Osmotic Inhibition of Prolactin Secretion in Rats

Chronic hyponatremia is known to cause inhibition of pituitary vasopressin (AVP) and oxytocin (OT) secretion in response to most physiological stimuli, as well as a marked inhibition of synthesis of these peptides. Because many studies have implicated neurohypophyseal peptides in the regulation of pituitary prolactin (PRL) secretion, we investigated the effects of chronic hyponatremia on basal and stimulus-induced PRL secretion in rats. Hyponatremia was induced by subcutaneous infusion of 1-deamino-[8-D-arginine]-vasopressin (dDAVP) (5ng/h) to rats fed a nutritionally balanced liquid diet, and plasma [Na+] was maintained ≤115 mmol/l for 10–12 days. After this period, hyponatremic rats and normonatremic controls fed the same diet without dDAVP were subjected to one of the following stimuli known to stimulate PRL release in rats: 3 min exposure to ether, hemorrhage (20 ml/kg), intravenous injection of 5-hydroxytryptophane (5-HTP, 10 mg/kg), or intravenous injection of estradiol (5 μg/kg). A baseline blood sample was collected before each stimulus, and 3–6 additional blood samples were collected at selected intervals after the stimulus. Baseline levels of plasma PRL were not different between normonatremic and hyponatremic rats. However, PRL responses induced by ether or estradiol, but not those induced by hemorrhage or 5-HTP, were very significantly blunted in the chronically hyponatremic rats. Plasma AVP and OT responses were measured as an index of magnocellular secretion, but did not correlate with the PRL responses for any of the stimuli tested. Our results therefore demonstrate that ether- and estradiol-induced PRL release can be osmotically inhibited, but the mechanisms underlying this inhibition appear to be relatively independent of effects on magnocellular AVP and OT secretion. This allows the possibility that either some parvocellular systems regulating PRL secretion are osmosensitive, or alternatively that other substances released from the neural lobe may selectively modulate pituitary PRL release in response to some, but not all, stimuli.     

Effects of antidepressants on thyroid stimulating hormone release in rats under ether stress

Abstract We found inhibitory effects of antidepressants (clomipramine, maprotyline, mianserin and zimelidine) and 5-hydroxytryptophan (5-HTP) on thyroid stimulating hormone (TSH) release induced by ether stress in freely moving rats. We confirmed that ether stress suppressed the plasma TSH levels after 30 min. We then injected intravenously 250 ng thyrotropin releasing hormone (TRH), 0.1 mg/kg clomipramine, 2.5 mg/kg maprotyline, 2.5 mg/kg mianserin, 0.5 mg/kg zimelidine and 25 mg/kg 5-HTP simultaneously. These materials blocked the influences on plasma TSH levels by the ether stress. Serotonergic antidepressants (clomipramine, zimelidine) and 5-HTP (precursor of serotonin) had a higher potency against the ether stress. These results suggest that antagonizing effects against the ether stress may involve the serotonergic system in the pituitary gland.     

Estradiol-induced prolactinomas: differential effects on dopamine in posterior pituitary and median eminence

Prolactin release is inhibited by dopamine and stimulated by estradiol. Dopamine is released from nerve terminals in the median eminence and posterior pituitary. Estradiol may act directly on the anterior pituitary or by modulating the two dopaminergic systems. Estradiol treatment induces the formation of prolactinomas in Fischer 334 rats. Therefore, this strain was chosen as the experimental model. The first objective was to determine whether estradiol differentially regulates the two dopaminergic systems. The second objective was to explore whether the anterior pituitary in estradiol-treated rats acquires the capability for de novo synthesis of dopamine. Rats were ovariectomized and implanted with estradiol capsules (OVEX + E2). Controls were untreated ovariectomized rats (OVEX). Three weeks thereafter, rats were killed. Anterior and posterior pituitaries and medial basal hypothalami (MBH) were removed and individually incubated for 60 min in Hank's balanced salt solution containing 10 microCi [3H-]tyrosine. The median eminence was then dissected from the MBH. Tissues were homogenized in perchloric acid and the supernatant fluids were extracted with alumina. Both endogenous and tritiated dopamine were simultaneously quantitated by HPLC. Prolactinoma formation in OVEX + E2 rats was confirmed by dramatic rise (50-fold) in plasma prolactin levels and marked enlargement (3-fold) of the anterior pituitary. Estradiol treatment caused a significant 60% reduction in both dopamine content and synthesis in the median eminence. In contrast, estradiol treatment affected neither dopamine content nor synthesis in the posterior pituitary. There was no evidence for de novo synthesis of dopamine in anterior pituitaries from either OVEX or OVEX + E2 rats. We conclude that the two dopaminergic systems which regulate prolactin secretion, exhibit a differential response to estradiol.     

Sleep in rats rendered chronically hyperprolactinemic with anterior pituitary grafts

A hyperprolactinemic rat model [rats bearing anterior pituitary grafts under the capsule of the kidney (AP-grafted rats)] was used to study sleep–wake activity and cortical brain temperature (T_crt). Fisher 344 male rats (n=24) were implanted with anterior pituitaries from rat pups; the control rats (n=12) were sham-operated. Sleep–wake activity and T_crt were recorded for 2 days between weeks 3 and 7 after surgery. The hyperprolactinemic state of the rats was confirmed by plasma prolactin (PRL) assays on week 7 and by determination of PRL mRNA levels in the anterior pituitary of the AP-grafted rats. Neither growth hormone plasma concentration nor pituitary mRNA levels were affected by the pituitary grafts. Duration of non-rapid eye movement sleep (NREMS) was slightly enhanced in the AP-grafted rats. A large increase in rapid eye movement sleep (REMS) during the 12-h light period was the major effect of the implantation of the extra pituitaries. Both the duration and the frequency of the REMS episodes increased and persisted for weeks 4–7 post-implantation. The nocturnal states of vigilance, T_crt, and intensity of NREMS (EEG slow wave activity) were not altered. The results clearly indicate that the enhancements in REMS persist during hyperprolactinemia, and support the hypothesis that PRL possesses REMS-promoting activity.© 1997 Elsevier Science B.V. All rights reserved.     

Changes in mediobasal hypothalamic dopamine and indoleamine metabolism after superior cervical ganglionectomy of rats

Summary Eight days after bilateral superior cervical ganglionectomy (Gx) of rats, norepinephrine content of medial basal hypothalamus (MBH) decreased significantly by 44–50%. To obtain information on other possible neurochemical sequela of Gx in MBH, we examined the metabolism of dopamine and serotonin in MBH of Gx rats by employing a high pressure liquid chromatography procedure. Eight days after Gx, MBH dopamine levels augmented significantly. Assessment of dopamine metabolism by measuring dihydroxyphenylacetic acid (DOPAC)/dopamine and homovanillic acid (HVA)/ dopamine indexes indicated a significant decrease of MBH DOPAC/dopamine ratio after Gx. MBH serotonin levels increased, and 5-hydroxyindoleacetic acid (5-HIAA)/serotonin index decreased significantly in Gx rats. To examine the interaction Gx-induced changes on MBH dopamine and serotonin with the modified hormonal milieu produced by an ectopic pituitary transplant, adult male rats bearing an ectopic pituitary within the pectoral muscles from day 5 of life were submitted to Gx on day 60 of life and were studied 8 days later. MBH dopamine content increased significantly after pituitary grafting, an effect counteracted by a subsequent Gx, while Gx alone augmented MBH dopamine levels. DOPAC and HVA contents augmented in pituitary-grafted animals, an effect counteracted by Gx. Gx increased MBH serotonin content in control but not in pituitary-grafted rats. After pituitary grafting a decrease in MBH 5-HIAA levels was found, an effect reversed by Gx. Pituitary transplants brought about a significant increase of MBH DOPAC/dopamine index, and a significant decrease in 5-HIAA/serotonin index, both effects being counteracted by Gx. Gx of control rats resulted in a significant decrease of MBH 5-HIAA/serotonin index. Analyzed as a main effect in a factorial analysis of variance, Gx decreased MBH DOPAC/dopamine and HVA/dopamine indexes significantly. Plasma prolactin increased in pituitary-grafted rats, an effect further increased by a subsequent Gx. In pituitary-grafted, Gx rats plasma GH levels augmented significantly. The data suggest that superior cervical ganglion removal affects differentially dopamine and indoleamine metabolism in MBH of control and pituitary-grafted rats.     

Serotonergic mediation of DRL 72s behavior: receptor subtype involvement in a behavioral screen for antidepressant drugs.

BACKGROUND: The functioning of the brain serotonin system has been implicated in the action of antidepressant drugs. The behavior of rats performing the Differential Reinforcement of Low Rate-72 sec (DRL 72s) has been used as a screen for drugs with antidepressant activity. Many antidepressant drugs alter serotonergic function. Hence, experiments were designed to investigate the role of the brain serotonin system in the performance of DRL 72s behavior. METHODS: Rats were trained to perform a DRL 72s, and then depleted (LESION) of brain serotonin (5-HT) using intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT). Control rats (SHAM) were injected with the 5,7-DHT vehicle. RESULTS: The 5,7-DHT-treated rats showed a higher response rate, a decrease in the number of reinforcements, and a shift in the interresponse time (IRT) distribution toward shorter IRTs when compared to SHAM and prelesion performance. The behavioral deficit in the 5,7-DHT rats persisted for 17 weeks. Postmortem assays indicated extensive depletion of 5-HT in all the assayed brain regions of the LESION rats. The effects of the serotonergic agonists 8-hydroxy-2-di-N-propylaminotetralin (8-OH-DPAT), 5-methoxy-dimethyltryptamine (5-MeODMT), buspirone, and 5-hydroxytryptophan (5-HTP) were assessed. 5-MeODMT and 8-OH-DPAT resulted in greater improvement of DRL 72s performance in the LESION rats than in the SHAM rats. Buspirone failed to ameliorate the behavioral deficit in the LESION rats and produced a behavioral deficit in the SHAM rats. 5-HTP improved performance in the SHAM rats and in the LESION rats. CONCLUSIONS: These results support the contention that the brain 5-HT system is involved in the mediation of antidepressant drug effects.     

Pituitary adenylate cyclase-activating polypeptide (PACAP) increases prolactin release and tuberoinfundibular dopaminergic neuronal activity

Pituitary adenylate cyclase activating polypeptide (PACAP) is a hypothalamic peptide that affects anterior pituitary cell function. This study examined the effects of PACAP on prolactin (PRL) release in vivo and on tyrosine hydroxylase (TH) activity in tuberoinfundibular dopaminergic neurons in vivo and in vitro. In ovariectomized rats, intravenous injection of PACAP increased circulating PRL levels 3-fold and TH activity in the stalk-median eminence (SME) by 30%. Incubation of the SME with 1 μM PACAP in vitro increased TH activity 2-fold. Intravenous infusion of ovine PRL (oPRL) by an osmotic mini-pump for 2 days in ovariectomized rats increased TH activity in the SME 1.7-fold and reduced circulating concentrations of endogenous rat PRL to 20% of control levels. PACAP induced a 4-fold rise in endogenous rat PRL levels in oPRL-treated rats and a 30% increase in TH activity that was additive to the elevation caused by hyperprolactinemia. In suckled lactating rats, PACAP did not alter circulating PRL levels or TH activity in the SME. When pups were removed from the dams for 4–5 h, systemic injection of PACAP stimulated PRL release without altering TH activity. However, PACAP, when administered in vitro, stimulated TH activity in the SME of lactating rats separated from their pups. These data indicate that PACAP may play a role in augmenting PRL release in female rats. The PACAP-induced rise in PRL release is modest and not due to a decrease in tuberoinfundibular dopaminergic neuronal activity. PACAP increases TH activity in the tuberoinfundibular dopaminergic neurons, possibly by a direct action on nerve terminals within the median eminence.     

Modulation of brain and pituitary dopamine receptors by estrogens and prolactin

1. Ovariectomized rats were treated for 2 weeks with 17β-estradiol (0.0002–100 μg/day). [³H] spiperone striatal dopamine receptor binding was maximally increased by 30% after 0.05 μg/day of 17β-estradiol and a similar increase is observed at higher doses. By contrast, plasma prolactin concentrations of these rats are unchanged after 0.05 μg/day and increased after 100 μg/day. A chronic estradiol treatment at very low doses (0.0002–0.001 μg/day) leads to increases in pituitary dopamine receptor binding while plasma prolactin levels are unchanged. At higher doses (1–100 μg/day) binding is decreased and plasma prolactin concentrations are elevated.

2. [³H]spiperone striatal dopamine receptor binding is elevated in lactating female rats compared to intact or ovariectomized female rats.

3. Anterior pituitary dopamine receptor concentrations fluctuate during the estrous cycle while striatal dopamine receptors are unchanged.

4. An injection of 30 ng of estradiol, which reproduces the estradiol proestrus surge, leads as in proestrus, to a decrease of anterior pituitary dopamine receptors.     

Sex-linked differences in cortisol, ACTH and prolactin responses to 5-hydroxy-tryptophan in healthy controls and minor and major depressed patients

Some researchers have found that the administration of 5-hydroxytryptophan (5-HTP) results in increased cortisol secretion in major depressives but not in healthy controls. Other authors observed gender-related differences in cortisol responses to 5-HTP in major depressives. In order to investigate the pituitary/adrenal responsivity to 5-HTP, the authors measured cortisol, adrenocorticotropic hormone (ACTH) and prolactin (PRL) in 30 healthy controls and in 90 depressed patients; the hormone levels were determined in baseline conditions and 60, 90 and 120 min after 125 mg L-5-HTP (orally, non-enteric coated). We found that healthy men had significantly higher cortisol responses to L-5-HTP than healthy women. In the major depressives with melancholia and/or psychotic features these differences were reversed: women exhibited significantly higher cortisol and PRL responses than men. In the female group the most severely depressed patients had increased cortisol and PRL responses to L-5-HTP. The amplitudes of the cortisol, ACTH and PRL responses to L-5-HTP were significantly and positively correlated. It was concluded that the central serotonergic regulation of ACTH and PRL is significantly different between the sexes and between healthy controls, minor depressives and severely depressed patients.     

The indoleamine hypothesis of depression: an overview and pilot study.

This paper reviews the evidence for a specific indoleamine deficiency in depression and the attempts to correct this suspected deficiency with serotonin precursors. It also presents the clinical and biochemical data on six patients with depression treated with L-5-HTP in a nonrandom, double-blind protocol. The oral administration of L5-HTP was associated with a rise in CSF5-HIAA, but only two of six patients studied had any decrease in depression ratings. 5-HTP was also shown to decrease urinary excretion of 17 hydroxycorticosteroids in twodepressed patients and three normal controls suggesting an interrelationship between serotonin metabolism and the pituitary adrenal system. This leads to the suggestion that in a postulated subgroup of depressed patients with pituitary adrenal hyperactivity and evidence of serotonin deficiency, L5-HTP deserves a further trial as an experimental treatment.     

Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat

The present study re-evaluated an existing notion that serotonin (5-hydroxytryptamine; 5-HT) could not cross the brain to the circulating blood via the blood-brain barrier (BBB). To elevate brain 5-HT alone, 5-hydroxytryptophan (5-HTP; 30-75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5-HT after 5-HTP administration). A microdialysis method and HPLC system were used to determine the brain 5-HT levels in samples collected from the frontal cortex. Blood 5-HT levels were determined from whole blood, not platelet-poor plasma, collected from the central vein. We found that blood 5-HT levels showed a significant augmentation whenever brain 5-HT levels were significantly elevated after the administration of 5-HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5-HT levels remained augmented. These results indicate that augmented brain 5-HT can cross the BBB through the 5-HT transporter from the brain to the circulating blood.     

Negative Feedback by Corticosterone is the Major Mechanism Responsible for Corticotropin-Releasing Factor-Induced Desensitization

Subcutaneous infusion of ovine corticotropin-releasing factor (oCRF) to male rats at a rate of 0.1 μg/h for 4 days did not alter the rise of plasma adrenocorticotropin (ACTH) and corticosterone induced by 3-min ether exposure. In contrast, 1.0 μg/h oCRF for 4 days virtually abolished the ACTH response to ether, whereas a substantial corticosterone response was preserved. Intravenous administration of phenoxybenzamine (5 mg/kg) prior to ether stress completely inhibited the corticosterone response. Plasma ACTH and corticosterone responses in chronic CRF-treated rats to an intravenous bolus injection of 2.0 μg oCRF were also markedly blunted by pretreatment with subcutaneous oCRF 1.0 μg/h for 4 days. Adrenalectomized rats given corticosterone in the drinking fluid at a concentration of 80 μg/ml showed a plasma corticosterone pattern mimicking the normal diurnal rhythm. Basal plasma ACTH and thymus weight were within normal limits. In these rats, the magnitude of ACTH rise to ether stress did not differ between the chronic CRF-treated rats and the vehicle-treated rats. In cultured pituitary cells prepared from animals infused with oCRF 1.0 μg/h for 4 days, the basal and CRF-stimulated ACTH release was reduced by 46%. We conclude that among the possible mechanisms proposed for ‘desensitization’ during long-term infusion of CRF, negative feedback by elevated corticosterone at both brain and pituitary levels is the primary factor. The results also suggest the existence of non-ACTH-mediated catecholaminergic systems in the stress-induced adrenocortical activation.     

Domperidone Stimulates Prolactin Secretion in Rats With Complete Destruction of the Mediobasal Hypothalamus

The main objective of this study was to further elucidate the functional relationship between endogenous dopamine and the prolactin (PRL)-releasing effect of the dopamine antagonists domperidone and haloperidol. We studied the effect of the above dopamine antagonists on the PRL secretion in control and mediobasal hypothalamus (MBH)-lesioned rats. Significant increase in basal plasma PRL levels was detected 7 days after complete surgical destruction of the MBH. Haloperidol injection (0.5 mg/kg, IV) was followed by an increased plasma PRL concentration in the sham-operated animals; however, in the MBH-lesioned rats where the basal PRL levels were high haloperidol failed to produce additional PRL release. In contrast to haloperidol, domperidone (0.1 mg/kg, IV) was able to further elevate the MBH-lesion induced high plasma PRL concentration. Moreover, the change in plasma PRL levels of the MBH-lesioned rats was parallel with that in the sham-lesioned animals after domperidone injections. When haloperidol was given prior to the domperidone injection it did not influence the PRL releasing effect of domperidone in MBH-lesioned animals. The PRL stimulatory effect of domperidone (0.3 mg/kg, IV) in MBH-lesioned rats was antagonized by dopamine (20 μg/kg, IV) and bromocryptine (20 μg/kg, IV). The above results suggest that the stimulatory effect of domperidone on the pituitary PRL secretion is mediated—at least in part—through the pituitary D₂ dopamine receptors, but not by the displacement of endogenous dopamine originating from the MBH and reaching the pituitary via portal vessels.     

In vivo and in vitro effects of cholecystokinin on gonadotropin, prolactin, growth hormone and thyrotropin release in the rat

Varying doses of cholecystokinin (CCK) dissolved in 2 μl of 0.9% NaCl or 2 μl of saline alone were injected into the third ventricle of conscious ovariactomized (OVX) rats bearing 3rd ventricular cannulae. Plasma luteinizing hormone (LH), prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and follicle stimulating hormone (FSH) levels were measured by RIA in jugular blood samples drawn through an indwelling silastic cannula. Control injections of saline i.v. or into the 3rd ventricle did not modify plasma hormone levels. Intraventricular injections of 4, 40 and 500 ng CCK produced a significant suppression of plasma LH within 5 min of injection. Injection of 4 or 500 ng doses of CCK has no effect on plasma PRL levels, but injection of the 40 ng dose produced a significant elevation of plasma PRL within 15 min. Plasma GH levels increased significantly within 15 min of the 3rd ventricular injection of each dose of CCK. The 40 ng dose of CCK caused a progressive reduction of plasma TSH which was significant by 15 min and lasted through the 60 min of experimentation. The highest dose of 500 ng reduced plasma TSH levels within 5 min. Plasma FSH was not altered by any dose of CCK. Intravenous injection of CCK caused a dose-related increase in plasma prolactin levels within 5 min, but only the highest dose of 1000 ng produced a significant decrease in plasma LH. No significant changes in GH, TSH or FSH levels were observed after i.v. injection of CCK. In vitro incubation of hemipituitaries from male rats with doses of CCK ranging from 10 ng to 5 μg had no effect on pituitary hormone release into the medium. The results indicate that CCK can alter pituitary hormone release via a hypothalamic action and suggest that it may act as t transmitter or modulator of neuronal activity controlling the release of hypothalamic releasing and/or inhibiting hormones.     

Angiotensin II receptors in the arcuate nucleus mediate stress-induced reduction of prolactin secretion in steroid-primed ovariectomized and lactating rats

Angiotensin II (Ang II) is a peptide that exerts an inhibitory effect upon pituitary prolactin (PRL) release through the hypothalamic arcuate nucleus (ARC). Since both PRL and Ang II are known to be affected by stress, the experiments reported here were conducted to investigate the possible participation of Ang II in the stress-induced response of PRL in situations in which pre-stress PRL levels are high, as during the PRL surge induced by estradiol (E(2)) and progesterone (P) in ovariectomized rats (OVXE(2)P) and lactating females on day 7 post-partum. Adult female rats were stereotactically implanted with bilateral guide-cannulae in the ARC; 3 days later, they were microinjected with saline or losartan and, after a 15-min interval, they were submitted to stress by ether inhalation during 1 min. Five minutes after stress, trunk blood samples were collected. Plasma PRL was measured by radioimmunoassay (RIA). In OVXE(2)P and lactating rats, a significant reduction in PRL levels was detected after stress compared to non-stressed animals. The microinjection of losartan in the ARC before stress blocked the reduction of PRL in both OVXE(2)P and lactating females. In conclusion, the stress-induced reduction of plasma PRL in OVXE(2)P and lactating rats is mediated by Ang II through AT(1) receptors in the ARC.     

Changes in growthormone and prolactin release after superior cervical ganglionectomy of rats

Superior cervical ganglionectomy (SCG×) decreased significantly serum growthormone (GH) levels in rats 14–96 after surgery, during and immediately after anterograde degeneration of regional sympathetic terminals. At later times (up to 28 days after SCG×) an increase in serum Gwas observed. SCG× augments prolactin (PRL) release, but only at the earliest time examined (14 after surgery). Injection of the α-adrenoceptor blocker, phenoxybenzamine, but not of the β-blocker, propranolol, negated the depression in serum Gfound in SCG× rats 14 after surgery, without affecting PRL release.     

Regulation of prolactin secretion in parental rats: roles of steroid priming and pituitary responsiveness

Whereas prolactin (PRL) release increases in female rats as a result of stimuli from rat young, parental male rats fail to show a rise in plasma PRL levels in response to pup stimuli. In the present study, we have characterized two aspects of the endocrine control of PRL release in male and female rats in an attempt to account for this sex difference in pup-induced PRL secretion. First, we compared the patterns of PRL secretion throughout a prolonged steroid priming treatment that effectively stimulates the onset of parental responsiveness in both sexes. Second, we measured pituitary responsiveness to a PRL releasing agent (thyrotropin releasing hormone: TRH) in male and female rats that had previously experienced the steroid treatment. We found that in the presence of estradiol alone or soon after the onset of progesterone treatment in the presence of estrogen, female but not male rats displayed afternoon elevations in PRL. We also found that, following steroid treatment, TRH caused significant and comparable elevations in plasma PRL in both sexes. These experiments demonstrate differences in patterns of PRL secretion in male and female rats during the early phase of a steroid priming treatment that induces parental responsiveness, yet comparable pituitary sensitivity to TRH-induced PRL release following this 3 week steroid treatment. These data suggest that sex differences in pup-induced PRL secretion in rats do not result from fundamental differences in endocrine priming or from sex differences in pituitary responsiveness.     

Acetyl-L-Carnitine Effect on Pituitary and Plasma β-Endorphin Responsiveness to Different Chronic Intermittent Stressors

The aims of the present study were: 1) to compare the effect of two different chronic intermittent stressors i.e. cold-swimming versus ether, on the pituitary opioidergic system; 2) to evaluate the response of pituitary and plasma β-endorphin (βS-EP) to an acute stress in chronically stressed rats; and 3) to evaluate the effect of acetyl-l-carnitine treatment (10 mg/day/rat per os at night) on pituitary and plasma β-EP changes induced by two different types of chronic stress. The stressors were applied twice a day for 10 days. Rats were killed either before, during or after the last swimming or ether stress session. β-EP was measured by radioimmunoassay in anterior pituitary and in neurointermediate lobe extracts and in plasma. The following observations were made; 1) Chronic intermittent cold-swimming stress increased anterior pituitary contents and plasma β-EP levels; 2) both chronic intermittent cold-swimming stress and ether stress caused an increase of neurointermediate lobe β-EP contents; 3) as in control animals, rats exposed to chronic intermittent swimming stress reduced pituitary β-EP contents and raised plasma β-EP levels in response to the last acute swimming stress; 4) in contrast to control animals, rats exposed to chronic intermittent ether stress did not show any significant response of the pituitary-plasma opioidergic system to the last acute ether session; 5) the acetyl-l-carnitine treatment counteracted the changes evoked by chronic intermittent cold-swimming stress on the pituitary and plasma β-EP levels. The present data show that chronic intermittent ether stress impairs the capacity to respond to the acute stress and that acetyl-l-carnitine may modulate the changes of β-EP levels following chronic cold-swimming stress exposure.     

Effect of ageing on melatonin synthesis induced by 5-hydroxytryptophan and constant light in rats.

1. This paper describes the effect of the serotonin precursor 5-hydroxytryptophan (5-HTP) on pineal melatonin synthesis young and old rats. 2. 5-HTP itself increased pineal melatonin levels in old rats but did not change melatonin concentrations in young rats kept under 12 hr/12 hr light/dark conditions. 3. After continuous exposure to light for 72 hrs, 5-HTP induced a significant increase in melatonin levels in young rats but did not change the 5-HTP effect on melatonin in old animals. 4. These results are discussed in consideration of previous reports of altered beta-receptor up-regulation by light in old animals, and suggest that the age-related decrease in melatonin synthesis is not entirely related to changes of the enzymatic machine for melatonin synthesis.     

Neuroendocrine alterations in a high-dose,extended-access rat self-administration model of escalating cocaine use

One approach for studying cocaine addiction has been to permit escalating patterns of self-administration (SA) by rats by prolonging daily drug availability. Rats provided long access (LgA) to high cocaine doses, but not rats provided shorter cocaine access (ShA), progressively escalate their cocaine intake and display characteristics of human addiction. The purpose of the present study was to investigate the effects of 14 days of ShA or LgA, high-dose cocaine SA on plasma corticosterone (CORT), prolactin (PRL), and related mRNAs. Acutely, cocaine SA increased plasma CORT and reduced plasma PRL levels. SA training produced circadian increases in CORT that appeared to occur in anticipation of cocaine availability. With repeated LgA, high-dose SA, the daily CORT area under the curve (AUC) progressively decreased, apparently due to tolerance to cocaine's effects on CORT and a reduction in basal CORT levels. In contrast, the daily CORT AUC in ShA rats increased across testing despite constant rates of SA. When measured 12 days after SA testing, pro-opioimelanocortin and glucocorticoid receptor mRNA levels in the anterior pituitary were lower in LgA rats than in ShA rats. The effects of SA on PRL remained constant across SA testing in LgA rats, but increased in duration in ShA rats. Anterior pituitary dopamine D2 receptor mRNA levels were lower in LgA rats than in ShA rats. These findings indicate that the transition to escalating patterns of SA may be associated with altered levels of hormones and gene expression within neuroendocrine systems. Such changes may underlie the onset of human addictive disease.