Periventricular-hypophysial Dopaminergic Neurons Research Articles

Neurokinin B- and kisspeptin-positive fibers as well as tuberoinfundibular dopaminergic neurons directly innervate periventricular hypophyseal dopaminergic neurons in rats and mice

Neurons co-expressing kisspeptin, neurokinin B (NKB), and dynorphin in the hypothalamic arcuate nucleus, named KNDy neurons, are directly affected by sex hormones, and are well known for regulating the secretion of gonadotropin-releasing hormone. However, recent studies have shown that KNDy neurons also project and terminate to tuberoinfundibular dopaminergic (TIDA) neurons, suggesting a role in prolactin secretion. Moreover, there is a possibility that other neurosecretory dopaminergic neurons regulating prolactin secretion, such as periventricular hypophyseal dopaminergic (PHDA) neurons, may also be innervated by KNDy neurons. In the present study, by means of double immunohistochemistry and retrograde neural tracer, we examined whether KNDy neurons project directly to PHDA neurons that project to blood vessels, as well as to TIDA neurons. The results revealed that KNDy neurons are widely projecting to neurosecretory dopaminergic neurons of the PHDA and TIDA neurons in rats and mice. Secondary, presence of a major receptor for NKB, neurokinin-3 receptor (NK3R), in PHDA and TIDA neurons was examined and it appeared that most TIDA and PHDA neurons possess NK3R. These findings indicate that, in rodents, KNDy neurons widely project to neurosecretory dopaminergic neurons distributed in the hypothalamus, and may affect them via the NKB-NK3R signaling pathway.

Ovarian steroids influence the activity of neuroendocrine dopaminergic neurons

The secretion of prolactin (PRL) from the anterior lobe (AL) of the pituitary gland is tonically inhibited by dopamine (DA) of hypothalamic origin. While ovarian steroids play a role in the regulation of the secretion of PRL, their effect on all three populations of hypothalamic neuroendocrine dopaminergic neurons is not fully understood. In this study we describe the effects of ovarian steroids on regulation of the release of DA from tuberoinfundibular dopaminergic (TIDA), tuberohypophyseal dopaminergic (THDA) and periventricular-hypophyseal dopaminergic (PHDA) neurons. Adult female rats were bilaterally ovariectomized (OVX) and, 10 days following ovariectomy (day 0), injected with corn oil (vehicle), estrogen, or estrogen plus progesterone (day 1). Animals were sacrificed every 2 h from 09.00 to 21.00 h by rapid decapitation. Trunk blood was collected and the concentration of PRL in serum was determined by radioimmunoassay. The median eminence (ME) and the AL, intermediate (IL) and neural (NL) lobes of the pituitary gland were dissected and the concentration of DA and DOPAC in each was measured by HPLC-EC. OVX rats presented small but significant increases in the secretion of PRL at 15.00 and 17.00 h. Replacement of estrogen or estrogen plus progesterone increased the basal concentration of PRL. Moreover, injection of estrogen only, or estrogen plus progesterone increased the concentration of PRL in serum at 15.00 h through 19.00 h, respectively, followed by a decrease to baseline thereafter. The turnover of DA in the ME and NL of OVX rats increased at 13.00 and returned to low levels. Turnover of DA in the IL of OVX rats increased in the morning by 11.00 h and remained elevated before decreasing by 17.00 h. The turnover of DA in the ME, IL and NL of OVX rats increased by 19.00 h. Injection of estrogen advanced the increase of TIDA activity by 2 h in the ME compared to OVX rats. Moreover, administration of estrogen suppressed the activity of THDA and PHDA neurons in the afternoon compared to OVX rats. In estrogen plus progesterone-treated rats, the activity of hypothalamic neuroendocrine dopaminergic neurons terminating in the ME, IL, and NL was inhibited prior to the increase in the secretion of PRL. The concentration of DA in the AL diminished prior to the estrogen-induced increase of PRL. Administration of progesterone, in concert with estrogen, delayed the increase of PRL in serum and the decrease of DA in the AL, compared to estrogen-treated rats, by 4 h. These data suggest a major role for ovarian steroids in controlling increases in the secretion of PRL by not only stimulating PRL release from lactotrophs, but also by inhibiting the activity of all three populations of hypothalamic neuroendocrine DAergic neurons.

The σ receptor ligand rimcazole alters secretion of prolactin and α-melanocyte stimulating hormone by dopaminergic and non-dopaminergic mechanisms

The role of tuberoinfundibular and periventricular-hypophysial dopaminergic neurons in mediating rimcazole-induced decreases in plasma concentrations of prolactin and α-melanocyte stimulating hormone was assessed. Dopaminergic neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence and intermediate lobe of the pituitary which contain terminals of tuberoinfundibular and periventricular-hypophysial dopaminergic neurons, respectively. Rimcazole decreased plasma concentrations of both prolactin and α-melanocyte stimulating hormone, increased the concentration of DOPAC in median eminence, but did not alter DOPAC concentrations in the intermediate lobe of the pituitary. Pretreatment with a ‘putative’ σ receptor agonist, pentazocine, prevented the rimcazole-induced increase of the concentration of DOPAC in the median eminence, but did not block the ability of rimcazole to decrease plasma concentrations of prolactin. The results of this study reveal that the ability of rimcazole to decrease α-melanocyte stimulating hormone secretion is not mediated by a dopaminergic mechanism, whereas the ability of rimcazole to decrease prolactin secretion appears to be mediated by both dopaminergic and non-dopaminergic mechanisms.

Neurochemical evidence that AMPA receptor-mediated tonic inhibition of hypothalamic dopaminergic neurons occurs via activation of inhibitory interneurons

Blockade of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors with 6-nitro-7-sulfamoyl-benzo-[f]quinoxaline-2,3(1H,4H)-dione (NBOX) activates tuberoinfundibular (TIDA) and periventricular-hypophysial dopaminergic (PHDA) neurons suggesting that these neurons are tonically inhibited by endogenous excitatory amino acid neurotransmitters acting at AMPA receptors. The purpose of the present study was to identify prospective inhibitory neurotransmitters mediating this effect by examining the ability of γ-aminobutyric acid (GABA) A and κ-opioid receptor agonists to reverse the stimulatory effects of NBQX on the activity of these neurons (estimated from concentrations of 3,4-dihydroxyphenylacetic acid [DOPAC] in the median eminence and intermediate lobe of the pituitary). The GABA A receptor agonist isoguvacine prevented the NBQX-induced increase in DOPAC concentrations in the median eminence but not in the intermediate lobe. The κ-opioid receptor agonist U-50,488 had no effect in the median eminence, but attenuated the NBQX-induced increase of DOPAC concentrations in the intermediate lobe. These results suggest that excitatory amino acid neurotransmitters activate AMPA receptors and increase release of GABA, which by acting at GABA, which by acting at GABA A receptors tonically inhibits TIDA neurons. On the other hand, AMPA receptor-mediated tonic inhibition of PHDA neurons occurs, at least in part, by a mechanism involving endogenous κ-opioids.

MDL-101,562 blocks the stimulatory effects of bombesin and gastrin-releasing peptide on hypothalamic dopaminergic neurons.

The effects of central administration of bombesin, gastrin-releasing peptide (GRP) and a putative bombesin/GRP receptor antagonist [Phe8 psi[CH2S]Leu9]litorin (MDL-101,562) were determined on the activities of hypothalamic tuberoinfundibular and periventricular-hypophysial dopaminergic neurons in male rats. Dopaminergic neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence and the intermediate lobe of the posterior pituitary which contain terminals of these neurons. Intracerebroventricular injections of bombesin and GRP increased DOPAC concentrations in both the median eminence and intermediate lobe. MDL-101,562 had no effect on median eminence or intermediate lobe DOPAC concentrations per se, but blocked the stimulatory actions of bombesin and GRP on DOPAC concentrations in these regions. These results suggest that MDL-101,562 may be a useful pharmacologic tool in the study of the central actions of bombesin and related peptides.

δ-Opioid receptor-mediated regulation of central dopaminergic neurons in the rat

Effects of intraventricular injections of the δ-opioid receptor agonist [ D-Pen 2, D-Pen 5]enkephalin (DPDPE) and antagonist 17-cyclopropylmethyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2′,3′-indol morphinan (naltrindole) hydrochloride were determined on the activities of mesolimbic, nigrostriatal, tuberoinfundibular and periventricular-hypophysial dopaminergic neurons in brains of male rats. Dopaminergic neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of the decarboxylase inhibitor 3-hydroxybenzylhydrazine in regions of the brain (nucleus accumbens, striatum, median eminence) and the intermediate lobe of the pituitary which contain terminals of these neurons. DPDPE produced a dose- and time-related increase in concentrations of DOPAC and accumulation of DOPA in nucleus accumbens and median eminence, but had no effect in striatum or intermediate lobe of the pituitary. Naltrindole hydrochloride had no effect per se, but blocked the ability of DPDPE to increase DOPAC concentrations in nucleus accumbens and median eminence. These results reveal that activation of δ-opioid receptors selectively increases the activities of mesolimbic and tuberoinfundibular but not of nigrostriatal or periventricular-hypophysial dopaminergic neurons.

Sexual differences in the stimulatory effects of bombesin on tuberoinfundibular dopaminergic neurons

The purpose of this study was to (1) examine the effects of central administration of bombesin on the activity of tuberoinfundibular dopaminergic (DA) neurons in male and female rats, and (2) determine if sexual differences in the responsiveness of these neurons to bombesin were due to the presence of prolactin or gonadal steroids. The activity of tuberoinfundibular DA neurons was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in terminals of these neurons in the median eminence. The effects of bombesin on the secretion of prolactin and α-melanocyte stimulating hormone (αMSH), and the activities of nigrostriatal, mesolimbic, and periventricular-hypophysial Da neurons were also determined in gonadally intact male and female rats. Central administration of bombesin (10 ng/rat; i.c.v.) decreased prolactin secretion in gonadally intact male and female rats, but only in males was this associated with an increase in the activity of tuberoinfundibular DA neurons. In contrast, bombesin increased the activity of periventricular-hypophysial DA neurons terminating in the intermediate lobe of both male and female rats, and this was associated with a decrease in αMSH secretion in both sexes. Bombesin had no effect on the activities of nigrostriatal, mesolimbic, or periventricular-hypophysial DA neurons terminating in the neural lobe in either sex. The loss of endogenous gonadal hormones following ovariectomy rendered tuberoinfundibular DA neurons responsive to the stimulatory effects of bombesin, whereas immunoneutralization of endogenous prolactin following administration of prolactin antiserum had no effect on the inability of bombesin to alter the activity of these neurons in female rats. Estrogen administration to both ovariectomized and ovariectomized + prolactin antiserum-treated rats reinstated the lack of responsiveness of tuberoinfundebular DA neurons to bombesin, whereas neither orchidectomy nor testosterone administration to orchidectomized male rats altered the stimulatory effects of bombesin on the activity of tuberoinfundibular DA neurons. Taken together, these results reveal that sexual differences in the responsiveness of tuberoinfundibular DA neurons to the stimulatory effects of bombesin are due, at least in part, to the prolactin-independent effects of estrogen.

Effects of immunoneutralization of dynorphin 1–17 and dynorphin 1–18 on the activity of central dopaminergic neurons in the male rat

The effect of administration of antibodies against dynorphin 1–17 (DYN 1–17-AB) and dynorphin 1–N(DYN 1–N-AB) were examined on the activity of dopaminergic (DA) neurons comprising the nigrostriatal, mesolimbic, tuberoinfundibular and periventricular-hypophysial systems in the male rat brain. DA neuronal activity was estimated by measuring the concentration of the dopamine metabolite 3,4-dihydrophenylacetic acid (DOPAC) in brain (striatum, nucleus accumbens, median eminence) and pituitary regions (intermediate lobe) containing terminals of these neurons. The intracerebroventricular administration of either DYN 1–17-AB or DYN 1–N-AB produced a time-related increase in the activity of tuberinfundibular and periventricular-hypophysial DA neurons, but failed toalter the activity of nigrstriatal or mesolimbic DA neurons. The ability of both DYN 1–17-AB to endhance of tuberofundibular and periventricular-hypophysial DA neurons was reversed by the kappa opioid ag50,488. These results indicate that 1–17-AB and and DYN 1-N-AB, presumably by binding endogenous dynorphins, remove a tonic inhibitory action of these opioid peptides on tuberoinfundibular and periventricular-hypophysial DA neurons.

Sexual differences in the activity of periventricular-hypophysial dopaminergic neurons in rats

The activities of periventricular-hypophysial dopaminergic (DA) neurons were compared in male and female rats by measuring dopamine synthesis (accumulation of 3,4-dihydroxyphenylalanine [DOPA] after inhibition of L-aromatic amino acid decarboxylase) and metabolism (concentrations of 3,4-dihydroxyphenylacetic acid [DOPAC]) in terminals of these neurons in the intermediate lobe of the pituitary. For comparison, the synthesis and metabolism of dopamine in the neural lobe of the pituitary and median eminence were also determined. The concentrations of DOPAC and accumulation of DOPA were higher in females than in males in both the intermediate lobe and median eminence, revealing a sexual difference in the basal activity of periventricular-hypophysial and tuberoinfundibular DA neurons. In contrast, there were no differences between male and female rats in activity of DA neurons terminating in the neural lobe. One week following gonadectomy, DOPA accumulation in the median eminence was decreased in females and increased in males, but remained unchanged in the intermediate lobe. These results indicate that sexual differences in the activity of periventricular-hypophysial DA neurons terminating in the intermediate lobe are not dependent upon the presence of circulating gonadal steroids, and in this respect, these neurons differ from tuberoinfundibular DA neurons.

Neurotensin-induced activation of hypothalamic dopaminergic neurons is accompanied by a decrease in pituitary secretion of prolactin and α-melanocyte-stimulating hormone

The effects of neurotensin on the activity of hypothalamic tuberoinfundibular and periventricular-hypophysial dopaminergic (DA) neurons, and on the secretion of pituitary hormones that are tonically regulated by these neurons (i.e. prolactin and α-melanocyte-stimulating hormone [αMSH], respectively) were examined in estrogen-primed ovariectomized rats. The activity of tuberoinfundibular and periventricular-hypophysial DA neurons was estimated by measuring concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the terminals of these neurons in the median eminence and intermediate lobe of the posterior pituitary, respectively. Intracerebroventricular administration of neurotensin caused a dose- and time-related increase in DOPAC concentrations in both the median eminence and intermediate lobe, and a concurrent decrease in plasma levels of prolactin and αMSH. These results suggest that neurotensin-induced inhibition of secretion of prolactin and αMSH from the pituitary may be due to the stimulatory action of this neuropeptide on the release of dopamine from tuberoinfundibular and periventricular-hypophysial neurons.