeine solutions within a range of plasma levels observed in humans resulted in quantitatively distinct changes in psychostimulant-induced nonoperant and operant measures of behavior. These results suggest that dietary consumption of moderate doses of caffeine may be associated with enhanced reactions to some psychostimulants.     

The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. I. Acute effects on HPA axis activity and corticotropin-releasing factor-containing neurons in the rat brain.

Corticotropin-releasing factor (CRF) is the major physiological regulator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary. In vivo and in vitro studies have suggested that hypothalamic CRF secretion is under stimulatory serotonergic control, although the receptor subtype(s) responsible have not been definitely determined. The acute effects of the 5-hydroxytryptamine2 agonist, (+-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), were examined on a number of biochemical indices of hypothalamic-pituitary-adrenal axis activity in vivo. DOB increased plasma ACTH and corticosterone concentrations at doses greater than 0.1 mg/kg. This effect is dose-dependent. Peak effects occurred 30 min postinjection and returned to basal levels by 4 hr after DOB injection. These effects of DOB are hypothesized to be mediated by the release of hypothalamic CRF because pretreatment with the CRF receptor antagonist (alpha-helical CRF9-41) significantly attenuated the ACTH response to DOB. Median eminence CRF content was also decreased following DOB administration in the presence of the protein synthesis inhibitor, cycloheximide (200 mg/kg i.p.), suggestive of release of CRF from median eminence terminals as a result of DOB activation of CRF neurons. DOB administration was without effect on brain CRF concentrations in all of the 12 extrahypothalamic brain regions studied 60 min after injection. These results, taken together, support a stimulatory role for 5-hydroxytryptamine2 receptors on hypothalamic CRF secretion.     

Effect of chronic methadone administration on neuroendocrine function in young adult rats

This study reports the endocrine effects of chronic methadone (METH) administration. Two treatment regimens were tested: a constant (5 mg/kg/day, CD) or increasing dose (5 mg/kg twice daily, increasing 1 mg/kg/day, ID). Basal hormone levels and endocrine responses to opiate challenge were determined on days 5, 10 and 20 and after withdrawal. METH effects on hormone secretion varied with treatment duration, dose and hormone. Tolerance to METH effects on corticosterone (CS), prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH) and luteinizing hormone (LH) developed during the ID regimen and basal CS, TSH and LH levels were altered. In addition, serum testosterone, T3 and T4 decreased significantly during this regimen. In contrast, only CS secretion was affected markedly by the CD regimen. Resting levels were elevated by day 5 and the CS response to acute METH challenge was reversed. Tolerance also developed to METH-induced TSH suppression, but only with longer treatment. Similarly, basal TSH and LH levels were affected only with longer treatment. Basal PRL, GH and LH levels and LH, PRL and GH responses to acute METH challenge were not affected by the CD regimen. Changes in basal CS and TSH levels observed in these studies probably reflect abstinence, as even more pronounced changes occurred after naloxone-precipitated abstinence and suppressed rather than reversed responses were observed if animals were withdrawn for 36 hr before testing. Tolerance in some endocrine systems appears to be quite long-lasting, as CS, TSH and PRL responses to METH challenge were still decreased 3 weeks after withdrawal from the ID regimen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Delayed activation of tuberoinfundibular dopamine neurons and suppression of prolactin secretion in the rat after morphine administration

The effect of morphine administration on the subsequent stimulation of prolactin (PRL) secretion and the release of dopamine from tuberoinfundibular neurons was examined in this study. The administration of morphine (15 mg/kg s.c.) resulted 4 hr later in suppressed serum PRL concentrations. In addition, the increase in serum PRL concentrations induced by restraint stress was attenuated greatly in rats treated 4 hr earlier with morphine. The morphine-induced attenuation of the PRL response to restraint stress was time-dependent and dose-related. The suppressive effect of morphine on PRL secretion was observed 3 to 6 hr after its administration and at doses of 10 to 20 mg/kg. A single injection of morphine also resulted 4 hr later in an attenuation of the PRL response to a second injection of morphine (7.5 mg/kg); however, the increase in serum PRL concentration produced by alpha-methyltyrosine (250 mg/kg) was unaltered by prior morphine administration. The suppressive effect of morphine on PRL secretion was not observed in rats treated with the opiate antagonist naloxone (2.5 mg/kg). Associated with the delayed suppressive effect of morphine on serum PRL concentrations was a delayed increase in the concentration of dopamine in hypophysial portal plasma and an increase in the turnover of dopamine in the median eminence. The morphine-induced stimulation of the release of dopamine into hypophyseal portal blood was attenuated significantly in animals treated with naltrexone (1 mg/kg). It is concluded that morphine exerts a biphasic effect on both the secretion of PRL and the release of dopamine from tuberoinfundibular neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of ranitidine, famotidine and omeprazole on plasma gastrin in the rat

In the rat, treatment with gastric inhibitory drugs may result in hypergastrinemia, an effect thought to be in response to increased gastric pH caused by inhibition of acid secretion. This study compared 24-hr profiles of plasma gastrin levels associated with three different compounds at equivalent, highly effective antisecretory doses. Ranitidine, famotidine and omeprazole at 60, 20 and 40 mg/kg p.o., respectively, inhibited basal acid secretion of chronic gastric fistula rats by greater than 95% and raised intraluminal pH to above 7.0 for 5 hr. The peak plasma gastrin levels associated with each agent were observed 5 hr after dosing. Ranitidine, famotidine and omeprazole induced statistically significant and distinct peak hypergastrinemic responses of 312 +/- 20, 483 +/- 28 and 616 +/- 27 pg/ml, respectively. After 8 hr ranitidine and famotidine associated gastrin values returned to control levels, whereas those of omeprazole remained substantially above control values until the 12th hr. Differences in peak gastrin levels between compounds disappeared at increased dose levels of 500 mg/kg for ranitidine, 200 or 2000 mg/kg for famotidine and 140 mg/kg for omeprazole. Unlike high dose famotidine, omeprazole (140 mg/kg) maintained peak plasma gastrin levels at 8, 12, and 16 hr after dosing. These studies demonstrate clearly hypergastrinemic responses to single dose administration of ranitidine, famotidine and omeprazole. The differences observed in peak plasma gastrin levels at equivalent antisecretory doses of these agents suggests the presence of luminal acid independent components that effect gastrin release. Moreover, these studies indicate that, in the rat, the most unique aspect of omeprazole-associated hypergastrinemia is the magnitude of its prolonged response.     

Repeated amphetamine pretreatment alters the responsiveness of striatal dopamine-stimulated adenylate cyclase to amphetamine-induced desensitization

The repeated daily administration of moderate doses of amphetamine results in an augmentation of the behavioral response to subsequent amphetamine challenge. One feature of the augmentation is a shift in the type of perseverative behaviors to those generally associated with higher acute doses of the drug. Consistent with these observations, rats pretreated with six daily injections of amphetamine (3 mg/kg) exhibited primarily oral stereotypies to a challenge dose of 2.5 mg/kg of amphetamine, whereas control animals exhibited focused sniffing and repetitive head movements. Previously we found that the acute administration of amphetamine or methylphenidate only at doses which induce oral stereotypies promotes a rapid desensitization of striatal dopamine-stimulated adenylate cyclase. We therefore examined the effects of repeated amphetamine pretreatment on this index of D1 dopamine receptors. The administration of 2.5 mg/kg of amphetamine produced a 2-fold shift to the right in the concentration-response curve for dopamine-stimulated adenylate cyclase in animals pretreated with amphetamine, but not in saline pretreated controls. No effect of the chronic amphetamine pretreatment on dopamine stimulated cyclase in the absence of amphetamine challenge was observed. The binding of [3H]cis-flupenthixol to striatal D1 dopamine receptors was not affected by acute or chronic amphetamine. These results suggest a relationship between stimulant-induced desensitization of striatal D1 dopamine receptors and the induction of oral stereotypies.     

Direct effect of ethanol on adrenocorticotropin (ACTH) release in vitro

In order to determine whether the pituitary directly contributes to the stimulatory action of ethanol on adrenocorticotropin (ACTH) release, the response of rat pituitaries to ethanol was studied in vitro. Acute exposure of superfused rat pituitaries to ethanol (20-200 mg/dl) produced dose-related increases in ACTH which were significant at doses of 40, 80 and 160 mg/dl. The response to each dose was multiphasic, consisting of three peaks of ACTH in the 28-min sampling period after addition of ethanol. The dose-response profile of each peak revealed a maximally effective stimulatory dose of 40 mg/dl of ethanol and the direct stimulatory effect decreased with higher doses, resulting in a bell-shaped pattern. In contrast, ovine corticotropin-releasing factor, in doses of 1.0 to 10.0 nM, produced a single dose-dependent ACTH response, indicating a unitary mechanism for its action as opposed to the probable multiple mechanisms of ethanol's action on the corticotrophs. These results indicate that low doses of ethanol act directly on the pituitary to induce ACTH release, while higher doses may have their primary site of action on the hypothalamus.     

Central serotonergic stimulation of aldosterone secretion.

Serotonin stimulates aldosterone secretion both in vitro and in vivo, and serotonin antagonism decreases plasma aldosterone levels in patients with idiopathic aldosteronism. This study was designed to assess the effects of the serotonin precursor, 5-hydroxytryptophan (5HTP), upon aldosterone secretion in man, and to determine whether stimulatory effects of 5HTP are mediated through the central nervous system. Oral 5HTP, administered as a single 200-mg dose, increased plasma aldosterone levels from 4.7 +/- 0.6 to 13.3 +/- 2.8 ng/dl in dexamethasone-pretreated, normal volunteers. Peripheral inhibition of decarboxylation of 5HTP, achieved by pretreatment with carboxydopa, 25 mg three times daily for 3 d, significantly increased the stimulatory effects of 5HTP on aldosterone levels (P less than 0.001). No change in aldosterone levels occurred in subjects who received placebo after pretreatment with dexamethasone and carboxydopa. Increased aldosterone was not accompanied by increases in plasma levels of renin activity, potassium, or ACTH. Plasma levels of 5HTP were markedly increased by carboxydopa pretreatment, but peak plasma levels of serotonin were not significantly altered. Four patients with idiopathic aldosteronism all had an increase in plasma aldosterone levels after 5HTP administration, whereas the response in four patients with aldosterone-producing adenoma was variable. Incubation of isolated human and rat adrenal glomerulosa cells with serotonin resulted in increased aldosterone secretion by both sets of cells, whereas 5HTP was ineffective in stimulating aldosterone secretion in vitro. We conclude that central serotonergic pathways are involved in the stimulation of aldosterone induced by administration of 5HTP. This mechanism may be an important etiologic factor in the hypersecretion of aldosterone that occurs in patients with idiopathic aldosteronism.     

Gestational nicotine exposure attenuates nicotine-stimulated dopamine release in the nucleus accumbens shell of adolescent Lewis rats

The effects of chronic gestational exposure to nicotine on the nucleus accumbens dopamine response to acute nicotine were determined during adolescence (postnatal day 29-36) in cross-fostered and noncross-fostered Lewis rats. In both males and females, gestational nicotine exposure diminished the adolescent nucleus accumbens dopamine response to 0.07 mg/kg nicotine i.v. (p < 0.05). However, dopamine responses to 0.105 mg/kg nicotine were unaffected by gestational nicotine treatment and were similar in both genders. Furthermore, in both female and male gestational nicotine and control groups, the dopamine response to nicotine (0.105) was the same as that observed to the lower dose of nicotine in gestational controls. Thus, in adolescent male and female Lewis rats, gestational nicotine exposure attenuated nucleus accumbens dopamine release to a maximally stimulative dose of nicotine. Unexpectedly, in female gestational controls cross-fostering per se reduced nucleus accumbens dopamine secretion to 0.07 mg/kg nicotine (p < 0.05). These investigations suggest that gestational nicotine exposure could modify the acute reinforcing effects of nicotine in adolescent rats, whereas early postnatal stressors, (e.g., cross-fostering) may affect nicotine-induced reinforcement in female but not male adolescents.     

Dose-response analysis of nicotine tolerance and receptor changes in two inbred mouse strains

Mice of two inbred strains, DBA and C3H, were infused i.v. with saline, or 2, 4 or 6 mg/kg/hr of nicotine for 10 days. Two hours after termination of infusion the mice were challenged with one of several nicotine doses and the effects on respiration rate, Y-maze activity and rears, acoustic startle response, heart rate and body temperature were measured. Saline-infused C3H mice were less responsive than were DBA mice for all these tests with the exception of the acoustic startle response test. Nicotine-treated DBA mice developed a dose-related tolerance for most measures, whereas C3H mice did not appear to develop tolerance to any measure until the infusion dose reached 4 mg/kg/hr. The two mouse strains did not differ in the number of [3H] nicotine binding sites in six brain regions, and chronic nicotine treatment elicited similar changes in the binding of this ligand in the two strains. C3H mice had greater concentrations of alpha-[125I] BTX binding in hippocampus, midbrain and hypothalamus than did DBA mice. Chronic nicotine treatment resulted in an identical increase in bungarotoxin binding in the two mouse strains such that the initial strain differences were maintained. These results indicate that a threshold in drug response must be surpassed before a mouse develops tolerance to nicotine. In addition, mechanisms other than differences in receptor numbers must be invoked to explain differences in response to nicotine.     

Effects of acute ethanol administration on the hepatic xanthine dehydrogenase/oxidase system in the rat

Administration of ethanol (5 g/kg p.o.) to female Sprague-Dawley rats resulted in conversion of a portion of hepatic xanthine dehydrogenase to xanthine oxidase 12 hr after treatment. Conversion was partly reversed in vitro by treatment of hepatic 100,000 X g supernatant with dithiothreitol, whereas pretreatment of rats with pyrazole (100 mg/kg i.p.) prevented conversion 18 hr after ethanol administration. Incubation of acetaldehyde with rat liver supernatant at 37 degrees C converted xanthine dehydrogenase to xanthine oxidase in a dose-dependent manner, whereas incubation of ethanol with rat liver supernatant did not lead to conversion. Acetaldehyde-induced conversion in vitro was reversed by treatment with dithiothreitol, and was partially blocked by addition of equimolar concentrations of reduced glutathione. These data suggest that biotransformation of ethanol is required for conversion of hepatic xanthine dehydrogenase to xanthine oxidase. Because xanthine oxidase utilizes molecular oxygen to produce superoxide radical, ethanol-induced conversion of xanthine dehydrogenase to xanthine oxidase could contribute to the enhanced lipid peroxidation reported previously after administration of a single dose of ethanol.     

A Study of the Mechanisms by Which Adrenocorticotropic Hormone Maintains Adrenal Steroidogenic Responsiveness

Following hypophysectomy in the rat, there was a progressive decline in the rate of adrenal protein synthesis in vivo during the ensuing 24-48 hr, and an accompanying decrease in the acute corticosterone secretory response to an intravenous injection of ACTH. There was a similar decrease in the in vitro conversion of Delta(5)-pregnenolone, progesterone, and deoxycorticosterone to corticosterone. These in vivo and in vitro effects of hypophysectomy could be reversed by the administration of depot ACTH for an additional 7 hr period. However, if cycloheximide, an inhibitor of protein synthesis, was administered concomitantly with the depot ACTH, then the restorative actions of ACTH on the steroid biosynthetic pathway were prevented. These experiments suggest that ACTH maintains not only the general structure of the adrenal cortex, but also the level of the steroid biosynthetic mechanism, through its effects on adrenal protein synthesis.     

Human corticotropin-releasing factor plus lysine vasopressin test during glucocorticoid therapy.

1.0 micrograms/kg body wt human corticotropin-releasing factor (hCRF) and 0.005 IU/kg body wt lysine vasopressin (LVP) were administered in a bolus dose to patients receiving daily or alternate-day glucocorticoid therapy. In normal subjects with this hCRF-LVP test, the plasma ACTH increment was significantly greater (approximately 2.5-fold) 15 min after injection than under the CRF test. In patients receiving daily glucocorticoid therapy (greater than 15 mg prednisolone or an equivalent daily dose), the plasma ACTH and cortisol responses to hCRF-LVP were suppressed 2 wk to 1 mo after the beginning of glucocorticoid administration but partially improved at 2-10 mo, and was markedly suppressed several years later. On the other hand, in patients receiving alternate-day glucocorticoid therapy, the plasma ACTH response was normal at 2 wk, normal or higher at 1-3 mo, and normal after 4 mo. A normal plasma cortisol response was observed throughout the test period in patients receiving alternate-day therapy after pulse therapy, whereas plasma cortisol response was gradually improved in patients receiving alternate-day therapy after several months of daily therapy.     

Genotype influences the development of tolerance to nicotine in the mouse

Previous studies have demonstrated that chronic infusion of DBA/2 inbred mice with nicotine results in a dose- and time-dependent tolerance to many of the effects elicited by a challenge dose of nicotine. This tolerance was paralleled by increases in the number of brain nicotinic receptors measured with L-[3H]nicotine and alpha-[125I]bungarotoxin binding, suggesting that receptor up-regulation may underlie tolerance to nicotine. The studies reported here assessed the development of tolerance to nicotine in five inbred mouse strains that differ markedly in sensitivity to acute doses of nicotine. Mice were infused with nicotine doses ranging between 0 and 6 mg/kg/hr for 10 days and were tested for sensitivity to nicotine using several tests 2 hr after infusion was stopped. Some mouse strains, such as the C57BL/6, developed tolerance to nicotine, as measured by shifts to the right of dose-response curves, at the lowest infusion doses, whereas other strains, such as the C3H/2 and BUB, did not develop measurable tolerance until the highest infusion doses were used. A correlation between sensitivity to acute nicotine treatment and the threshold for tolerance development was observed, suggesting that tolerance develops only after a physiological effect is elicited. All of the mouse strains exhibited a dose-dependent increase in nicotine binding in all brain regions; no marked strain differences were seen in up-regulation of this binding site. Chronic nicotine infusion also evoked increases in alpha-bungarotoxin binding, but higher doses were required to elicit this effect. Changes in this binding site were observed after treatment with nicotine doses that elicited tolerance in those mouse strains that are more resistant to an acute dose of nicotine. These results indicate that the relationship between tolerance development and brain nicotinic receptor up-regulation may not be simple.     

CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [3H] acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA2 = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [3H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC50 of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P2 fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[3H]glutamate, or to interact with aconitine-induced inhibition of L-[3H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED50 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED50 = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.     

Evidence for prolactin-releasing and release-inhibiting effects of melatonin, serotonin and arginine vasotocin

Adult female Wistar rats (in 12 hr light/12 hr dark) were pinealectomized (PX) or sham-operated (SO) either 21 days after ovariectomy or on the 15-17th day of pregnancy. Ovariectomized (OVX) rats were injected with estrogen and progesterone (EP) 48 hr before decapitation. Melatonin, serotonin or arginine vasotocin (AVT; 50, 100 or 200 micrograms) were administered intravenously into OVX-EP rats 9 days after pineal removal. In PX and SO groups, the same study was done 3 days after delivery. Sera and pituitaries were collected 30 min after injection in order to determine prolactin (PRL) levels. Fifty micrograms melatonin significantly suppressed serum PRL levels in PX-OVX-EP rats and PX postpartum rats, but had not significant effect in SO-OVX-EP or PX postpartum rats. After administration of AVT, serum PRL levels markedly rose in PX and SO rats. These results suggest that melatonin may act not only to stimulate but also to inhibit rat PRL secretion and that the stimulatory function would be superior to its inhibitory function when the pineal gland is intact.