1-methyl-3-4-dihydroisoquinoline and salsolinol

The aim of the study was to test the hypothesis that salsolinol, a derivative of dopamine, is involved in the regulation of hypothalamic-pituitary gonadotropic (GnRH/LH) axis activity in lactating sheep. In the first experiment performed on sheep during the fifth week of lactation, a structural analogue of salsolinol (1-MeDIQ) was infused into the third brain ventricle (IIIv) to antagonize its action within the central nervous system (CNS). A push-pull perfusion of the infundibular nucleus/median eminence was performed simultaneously, and blood samples were collected from the jugular vein. In the second experiment, sheep received infusions of salsolinol into the IIIv, 48 hours after the weaning of their 8-week-old lambs. Blood samples were collected during the experimental periods, and the anterior pituitary (AP) tissue was dissected immediately after the end of the experiment. Perfusate GnRH concentration (experiment 1), plasma LH concentration (experiments 1 and 2), and relative LHβ mRNA levels in the AP tissue (experiment 2) were assayed. Blocking of salsolinol action in the CNS of lactating sheep caused a significant (P < 0.001) decrease in the perfusate GnRH concentrations in comparison with controls. Treatment with 1-MEDIQ also significantly decreased (P < 0.001) the LH concentration in the blood plasma. In turn, salsolinol infused 48 hours after lamb weaning significantly (P < 0.001) increased plasma LH concentration, reflected in the significant (P < 0.05) increase in the amplitude of LH pulses in the treated sheep as compared to the control animals. There was no significant difference in the relative levels of LHβ-subunit mRNA in the AP between control and salsolinol-infused sheep. The results lead to a conclusion that salsolinol affects the secretory activity of the GnRH/LH axis in sheep during lactation. Whether salsolinol infused into the IIIv evokes this stimulatory effect by itself or by modulation of other regulatory systems needs to be clarified.

Topics: Animals; Female; Gonadotropin-Releasing Hormone; Hypothalamo-Hypophyseal System; Injections, Intraventricular; Isoquinolines; Lactation; Luteinizing Hormone; Sheep

This study tested the hypothesis that salsolinol, a derivative of dopamine, affects GnRH and LH secretion in lactating sheep. In the in vivo experiment, the structural analogue of salsolinol, 1-methyl-3,4-dihydroisoquinoline (1-MeDIQ), was infused into the infundibular nucleus-median eminence of sheep at the fifth wk of lactation to antagonize salsolinol's action. Simultaneously, cerebrospinal fluid from the third brain ventricle, to determine GnRH concentration, and plasma samples, to measure LH concentration, were collected. In the in vitro experiment, the anterior pituitary (AP) explants from weaned sheep were incubated in culture medium containing 2 doses of salsolinol, 20 and 100 μg/mL (S20 and S100, respectively). The concentration of LH in the collected media and relative expression of LHβ subunit messenger RNA in the AP explants were determined. No significant difference was found in mean GnRH concentration in response to 1-MeDIQ infusion, but both mean plasma LH concentration and LH pulse frequency increased significantly (P < 0.001 and P < 0.05, respectively) compared with those in controls. Significantly higher LH concentrations occurred during the first (P < 0.001), second (P < 0.001), and fourth (P < 0.05) h of 1-MeDIQ infusion. In the in vitro study, both the S20 and S100 doses of salsolinol caused a significant decrease in the mean medium LH concentration compared with that in the control (P < 0.01 and P < 0.001, respectively). Salsolinol had no effect on the relative LHβ subunit messenger RNA expression in the incubated tissue. In conclusion, salsolinol is a potential inhibitor of the secretory activity of the gonadotropic axis in lactating sheep, at least at the AP level. Although no significant changes in GnRH release were directly confirmed, an increase in the frequency of LH pulses does not allow to exclude the central action of salsolinol.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Culture Media, Conditioned; Female; Gene Expression; Gonadotropin-Releasing Hormone; Isoquinolines; Lactation; Luteinizing Hormone; Luteinizing Hormone, beta Subunit; Median Eminence; Pituitary Diseases; RNA, Messenger; Sheep; Tissue Culture Techniques

In mammals, the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stress is reduced during lactation and this mainly results from suckling by the offspring. The suckling stimulus causes a release of the hypothalamic 1-metyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) (a derivative of dopamine), one of the prolactin-releasing factors. To investigate the involvement of salsolinol in the mechanism suppressing stress-induced HPA axis activity, we conducted a series of experiments on lactating sheep, in which they were treated with two kinds of isolation stress (isolation from the flock with lamb present or absent), combined with suckling and/or i.c.v infusion of salsolinol and 1-methyl-3,4-dihydro-isoqinoline (1-MeDIQ; an antagonistic analogue of salsolinol). Additionally, a push-pull perfusion of the infundibular nucleus/median eminence (IN/ME) and blood sample collection with 10-min intervals were performed during the experiments. Concentrations of perfusate corticotrophin-releasing hormone (CRH) and catecholamines (noradrenaline, dopamine and salsolinol), as well as concentrations of plasma adenocorticotrophic hormone (ACTH), cortisol and prolactin, were assayed. A significant increase in perfusate noradrenaline, plasma ACTH and cortisol occurred in response to both kinds of isolation stress. Suckling and salsolinol reduced the stress-induced increase in plasma ACTH and cortisol concentrations. Salsolinol also significantly reduced the stress-induced noradrenaline and dopamine release within the IN/ME. Treatment with 1-MeDIQ under the stress conditions significantly diminished the salsolinol concentration and increased CRH and cortisol concentrations. Stress and salsolinol did not increase the plasma prolactin concentration, in contrast to the suckling stimulus. In conclusion, salsolinol released in nursing sheep may have a suppressing effect on stress-induced HPA axis activity and peripheral prolactin does not appear to participate in its action.

Topics: Adrenocorticotropic Hormone; Animals; Animals, Suckling; Arcuate Nucleus of Hypothalamus; Catecholamines; Corticotropin-Releasing Hormone; Female; Hydrocortisone; Hypothalamo-Hypophyseal System; Isoquinolines; Lactation; Male; Median Eminence; Pituitary-Adrenal System; Prolactin; Sheep, Domestic; Social Isolation; Stress, Psychological

The prolactin release caused by salsolinol (a derivative of dopamine, DA) in rats could be prevented by its structural analogue 1-methyl-3,4-dihydroisoqinoline (1-MeDIQ). To study the participation of salsolinol in the neural stimulatory mechanism of prolactin release in lactating sheep, we tested whether 1-MeDIQ, acting at the central nervous system (CNS) level, would diminish basal prolactin release and reduce prolactin surge induced by suckling. A series of intracerebroventricular (icv) infusions of 1-MeDIQ (5 x 60 microg/60 microl/30 min, at 30-min intervals) were performed in nursing ewes (n=8) during the fifth week of lactation. Additionally, by combining these infusions with push-pull perfusion, we studied the concentration of dopaminergic components, i.e., salsolinol, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) within the infundibular nucleus/median eminence (IN/ME) in four of the ewes. Treatment with 1-MeDIQ significantly (P<0.001) reduced either the basal prolactin release during the non-suckling period or the suckling-induced prolactin surge. Specifically, the suppressive effect occurred gradually, affecting both the duration and amplitude of the prolactin surge. In the control ewes, the perfusate salsolinol concentration increased significantly (P<0.001) during suckling, while in the ewes treated with 1-MeDIQ only vestigial amounts of this compound were found during the non-suckling period. No DA was detected in the perfusates collected from the IN/ME of control and 1-MeDIQ-treated groups and no significant differences were found in the DOPAC concentrations between these groups. In conclusion, 1-MeDIQ is able to inhibit prolactin secretion in lactating sheep, acting at the CNS level. In addition, one of the way of 1-MeDIQ action may be directed to the local salsolinol release within the mediobasal hypothalamus.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Animals, Newborn; Chromatography, High Pressure Liquid; Dopamine; Electrochemistry; Female; Hypothalamus, Middle; Injections, Intraventricular; Isoquinolines; Lactation; Male; Pituitary Gland; Prolactin; Sheep; Time Factors

Suckling induces a GH surge simultaneously to that of prolactin, so we tested whether salsolinol, a dopamine derivative (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), participates in the regulatory process of GH secretion in lactating sheep. A series of intracerebroventricular (i.c.v.) infusions of salsolinol, in two doses, was performed in nursing sheep, without suckling, during the fifth week of lactation. In other suckling sheep, we infused i.c.v. a structural analogue of salsolinol-1-methyl-3,4-dihydroisoqinoline (1-MeDIQ), which is able to antagonize salsolinol's action. Intracerebroventricular treatment of nursing sheep with a lower dose of salsolinol (total 50 ng) significantly increased plasma GH concentration, as compared with the concentrations noted before the infusion and in nursing controls. A higher dose of salsolinol (total 5 micrograms) did not affect GH release significantly. Intracerebroventricular treatment with 1-MeDIQ (total 300 micrograms) significantly reduced basal GH release, not affecting a pattern of GH surge in response to suckling. In conclusion, salsolinol may affect the regulatory process of GH secretion in lactating sheep, but its role seems not to be major.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Drug Administration Routes; Female; Growth Hormone; Isoquinolines; Lactation; Pregnancy; Sheep; Sucking Behavior

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.

Topics: Animals; Dopamine; Female; Ganglia, Sympathetic; In Vitro Techniques; Isoquinolines; Male; Median Eminence; Mice; Mice, Inbred C57BL; Mice, Knockout; Norepinephrine; Pituitary Gland; Presynaptic Terminals; Prolactin; Rats; Rats, Sprague-Dawley; Reserpine

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.

Topics: 5-Hydroxytryptophan; Animals; Catecholamines; Dopamine; Dopamine beta-Hydroxylase; Isoquinolines; Male; Median Eminence; Norepinephrine; Pituitary Gland; Prolactin; Rats; Receptors, Dopamine D2; Receptors, Presynaptic

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.

Topics: Adaptation, Physiological; Animals; Animals, Suckling; Dose-Response Relationship, Drug; Female; Isoquinolines; Lactation; Male; Pituitary Gland, Anterior; Prolactin; Prolactin Release-Inhibiting Factors; Rats; Rats, Sprague-Dawley; Stress, Psychological; Thyrotropin-Releasing Hormone

It has been recently observed that salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a putative endogenous prolactin-releasing factor is a potent inhibitor of stress-induced release of epinephrine and norepinephrine. The prolactin release caused by salsolinol was inhibited by 1-methyl-3,4-dihydroisoquinoline (1MeDIQ). Therefore, the aim of our present studies was to investigate the effect of 1MeDIQ on plasma catecholamine levels. It has been found that 1MeDIQ is able to induce a massive increase in plasma catecholamine levels. Pretreatment of the animals with a ganglionic blocker, chlorisondamine, could completely abolish the effect of 1MeDIQ on plasma norepinephrine, and plasma epinephrine levels were only significantly attenuated. Spinal cord transection between cervical and thoracic segments eliminated 1MeDIQ induced increase in epinephrine, whereas increase in plasma norepinephrine was not affected. Hence, this effect of 1MeDIQ on sympathoadrenal system activity is most probably mediated through the level of sympathetic ganglia or partially at more centrally located sites of the nervous system. These results suggest that elevation of plasma catecholamines is involved in the mechanism of action of 1MeDIQ inhibiting the biological effect of salsolinol.

Topics: Animals; Epinephrine; Isoquinolines; Male; Norepinephrine; Rats; Rats, Sprague-Dawley; Thyrotropin-Releasing Hormone