M.J. Eaton

Efferent projections from the region of the medial zona incerta containing A13 dopaminergic neurons: a PHA-L anterograde tract-tracing study in the rat

Potential efferent projections of A13 dopaminergic (DA) neurons were identified in the present study by examining the distribution of labelled fibers following iontophoretic injection of the anterogradely transported lectin Phaseolus vulgaris leucoagglutinin (PHA-L) into the medial zona incerta (MZI), the region of the diencephalon containing A13 DA neuronal perikarya. One week after injection, PHA-L labelled fibers were found throughout the brain with the heaviest labelling occurring ipsilateral to the injection site in the anterior hypothalamic area, lateral hypothalamus, lateral preoptic area, horizontal diagonal band of Broca, and parvocellular region of the paraventricular nucleus. Moderate labelling was observed in the ipsilateral median preoptic nucleus, lateral septum, lateral aspect of the bed nucleus of the stria terminalis, and central nucleus of the amygdala. Moderate labelling was also found in the contralateral MZI and parvocellular region of the paraventricular nucleus. Light labelling was detected in the ipsilateral medial preoptic area, supraoptic nucleus, ventromedial nucleus, arcuate nucleus, vertical limb of the diagonal band of Broca, and in the contralateral lateral hypothalamus. Few immunopositive fibers were present in the dorsomedial nucleus of the hypothalamus or the magnocellular region of the paraventricular nucleus. These results reveal that neurons located in the MZI (possibly A13 DA neurons) have ipsilateral efferent axonal projections to a variety of brain regions including the lateral hypothalamus, lateral preoptic area, and the limbic structures at the diencephalic-telencephalic juncture.

Dopamine receptor-mediated regulation of corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus.

The present study examined the effects of intraperitoneal administration of selective D1 (SKF 38393) and D2 (quinelorane) dopaminergic receptor agonists on Fos-like immunoreactivity (Fos-LI) and levels of corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (cAMY). Ninety minutes after administration of the D1 agonist SKF 38393, Fos-LI was increased in both the PVN and cAMY. Administration of SCH 39166, a selective D1 antagonist, blocked and attenuated the SKF 38393-induced increase in Fos-LI in the PVN and cAMY, respectively. Similarly, 90 minutes after intraperitoneal injection of the D2 agonist quinelorane, Fos-LI was increased in both PVN and cAMY. Administration of the selective D2 antagonist raclopride prevented the ability of quinelorane to increase Fos-LI in the PVN and cAMY. Both SKF 38393 and quinelorane stimulated the expression of CRH and mRNA in the PVN, but failed to alter its expression in the cAMY. Taken together, these results indicate that stimulation of either D1 and D2 dopaminergic receptors activates CRH neurons in the PVN. Stimulation of either D1 or D2 receptors activates neurons in the cAMY, but these changes do not appear to be occurring in CRH neurons.

Comparison of the effects of the dopamine D2 agonist quinelorane on tuberoinfundibular dopaminergic neuronal activity in male and female rats

The purpose of the present study was to examine the effects of quinelorane (LY163502), a potent and selective D2 dopaminergic (DA) receptor agonist, on the activity of tuberoinfundibular DA neurons in male and female rats as estimated by determining the concentration of the primary metabolite of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), in terminals of these neurons in the median eminence (ME). In males, quinelorane produced dose- and time-related increases in the concentration of DOPAC in the Me which was blocked by the D2 receptor antagonist raclopride. The activity of tuberoinfundibular neurons in female rats is higher than it is in males because circulating levels of prolactin tonically stimulate these neurons in the female. In female rats, quinelorane markedly lowered plasma concentrations of prolactin but failed to alter DOPAC concentrations in the ME. Pretreatment of female rats with prolactin antiserum induced hypoprolactinemia and reduced DOPAC concentrations in the ME; in these animals quinelorane increased ME DOPAC concentrations. These results indicate that by acting on D2 receptors quinelorane is able to stimulate tuberoinfundibular DA neurons in both male and female rats, but in female rats the ability of quinelorane to reduce circulating levels of prolactin indirectly reduces the activity of tuberoinfundibular DA neurons and thereby masks the stimulatory action of this drug on these neurons.

Neurochemical evidence that 5-hydroxytryptaminergic neurons tonically inhibit noradrenergic neurons terminating in the hypothalamus.

The medial zona incerta (MZI) and dorsomedial nucleus of the hypothalamus (DMN), which contain cell bodies and terminals of incertohypothalamic dopaminergic (DA) neurons, are densely innervated by both noradrenergic (NE) and 5-hydroxytryptaminergic (5-HT) neurons. In view of emerging anatomical and pharmacological evidence suggesting possible interactions between 5-HT and catecholaminergic neurons, the effects of experimental procedures that inhibit or disrupt 5-HT neurons on the activities of catecholaminergic neurons terminating in these regions were examined in the present study. Catecholaminergic neuronal activity was estimated by measuring catecholamine synthesis (accumulation of 3,4-dihydroxyphenylalanine [DOPA] after administration of a decarboxylase inhibitor) and metabolism (concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)) in the MZI and DMN of both male and female rats. Inhibition of 5-HT neurons following administration of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the accumulation of DOPA in the DMN and the concentrations of DOPAC in the MZI and DMN, indicating an activation of catecholaminergic neurons in these regions. Concentrations of MHPG were increased in the MZI and DMN by 8-OH-DPAT or 5,7-dihydroxytryptamine-induced lesions of 5-HT neurons, revealing that NE neurons terminating in these regions were activated following procedures that decrease 5-HT neuronal function. Following destruction of NE neurons projecting to the MZI and DMN, 8-OH-DPAT no longer increased DOPAC concentrations in these brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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

Abstract 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.

The σ ligand rimcazole activates noradrenergic neurons projecting to the paraventricular nucleus and increases corticosterone secretion in rats

Intraperitoneal injection of rimcazole, a sigma ligand, into male rats increased plasma concentrations of corticosterone in a dose- and time-related fashion. Concurrently, rimcazole increased concentrations of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the paraventricular nucleus (PVN) of the hypothalamus, suggesting that the drug activates noradrenergic neurons terminating in this nucleus. This latter suggestion was confirmed by the finding that rimcazole also increased concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) in the PVN. Pentazocine, a sigma ligand was without effect per se, but blocked the ability of rimcazole to increase concentrations of MHPG in the PVN and corticosterone in plasma. Taken together, these results suggest that rimcazole activates noradrenergic neurons projecting to the PVN via a mechanism involving sigma binding sites, and this action may be responsible for the ability of this drug to increase secretion of corticosterone.

Characterization of opioid receptor-mediated regulation of incertohypothalamic dopamine neurons: lack of evidence for a role of 5-hydroxytryptaminergic neurons in mediating the stimulatory effects of morphine.

The purpose of the present study was to characterize opioid receptor-mediated regulation of incertohypothalamic dopaminergic (DA) neurons in the rat brain by examining the acute effects of selective mu or kappa opioid receptor agonists and antagonists on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial zona incerta (MZI) and the dorsomedial hypothalamic nucleus (DMN) which contain cell bodies and terminals, respectively, of these neurons. Morphine caused a dose- and time-related increase in concentrations of DOPAC in MZI and DMN; this stimulatory effect was blocked by the mu opioid receptor antagonist naltrexone. In contrast, activation or blockade of kappa opioid receptors following administration of U-50,488 or nor-binaltorphimine, respectively, had no effect on DOPAC concentrations in either the MZI or DMN. The basal activity of incertohypothalamic DA neurons and their response to morphine was similar in male and female rats. Morphine also increased the concentrations of 5-hydroxyindoleacetic acid in MZI and DMN, indicating that morphine increases the activity of 5-hydroxytryptamine (5HT) neurons projecting to these regions. This might suggest that morphine-induced activation of incertohypothalamic DA neurons is mediated by 5HT neurons; but 5,7-dihydroxytryptamine-induced lesions of 5HT neurons did not alter the ability of morphine to increase DOPAC concentrations in MZI and DMN. These results indicate that the stimulatory effects of mu opioid receptor activation on incertohypothalamic DA neurons is not dependent upon the presence of 5HT neurons.

Remoxipride and raclopride differentially alter the activity of incertohypothalamic dopaminergic neurons

The effects of two dopaminergic (DA) antagonists, raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy- 6-methoxybenzamide(+)-tartrate) and remoxipride (S(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2, 6-dimethoxybenzamide hydrochloride monohydrate), were compared on the DA receptor-mediated regulation of incertohypothalamic and nigrostriatal DA neurons. Both drugs produced dose- and time-related increases in concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, which contains the terminals of the nigrostriatal DA neurons. On the other hand, raclopride but not remoxipride increased concentrations of DOPAC in the medial zona incerta and dorsomedial hypothalamic nucleus, regions that contains cell bodies and terminals, respectively, of incertohypothalamic DA neurons. These results suggest that raclopride blocks a population of DA receptors that regulates the activity of incertohypothalamic DA neurons, whereas remoxipride does not.

Differential effects of the D2 receptor agonist quinelorane on the secretion of prolactin and α-melanocyte-stimulating hormone

The purpose of the present study was to determine the effects of quinelorane, a selective D2 receptor agonist, on concentrations of prolactin and alpha-melanocyte-stimulating hormone (alpha-MSH) in plasma of male rats. Quinelorane decreased plasma concentrations of prolactin but not of alpha-MSH, whereas, the D2 receptor antagonist raclopride increased plasma concentrations of both hormones. Quinelorane reversed the effects of raclopride on circulating levels of prolactin, but not alpha-MSH. The results of this study suggest that secretion of hormones from melanotrophs and lactotrophs is regulated by different subtypes of D2 receptors.