The role of catecholamines in the prolactin release induced by salsolinol.

Salsolinol (1,2,3,4-tetrahydro-6,7-dihydroxy-1-methylisoquinoline) is an endogenous prolactin releasing agent. Its action can be inhibited by another isoquinoline, 1-methyl-3,4-dihydroisoquinoline (1MeDIQ), which has a strong norepinephrine releasing activity. Salsolinol does not alter the dopamine release in median eminence in vitro, providing evidence for the lack of interaction with presynaptic D2 dopamine receptors. At the same time, lack of norepinephrine transporter abolishes salsolinol's action. Salsolinol decreases tissue level of dopamine and increases norepinephrine to dopamine ratio in organs innervated by the sympathetic nervous system indicating a possible decrease of norepinephrine release. Enzymes of catecholamine synthesis and metabolism are probably also not the site of action of salsolinol. In summary, based upon all of these observations a physiologically relevant interplay might exist between the sympatho-neuronal system and the regulation of prolactin release.

The peripheral noradrenergic terminal as possible site of action of salsolinol as prolactoliberin.

Salsolinol, an endogenous isoquinoline, induces selective prolactin release in rats [Tóth, B.E., Homicskó, K., Radnai, B., Maruyama, W., DeMaria, J.E., Vecsernyés, M., Fekete, M.I.K., Fülöp, F., Naoi, M., Freeman, M.E., Nagy, G.M., 2001. Salsolinol is a putative neurointermediate lobe prolactin releasing factor. J. Neuroendocrinol. 13, 1042-1050]. The possible role of dopaminergic and adrenergic signal transduction was investigated to learn the mechanism of this action. The effect of salsolinol (10mg/kg i.v.) was inhibited by reserpine treatment (2.5mg/kg i.p.) and reinstated by pretreatment with monoamine oxidase inhibitor (pargyline 75 mg/kg i.p.). Salsolinol did not affect the in vitro release of dopamine (DA) in the median eminence, and did not inhibit the L-DOPA induced increase of DA level in the median eminence. 1-Methyl dihydroisoquinoline (1MeDIQ) is an antagonist of salsolinol induced prolactin release and causes increase in plasma NE level [Mravec, B., Bodnár, I., Fekete, M.I.K., Nagy, G.M., Kvetnansky, R., 2004. An antagonist of prolactoliberine induces an increase in plasma catecholamine levels in the rat. Autonom. Neurosci. 115, 35-40]. Using tissue catecholamine contents as indicators of the interaction between salsolinol and 1MeDIQ we found no interaction between these two agents to explain the changes in prolactin release in the median eminence, lobes of the pituitary, superior cervical and stellate ganglion. Increasing doses of salsolinol caused a dose dependent decrease of tissue dopamine concentration and increase of NE/DA ratio in the salivary gland, atrium and spleen. These changes of DA level and NE/DA ratio run parallel in time with the increase of prolactin release. 1MeDIQ antagonized the increase of prolactin release and decrease of tissue DA content caused by salsolinol. Neither this increase of prolactin secretion nor the decrease of DA level in spleen could be demonstrated in NE transporter (NET) knock out mice. The results presented argue for the possible role of peripheral norepinephrine release as a target for salsolinol in its action releasing prolactin. The dominant role of norepinephrine transporter may be suggested.

Pivotal role of an endogenous tetrahydroisoquinoline, salsolinol, in stress- and suckling-induced release of prolactin.

In mammals, the role of a prolactin-releasing factor (PRF) in the acute changes of prolactin (PRL) secretion that usually occur after challenges (e.g., suckling stimulus or stress) of homeostasis has been suspected for a long time. We have recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, salsolinol (SAL), produced by the hypothalamus and the neuro-intermediate lobe (NIL) of the pituitary gland, can selectively release PRL from the anterior lobe (AL). Moreover, binding sites for SAL have been detected in areas like median eminence, NIL, and AL. It has been proposed that SAL is a putative endogenous PRF. We have also found that a structural analogue of SAL, 1-methyl-3,4-dihydroisoquinoline (1MeDIQ), is able to block dose-dependently SAL-, suckling-, and immobilization (IMO) stress-induced release of PRL without having any influence on alpha-methyl-p-tyrosine (alphaMpT)-induced PRL responses. Neither SAL nor 1MeDIQ has any effect on alpha-melanocyte-stimulating hormone (alphaMSH), adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-END) and arginine-vasopressin (AVP) secretion. Moreover, SAL-induced PRL response was attenuated in male rats pretreated with dexamethasone (DEX). These results strongly suggest that SAL has an important role in the regulation of PRL release induced by physiologic and environmental stimuli; therefore, it can be considered as the strongest candidate for being the PRF in the hypothalamo-hypophysial system. Our findings also indicate that the adrenal steroids may play an inhibitory feedback role in SAL-mediated PRL response.

Stress- as well as suckling-induced prolactin release is blocked by a structural analogue of the putative hypophysiotrophic prolactin-releasing factor, salsolinol.

Prolactin is secreted from the anterior lobe of the pituitary gland in response both to suckling and to stress. We recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), produced in the neurointermediate lobe of the pituitary gland, as well as in the medial basal hypothalamus, can selectively release prolactin from the anterior pituitary. Therefore, it has been proposed that salsolinol is a putative endogenous prolactin-releasing factor (PRF). Here, we report that one structural analogue of salsolinol, 1-methyl-3,4-dihydroisoquinoline (1MeDIQ), can block salsolinol-induced release of prolactin, but does not affect prolactin release in response to thyrotropin releasing hormone (TRH), alpha-methyl-p-tyrosine (alpha MpT) (an inhibitor of tyrosine hydroxylase), domperidone (a D(2) dopamine receptor antagonist), or 5-hydroxytryptophan (5-HTP), a precursor of serotonin). 1MeDIQ profoundly inhibited suckling-, immobilization-, as well as formalin-stress induced prolactin release without any influence on corticosterone secretion. The 1MeDIQ-induced reduction in prolactin response to immobilization stress was dose-dependent. These results suggest that salsolinol can play a pivotal role in the regulation of prolactin release induced by either physiological (suckling) or environmental (stress) stimuli.

Salsolinol is a putative endogenous neuro-intermediate lobe prolactin-releasing factor.

The isolation and identification of a prolactin-releasing factor (PRF) from the neuro-intermediate lobe of the pituitary gland has been pursued for over a decade. Using high-pressure liquid chromatography with electrochemical detection (HPLC-ECD) and gas chromatography/mass spectrometry (GC/MS) (R)-salsolinol (SAL) (a dopamine-related stereo-specific tetrahydroisoquinoline) was found to be present in neuro-intermediate lobe as well as median eminence extracts of male, intact-, and ovariectomized female rats. Moreover, analysis of SAL concentrations in neuro-intermediate lobe revealed parallel increases with plasma prolactin in lactating rats exposed to a brief (10 min) suckling stimulus following 4-h separation. SAL appears to be a selective and potent stimulator of prolactin secretion in vivo and it was without effect on the secretion of other pituitary hormones. We have also found that SAL can elevate prolactin release, although to a lesser extent, in pituitary cell cultures as well as in hypophysectomized rats bearing anterior lobe transplants under the kidney capsule. Lack of interference of SAL with [3H]-spiperone binding to AP homogenates indicates that SAL does not act at the dopamine D2 receptor. Moreover, [3H]-SAL binds specifically to homogenate of AL as well as neuro-intermediate lobe obtained from lactating rats. Taken together, our data clearly suggest that SAL is synthesized in situ and this compound can play a role in the regulation of pituitary prolactin secretion.

Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia.

Over the past 20 years, several members of the 2,3-benzodiazepine family have been synthesized. Some of these compounds--tofisopam (Grandaxin), girisopam, nerisopam--exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines are mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous system shows a unique and specific distribution pattern: their binding sites are located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transections of the striato nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that these compounds mainly bind to projecting neurons of the striatum. The binding sites are transported from the striatum to the substantia nigra and the entopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augment the agonist potency of morphine to induce catalepsy and analgesia, and their action is diminished in morphine tolerant animals. The possible biochemical target of 2,3-benzodiazepines is an alteration in the phosphorylation of protein(s) important in the signal transduction process. Agents affecting emotional responses evoked by endogenous opioids without danger of tolerance and dependence may represent a new therapeutic tool in the treatment of addiction and affective disorders.

Dopamine transporters participate in the physiological regulation of prolactin.

Three populations of hypothalamic neuroendocrine dopaminergic (NEDA) neurons, arising from the arcuate and periventricular nuclei of the hypothalamus release dopamine (DA) that acts at the pituitary gland to regulate the secretion of PRL. It is generally accepted that NEDA neurons lack functional DA transporters (DATs), which are responsible for uptake of DA from the synaptic cleft into the presynaptic axon terminal. This study localized DATs to the hypothalamo-pituitary axis and evaluated the effect of DAT blockade on the hypothalamo-pituitary regulation of PRL. After 7 days of treatment with cocaine (a nonspecific amine transporter blocker) or mazindol (a specific DAT blocker), the relative abundance of PRL messenger RNA (mRNA) in the anterior lobe (AL) of OVX rats was significantly decreased, whereas the relative abundance of tyrosine hydroxylase mRNA in the hypothalamus was significantly increased. The effect of cocaine or mazindol administration on DA turnover and serum PRL concentration was examined in estradiol (E2)-treated OVX rats. E2 administration (i.v.) resulted in a significant increase in serum PRL within 4 h; however, cocaine or mazindol administration abolished the E2-induced increase of PRL. Cocaine or mazindol significantly increased the concentration of DA at the site of the axon terminals within the median eminence (ME), intermediate lobe (IL) and neural lobe (NL), indicating blockade of uptake. Because formation of DOPAC requires uptake of DA, concentrations of DOPAC in the ME, IL and NL decreased following treatment with either cocaine or mazindol. These data, together with the presence of immunopositive DAT in the ME, pituitary stalk, IL, and NL, suggest that a functional DAT system is present within all three populations of NEDA neurons. Moreover, similarity between the effects of cocaine and mazindol treatment indicate that blockade of the DAT, but not other amine transporters, is responsible for suppression of PRL gene expression and secretion. Blockade of DATs prevent uptake of DA into NEDA neurons and consequently increases the amount of DA that diffuses into the portal vasculature and reaches the AL. These data provide evidence that DATs play a physiological role in the regulation of DA release from and TH expression in NEDA neurons and consequently PRL secretion and PRL gene expression and further support our previous observation that the regulation of PRL secretion involves all three populations of NEDA neurons.

[(3)H]-girisopam, a novel selective benzodiazepine for the 2, 3-benzodiazepine binding site.

Several members of the 2,3-benzodiazepine family, such as tofisopam (Grandaxin((R))) nerisopam (GYKI-52 322) [F. Andrási, K. Horváth, E. Sineger, P. Berzsenyi, J. Borsy, A. Kenessey, M. Tarr, T. Láng, J. Korösi, T. Hámori, Neuropharmacology of a new psychotropic 2, 3-benzodiazepine, Arzneim.-Forsch. Drug. Res., 37 (1987) 1119-1124.] [1] or girisopam (GYKI-51 189) [K. Horváth, F. Andrási, P. Berzsenyi, M. Pátfalusi, M. Patthy, G. Szabó, L. Sebestyén, J. Korösi, P. Botka, T. Hámori, T. Láng, A new psychoactive 5H-2, 3-benzodiazepine with a unique spectrum of activity, Arzneim.-Forsch. Drug. Res., 39 (1989) 894-899.] [2] proved anxiolytic in man and various animal models. Moreover, girisopam could also be characterized as an atypical neuroleptic agent. In spite of the structural similarity, their pharmacological profiles differ significantly from that of the 'classical' 1,4-benzodiazepines. Importantly, according to the data obtained so far these drugs do not have an addiction potential. The novel 2,3-benzodiazepine antagonist girisopam binds with high affinity (K(d)=10.3+/-1.21 nM) and limited capacity (B(max)=6.94+/-1.8 pmol/mg protein) to a single class of recognition sites in rat striatum [J.E. Horváth, J. Hudák, M. Palkovits, Zs. Lenkei, M.I.K. Fekete, P. Arányi, A novel specific binding site for homophthalazines (formerly 2, 3-benzodiazepines) in the rat brain, Eur. J. Pharmacol., 236 (1993) 151-153.]. This protocol describes the use of [(3)H]-girisopam as a specific radioligand for the 2,3-benzodiazepines receptor.

Inhibition of protein phosphatase 2A (PP2A) mimics suckling-induced sensitization of mammotropes: involvement of a pertussis toxin (PTX) sensitive G-protein and the adenylate cyclase (AC).

In lactating rats, suckling renders mammotropes more responsive to prolactin (PRL)-releasing stimuli and less responsive to PRL-inhibiting secretagogues. We have previously shown that a decrease in the activity of protein phosphatase 2A (PP2A) may be responsible for the decrease in responsiveness to the inhibitory secretagogue dopamine (DA). In our present experiments, we have studied the involvement of the adenylate cyclase (AC), stimulatory and inhibitory GTP-binding proteins and also the role of PP2A in the sensitization phenomenon. Pituitary cells obtained from mother rats separated from their pups for 4 h prior to dispersion (non-suckled), suckled for 10 or 30 min after the separation period (suckled) and without separation (continual suckling) were incubated in the presence of different doses of forskolin to activate AC and DA. In a further study, pituitary cells of non-suckled rats were pretreated with cholera toxin (CTX) or pertussis toxin (PTX) and tested for the stimulatory action of forskolin or TRH on PRL release. Ocadaic acid (OA) pretreatment has been used to investigate the involvement of PP2A. Hormone secretion was measured by the reverse hemolytic plaque assay (RHPA). Our results have shown that cells from non-suckled rats were unresponsive to forskolin. A 10-min suckling stimulus sensitizes pituitary mammotropes to respond with a PRL release to a dose-dependent activation of AC by forskolin. This sensitization of AC becomes a permanent feature of the cells when suckling continues for an additional 20 min. We have also found that pituitary mammotropes from non-suckled dams respond to forskolin or TRH with PRL release when they were preincubated with either PTX or the PP2A inhibitor OA. It clearly indicates that the non-responsive pituitary can be shifted to the responsive stage by uncoupling of inhibitory G-protein from its receptor as well as by inhibition of PP2A. This latter finding, consonant with our previous results, suggests that suckling may cause selective changes in the function of G(i) of mammotropes due to a rapid phosphorylation which can remove tonic, GTP-dependent inhibitory function.

Protein phosphatase 2A plays a role in the suckling-induced changes in the responsiveness of pituitary mammotropes.

It is well established that PRL secretion is under a tonic inhibition exercised by the hypothalamic dopamine (DA). One feature of this regulation is an immediate withdrawal reaction (elevation of PRL release) of mammotropes after disruption of hypothalamic influence. Although plasma PRL rises rapidly, the suckling stimulus does not cause an acute diminution of hypothalamic DA, but, as we have previously demonstrated, it results in an almost immediate (within 10 min) desensitization of mammotropes as indicated by the change in dose response of DA to inhibit PRL release. Our present investigations relate to the phenomenon of this change in responsiveness of PRL cells. This was accomplished by using the reverse hemolytic plaque assay to evaluate the secretory characteristics of individual PRL secretors derived from lactating rats either before or after a 10-min suckling stimulus. To investigate the mechanism of these changes, the binding characteristics of [3H]spiperone on pituitary membranes from nonsuckled and suckled rats have been compared, and the possible involvement of dephosphorylating enzymes was tested by using okadaic acid (OA) in a dose of 2 nM that preferentially and selectively inhibits protein phosphatase-2A (PP2A) activity. We have also determined the activities of PP1 and PP2A in pituitary tissue samples as well as in enzymatically dispersed cells. Mammotropes from nonsuckled rats exhibited a depression of PRL release after both DA and OA treatment and an elevation after withdrawal of DA. This suggests that the secretory response of mammotropes obtained from nonsuckled rats still shows those two responses that are characteristic of the tonic inhibitory regulation. In contrast, superimposition of suckling in vivo or application of OA together with DA pretreatment in cells from nonsuckled rats in vitro resulted in a disappearance of the dissociation-induced elevation of PRL release, indicating an abolishment of the tonic inhibitory action of DA. Evidence is also presented that the PP2A, but not the PP1, activity of the anterior lobe is significantly lower after a 10-min suckling stimulus. Moreover, DA is able to decrease PP2A activity in dispersed pituitary cells obtained from nonsuckled, but not from suckled, animals. In contrast, there were no differences in either the affinity or the number of binding sites between nonsuckled and suckled rats. Taken together, our results suggest that the suckling-induced decrease in PP2A activity plays a role in the uncoupling of D2 receptors on mammotropes from the tonic inhibitory signaling pathway.

Selective interaction of homophtalazine derivatives with morphine.

Homophtalazines show specific binding sites in the nigrostriatal system and to find their target of action the interactions between these derivatives, nerisopam and girisopam, and chlorpromazine, chlordiazepoxide and morphine were assessed. The compounds did not influence the chlorpromazine induced decrease in motility and catalepsy, nor did they alter the antiaggressive and anticonvulsive action of chlordiazepoxide. However, nerisopam and girisopam augmented the agonist potency of morphine to induce catalepsy or analgesia; they also altered the opioid antagonist potency of naloxone. The naloxone-induced decrease in sucrose consumption in drinking water was augmented by nerisopam and girisopam. It is suggested that a possible target of action of homophtalazines is the opioid signal transduction.

Changes in specific binding sites of girisopam after chemical and surgical lesions in the striato-nigral system.

Neurotoxin (AMPA)-induced lesions in the caudate nucleus as well as unilateral surgical transection of the striato-nigral pathway strongly depleted the binding of a homophthalazine (formerly called 2,3-benzodiazepines) girisopam (GYKI-51189, EGIS 5810) selectively in the substantia nigra of the rat, ipsilateral to the lesions. In contrast to this, AMPA injections into the substantia nigra failed to effect on girisopam binding to either components of the nigro-striatal system. Data indicate that this homophthalazine may bind to a descending component of the striatum (striato-nigral projecting neurons), or its binding capacity to substantia nigra neurons depends on the integrity of striatal afferent pathways to the substantia nigra.

The possible role of protein phosphatase 2A in the sodium sensitivity of the receptor binding of opiate antagonists naloxone and naltrindole.

In striatal membrane preparation used for receptor binding experiments high levels of protein phosphatase 1 and 2A activities were detected using [32P]phosphorylase a as substrate. Sodium chloride decreased the activity of protein phosphatase 2A and increased the activity of protein phosphatase 1 in a concentration-dependent manner. Sodium chloride facilitated the saturation binding of naloxone and naltrindole in rat striatal membrane preparation preincubated with ATP (50 microM) and MgCl2 (5 mM). Preincubation with calyculin A (1 nM) further increased the binding of naloxone. Addition of okadaic acid in a concentration of 2 nM, which is specific for the inhibition of protein phosphatase 2A, augmented the number of binding sites of naloxone or naltrindole. The results suggest a protein phosphatase-dependent regulation of the binding of opiate ligands in the striatum.

Diurnal alteration in opiate effects on the hypothalamo-pituitary-adrenal axis: changes in the mechanism of action.

Opioid control of the hypothalamo-pituitary-adrenocortical axis has a characteristic circadian rhythm (Kiem, Kanyicska, Stark and Fekete, 1987). To elucidate the mechanisms leading to circadian alterations of opioid control of the hypothalamo-pituitary-adrenocortical axis, and to look for the receptor type at which the p.m. inhibitory action of opioids occurs, we examined the effect of morphine at different doses and the interaction between naloxone and morphine at different times of day in intact male Wistar rats. In the morning: morphine (10 and 30 mg/kg s.c.) significantly increased corticosterone secretion, while 3 mg/kg s.c. had no effect. Naloxone in a dose of 2.5 mg/kg i.p. significantly antagonized the corticosterone-releasing effect of morphine, suggesting that the secretion of corticosterone induced by morphine is mediated via mu-opioid receptors. In the afternoon: basal plasma corticosterone levels were higher than those in the morning, and morphine caused a significant corticosterone increase only at the dose of 30 mg/kg, and had no effect in the dose of 10 mg/kg. Morphine significantly decreased corticosterone levels in the dose of 3 mg/kg. This inhibitory action lasted approximately 3 h after morphine injection and was able to inhibit the circadian evening rise of corticosterone. The effect of morphine and the interaction between naloxone and morphine on prolactin secretion remained unchanged from a.m. to p.m.; naloxone (2.5 mg/kg i.p.) which inhibited the 30 mg/kg morphine-induced corticosterone rise in the morning failed to antagonize the 3 mg/kg morphine-induced decrease of corticosterone secretion in the afternoon. A high dose of naloxone (10 mg/kg i.p.) effectively prevented the 3 mg/kg morphine-induced p.m. inhibition of corticosterone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoradiographic localization and quantitative determination of specific binding sites of anxiolytic homophthalazines (formerly called 2,3-benzodiazepines) in the striato-pallido-nigral system of rats.

Homophthalazines (2,3-benzodiazepin-derivates, such as tofisopam, nerisopam, girisopam) constitute a drug family with strong anxiolytic and antipsychotic potencies. By autoradiography, all of these drugs showed a specific distribution pattern of binding sites exclusively in brain areas which relate to the striato-pallido-nigral system, while no specific label was found in any other brain areas in the rat. Quantitative analyses of the autoradiograms by computerized densitometry, as well as by a receptor binding assay on 32 microdissected brain areas showed very high concentrations of tritiated homophthalazines in the glubus pallidus, caudate nucleus, putamen and the substantia nigra. Relatively high density of binding sites was measured in the nucleus accumbens, the olfactory tubercle, the entopeduncular nucleus and the subthalamic nucleus. Concentrations measured in the cerebral cortical areas, cerebellum or brainstem nuclei did not differ from the background. No significant differences were found between the homophthalazines investigated in terms of the distribution patterns or density of binding sites.

A novel specific binding site for homophthalazines in the rat brain.

The specific binding sites of a homophthalazine, girisopam, in rat brain have been localized by qualitative and quantitative autoradiography. This substance exerts strong anxiolytic and antipsychotic effects both in rodents and in humans. High labeling was present in all major components of the extrapyramidal system, such as the caudate-putamen, globus pallidus, subthalamic nucleus, substantia nigra, and the extrapyramidal portion of the accumbens nucleus and the olfactory tubercle, while specific labeling was not seen in any other brain areas including the cerebral cortex, thalamus, cerebellum or brainstem areas. This novel distribution of girisopam is consistent with its antipsychotic effect and anxiolytic properties and may provide a morphological basis for further studies to elucidate the mechanisms of action of homophthalazines in the central nervous system.

A novel specific binding site for anxiolytic homophthalazines in the rat brain.

Radioligand binding studies were performed in order to elucidate the mechanism of action of anxiolytic-neuroleptic homophthalazines. Rat striatal membrane preparations were found to bind 3H-EGIS 6775 [3H-GYKI-52 322, 3H-(1-(4-aminophenyl)-4-methyl-7,8-dimethoxy-5H-homophthalazine)] in a specific and displaceable manner. Several other brain regions tested were devoid of similar binding activity. Saturation analysis revealed that binding affinity was in the 10(-8)-10(-7) M range. Binding was enhanced by Mg2+ ions and, to a smaller extent by Ca2+ ions. The binding principle was sensitive to heat or trypsin treatment. This specific binding site appears, according to competition studies, different from the receptors whose presence in the rat striatum has been reported earlier.

Prolactin response to morphine in intact and adrenalectomized lactating rats.

To examine the hypothesis that the increased adrenocortical activity during lactation induced the loss of the prolactin (PRL) -releasing effect of morphine, we studied the effect of morphine in adrenalectomized (ADX) and sham-operated primiparous lactating Wistar rats. Animals were adrenalectomized 4 days after delivery. On day 11 of lactation (7 days after ADX), pups were separated from their mother 2 h before morphine or haloperidol injection. Intravenous injection of 5 mg/kg morphine did not change plasma PRL levels in the sham-operated lactating rats, but it resulted in a significant increase of plasma PRL levels in ADX lactating animals, with or without corticosterone replacement. Catalepsy following 10 mg/kg i.v. morphine was also markedly enhanced in ADX lactating animals. The PRL response to 0.5 mg/kg haloperidol was higher in ADX lactating animals than that in the controls. Morphine given 2 h after haloperidol treatment resulted in a further increase of plasma PRL in ADX, but not in the sham-operated lactating animals. These results suggest that adrenal hyperfunction may lead to a loss of sensitivity to morphine during lactation.

Inhibition of suckling-induced prolactin release by dexamethasone.

The effect of dexamethasone (DEX) treatment (400 and 200 micrograms/kg BW 21 and 2 h before suckling stimulus, respectively) on suckling- and domperidone (DOMP)-induced PRL release was investigated in freely moving, primiparous lactating rats. DEX completely blocked suckling-induced plasma PRL release without affecting DOMP-induced release of the hormone suggesting a central action of DEX. The effect was transient because it could not be detected on the second day of testing. The effect of DEX implanted in three different brain areas on suckling- and DOMP-induced PRL release was also tested. Implants surrounding the hypothalamic paraventricular nuclei and dorsal hippocampus failed to affect PRL release induced by suckling stimulus. Surprisingly, DEX suppressed PRL release induced by suckling stimulus when it was implanted into the medial basal hypothalamus. These findings demonstrate that DEX is a potent inhibitor of the suckling-induced PRL release. They also indicate that the site of action of DEX is not at the anterior pituitary gland or the paraventricular nuclei and hippocampus because DEX treatment and DEX implants had no effect on plasma PRL levels induced by DOMP and suckling stimulus, respectively. Our data suggest that the effect of DEX is mediated through a region of the medial basal hypothalamus. The observed transient block in suckling-induced PRL release may be physiologically relevant during stress in lactating mothers for conserving pituitary stores of the hormone needed for milk production or being able to adapt to a rapid change in osmoregulation.

Adrenergic and dopaminergic regulation of circulating beta-endorphin-like immunoreactivity in hypertension.

The central alpha-2-adrenergic receptor agonist, clonidine (300 micrograms daily) significantly increased the plasma beta-endorphin-like immunoreactivity (beta ELI) in 12 patients with mild to moderate essential hypertension in a randomized, crossover study. A significant linear correlation between the increase in plasma beta ELI and the decrease in blood pressure (both systolic and diastolic) was found after clonidine administration. The role of the reduced central sympathetic tone, induced by alpha-2-adrenoceptor stimulation, in the elevation of circulating beta ELI can be suggested. The plasma beta ELI increased also significantly after the dopaminergic D-2 receptor agonist, bromocryptine treatment, (5 mg, daily) in 13 patients with borderline and mild essential hypertension in a randomized, crossover study. A significant drop in circulating noradrenaline and in arterial blood pressure and a significant linear correlation between the changes of plasma noradrenaline level and blood pressure was found after bromocryptine administration. There was no correlation between the rise in plasma beta ELI and the decrease in blood pressure after bromocryptine. The importance of the central sympathetic activity and not only a direct pituitary dopaminergic agonist effect on the beta-endorphin secretion can be stressed in the effect of bromocryptine on the immunoreactive beta-endorphin level.