Tuberoinfundibular Dopaminergic Activity Research Articles

Chronic estrogen affects TIDA neurons through IL-1β and NO: effects of aging.

Women are chronically exposed to estrogens through oral contraceptives, hormone replacement therapy or environmental estrogens. We hypothesized that chronic exposure to low levels of estradiol-17β (E2) can induce inflammatory and degenerative changes in the tuberoinfundibular dopaminergic (TIDA) system leading to reduced dopamine synthesis and hyperprolactinemia. Young (Y; 3–4 months) and middle-aged (MA; 10–12 months) Sprague-Dawley rats that were intact or ovariectomized (OVX) were either sham-implanted or implanted with a slow-release E2 pellet (20 ng E2/day for 90 days). To get mechanistic insight, adult 3- to 4-month-old WT, inducible nitric oxide synthase (iNOS) and IL-1 receptor (IL-1R) knockout (KO) mice were subjected to a similar treatment. Hypothalamic areas corresponding to the TIDA system were analyzed. E2 treatment increased IL-1β protein and nitrate levels in the arcuate nucleus of intact animals (Y and MA). Nitration of tyrosine hydroxylase in the median eminence increased with E2 treatment in both intact and OVX animals. There was no additional effect of age. This was accompanied by a reduction in dopamine levels and an increase in prolactin in intact animals. E2 treatment increased nitrate and reduced dopamine levels in the hypothalamus and increased serum prolactin in WT mice. In contrast, the effect of E2 on nitrate levels was blocked in IL-1R KO mice and the effect on dopamine and prolactin were blocked in iNOS KO animals. Taken together, these results show that chronic exposure to low levels of E2 decreases TIDA activity through a cytokine-nitric oxide-mediated pathway leading to hyperprolactinemia and that aging could promote these degenerative changes.

Expression of Ovarian Steroid Hormone Receptors in Tuberoinfundibular Dopaminergic Neurones During Pregnancy and Lactation

During late-pregnancy, tuberoinfundibular dopaminergic (TIDA) neurones, a critical component of the negative-feedback loop regulating prolactin secretion, become unresponsive to the stimulatory effects of prolactin. The change in TIDA responsiveness to prolactin at this time results in a decrease in dopamine secretion and a prolactin surge. As the onset of parturition and the antepartum prolactin surge depend on the withdrawal of progesterone in the presence of oestrogen, it is likely that ovarian steroid hormones mediate this change in TIDA responsiveness. To determine whether ovarian steroids can directly modulate TIDA activity, and whether changes of receptor numbers might contribute to overall steroid-regulation of these neurones, we investigated the level of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) expression within TIDA neurones during pregnancy and lactation. Animals were sacrificed on dioestrous, days 12, 19 and 21 of pregnancy and day 5 of lactation, and the proportion of TIDA neurones expressing ERalpha or PR, as well as the total number of PR expressing cells within the arcuate nucleus, was determined. Approximately 75% and 55% of tyrosine hydroxylase neurones expressed ERalpha and PR, respectively. Levels of steroid receptor expression within TIDA neurones remained fairly constant, except for an increase in ERalpha on days 12 and 19 of pregnancy compared to dioestrous and lactation day 5. The presence of steroid receptors on TIDA neurones during pregnancy and lactation supports the concept of a direct effect of steroid hormones on these neurones at this time. Thus, steroid hormones may directly act on TIDA neurones to regulate maternal prolactin secretion. The relatively stable level of expression during late pregnancy suggests that a shift in steroid receptor expression during late pregnancy does not contribute to the change in TIDA responsiveness to prolactin at this time.

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.

Anti-tumor effect of l-deprenyl is associated with enhanced central and peripheral neurotransmission and immune reactivity in rats with carcinogen-induced mammary tumors

l-Deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, has previously been shown to improve immune responses and restore noradrenergic (NA) nerve fibers in the spleen of old rats. In tumor-bearing rats, l-deprenyl inhibited tumor incidence and enhanced tuberoinfundibular dopaminergic (TIDA) neurotransmission in the hypothalamus. The aim of the present study was to investigate whether alterations in sympathetic NA activity and cellular immune responses in the spleen, and TIDA activity in the hypothalamus, accompany deprenyl-induced regression of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced mammary tumors. Rats with DMBA-induced mammary tumors were treated with 0, 2.5 mg, or 5.0 mg/kg body weight of deprenyl daily for 13 weeks. Saline-treated tumor-bearing rats exhibited reduced splenic IL-2 and IFN-γ levels, and lowered splenic norepinephrine (NE) concentration and hypothalamic dopaminergic activity, compared to rats without tumors. In contrast, treatment with 2.5 mg/kg and 5.0 mg/kg of deprenyl reduced the number and size of mammary tumors. Deprenyl-induced tumor regression was accompanied by increased immune measures in the spleen, including enhanced IL-2 and IFN-γ production, and NK cell activity. Neural measures enhanced by deprenyl included NE concentration in the spleen and TIDA neuronal activity in the hypothalamus. These results suggest that (1) mammary tumorigenesis is associated with the inhibition of sympathetic NA activity in the spleen, TIDA activity in the hypothalamus, and cell-mediated immunity, and (2) reversal of the inhibition of catecholaminergic neuronal activities of the central nervous system and peripheral nervous system by deprenyl may enhance anti-tumor immunity.

Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation.

Considerable evidence suggest that some responses to smoking and nicotine are mediated by forebrain beta-endorphinergic opioid mechanisms. It has also been demonstrated that nicotine stimulates rat tuberoinfundibular dopaminergic activity. Since we have proposed that interactions between mediobasohypothalamic (MBH) dopaminergic and beta-endorphinergic mechanisms have a key role in neuroendocrine integration, we investigated the effects of chronic nicotine treatment and withdrawal on: (1) MBH concentrations of proopiomelanocortin (POMC, precursor for beta-endorphin biosynthesis) mRNA; (2) MBH concentrations of tyrosine hydroxylase (TH, rate limiting enzyme in catecholamine biosynthesis) mRNA; (3) corresponding serum prolacin, corticosterone, luteinizing hormone (LH), and testosterone concentrations. POMC and TH mRNA levels were measured by RNase protection/solution hybridization assay; serum hormone levels were measured by radioimmunoassay. Adult male rats received subcutaneous injections of either nicotine or saline during the dark period of each day on an increasing frequency (1-3 injections/day) and dosage (0.4-0.5 mg nicotine/kg body weight) schedule over 4 weeks. The rats were sacrificed after 4 weeks treatment and at 1, 3, 7, 14 and 21 days withdrawal. Chronic daily nicotine administration induced significant changes in serum corticosterone, serum prolactin, MBH TH mRNA, and MBH POMC mRNA concentrations that tended to persist through day 3 of withdrawal; serum prolactin and MBH POMC mRNA concentrations were suppressed whereas serum corticosterone and MBH TH mRNA concentrations were stimulated. None of the parameters were significantly different from control levels following 7 or more days of withdrawal from nicotine, except for a significant decrease of MBH POMC mRNA concentrations on day 21. Chronic daily nicotine or withdrawal did not significantly alter serum LH or testosterone concentrations. These results suggest that chronic nicotine inhibited POMC gene expression and thus, probably, biosynthesis of beta-endorphin and other opiomelanocortins. We hypothesize that suppression of forebrain beta-endorphin synthesis in response to long-term nicotine exposure produces a chronically opioid deficient condition which may play an important role in maintaining nicotine self-administration and in mediating some changes during the nicotine withdrawal syndrome.

Norepinephrine Content in the Paraventicular Nucleus of the Hypothalamus as a Function of Photoperiod and Dopaminergic Tone

The decline in the release of various anterior pituitary hormones, particularly prolactin (PRL), as a result of exposure to inhibitory, short-day photoperiods in long-day breeders is a well-documented phenomenon. This alteration in the hypothalamic-hypophyseal-gonadal axis is largely controlled by changes in the duration of the nocturnal melatonin pulse secreted by the pineal gland. Increased duration of melatonin secretion serves to increase the inhibitory activity of the tuberoinfundibular dopaminergic (TIDA) neurons, which in turn suppress PRL release and synthesis. However, other hypothalamic factors also appear to stimulate anterior pituitary function, working in concert with changes in TIDA activity to modulate circulating PRL levels under different photoperiod conditions. Past work from this laboratory has suggested that neurochemical changes at the level of the hypothalamic paraventricular nuclei (PVN), particularly changes in norepinephrine (NE) activity, may represent one of these modulatory influences. The current study investigated potential alterations in NF, content within the PVN during the early stages of short-day exposure in Siberian hamsters. In addition, the interaction of NE content with the modulatory dopamine (DA) system was investigated via administration of a DA agonist (CD154) or antagonist (pimozide). Hamsters received CB 154 (500 micrograms), pimozide (45 micrograms), or control solution via the drinking water under either long days (16L:8D) or short days (10L:14D), and were sacrificed at 1, 3, or 5 wk of photoperiod and drug treatment. The brains were removed, and the PVN microdissected from the hypothalamus and analyzed for catecholamine content using high-pressure liquid chromatography with electrochemical detection (HPLC-EC). The results revealed the expected stimulation of circulating PRL under both photoperiods following pimozide administration, as well as the expected trend toward an accelerated suppression of PRL under short days induced by CB 154. For control animals, there were no changes in NE content, or the ratio of 3-methoxy-4-hydroxyphenyglycol (MHPG)/ NE in long-day exposed animalx, but for short-day animals, both NE content and the ratio of MHPG/NE declined over time. Administration of CB 154 had only a marginal effect on NE content and the ratio of MHPG/ NE, but pimozide administration resulted in a decline in NE content and an increase in the MHPG/NE ratio under short days, and an increase in NE content and the MHPG/NE ratio over time for long-day animals. These results suggest that both photoperiod and administration of a DA antagonist that increases circulating PRL levels induce alterations in NE terminal activity within the hypothalamic PVN.

Exposure to a Short Photoperiod Increases Sensitivity to Dopamine Inhibition of Prolactin Release from Siberian Hamster Pituitary

Prolactin (PRL) secretion from the anterior pituitary is tonically controlled by the activity of the hypothalamic tuberoinfundibular dopaminergic (TIDA) system. Changes in TIDA activity have been associated with the decrease in basal PRL levels shown by hamsters exposed to a short-day photoperiod. Potential concurrent changes in the sensitivity of pituitary lactotropes to the inhibitory actions of dopamine on PRL release were investigated in tissue harvested from animals that had been preexposed to either a stimulatory, long-day 16-hour-light:8-hour-dark (16L:8D) photoperiod, or to a nonstimulatory, short-day (10L:14D) photoperiod for 8-10 weeks. Tissue was maintained in a perifusion tissue culture system and received a 1-hour pulse of varying concentrations of dopamine (DA) shortly after the equilibration period. Fractions of the media were collected every 1/2 h and PRL concentrations in each sample determined via radioimmunoassay. At the highest concentration of DA (10(-6) M), a highly significant inhibition of PRL levels was seen for both 16L and 10L pituitaries. At both mid range concentrations of DA (10(-7) and 10(-8) M), both tissue types showed a significant suppression of PRL, but the reduction was greater for tissue that had been obtained from 10L animals. At the lowest concentration of DA (10(-9) M), a significant suppression of PRL occurred for tissue harvested from 10L animals, but not for tissue taken from 16L animals. These results indicate that the responsiveness of anterior pituitary tissue to the inhibitory effects of DA are altered by photoperiod exposure, and this change is likely a consequence of changes in the characteristics of the D2 receptor population on pituitary lactotropes. Short-day-induced increases in sensitivity to the inhibitory effects of DA may be due to increases in receptor number, or to increased affinity of the D2 receptor for its ligand.

Photoperiod effects on neurohypophyseal and tuberoinfundibular dopamine metabolism in the male hamster.

Exposure of golden hamsters to a short photoperiod (< 12.5 h light/day) leads to suppression of gonadal function secondary to reduced gonadotropin and PRL secretion. PRL secretion is decreased despite a reduction of tuberoinfundibular dopaminergic activity. In the present study, the ability of photoperiod to affect tuberohypophyseal dopamine (DA) turnover was evaluated in long day (LD; 16 h of light, 8 h of darkness) and short day (SD; 8 h of light, 16 h of darkness) male hamsters. Exposure to SD led to decreases in testicular weight within 10 weeks and decreases in plasma PRL levels within 1 week. DA turnover in the neurointermediate lobe of the pituitary, as estimated by measuring the depletion of DA 60 min after tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine (250 mg/kg), was significantly elevated 1 and 4 weeks after transfer to SD, but returned by 10 weeks to the levels seen in LD animals. After 14 days of SD exposure an enhanced lactotroph sensitivity to DA was demonstrated and may also have contributed to suppression of PRL levels. Similarly to the findings of previous studies, DA turnover in the median eminence was depressed in animals housed in SD. The DA content of the anterior pituitary was not significantly affected by photoperiod. The data from this study suggest that decreases in PRL secretion associated with the transfer of hamsters from LD to SD conditions are at least in part caused by an increase in DA turnover by neurohypophyseal neurons. However, the involvement of other PRL-inhibiting or -stimulating factors in mediating the effects of photoperiod on PRL secretion cannot be ruled out.

Basal and haloperidol-stimulated prolactin and symptoms of nonaffective and affective psychoses in neuroleptic-free men

The prolactin (PRL) response to 0.5 mg of intravenous haloperidol (HPL) IV may be a measure of tuberoinfundibular dopaminergic activity. Our earlier reports, using multidiagnostic strategies in schizophrenia, suggested that psychoses characterized by the absence of affective syndromes (Keks et al 1990) and the presence of thought disorder and passivity delusions (Keks et al 1992) are linked to blunted PRL responses. In this paper we evaluated the relationships between basal and HPL-stimulated PRL concentrations, and a number of potentially relevant symptom measures. Basal PRL was lower in patients without a depressive syndrome and suicidal ideation. Stimulated PRL was lower in patients without neurovegetative symptoms (versus patients with neurovegetative symptoms and controls), with depression (versus patients with no depression and controls) and those with disorder of associations (versus patients without association disturbance and controls). These findings can be interpreted as indicating a link between endocrine measures of dopaminergic function and a subtype of schizophrenic psychosis characterized by the presence of thinking disturbance in the absence of depression.

Possible role of the cytochrome P450-linked monooxygenase system in preventing δ9-tetrahydrocannabinol-induced stimulation of tuberoinfundibular dopaminergic activity in female rats

The administration of δ 9-tetrahydrocannabinol (THC) or related cannabinoids markedly affected neurobehavioral and neuroendocrine indices in male rodents but usually failed to affect those indices in females. We examined whether inhibition of the cytochrome P450-linked monooxygenase system in female rats is able to elicit the effects of THC on one of the most characteristic targets of cannabinoid action, tuberoinfundibular dopaminergic neurons, whose activity is known to increase after cannabinoid exposure in males. It was found that the administration of THC to ovariectomized rats acutely replaced with estradiol (to discard problems derived from differences in the estrogenic status) did not affect either dopamine and l-3,4-dihydroxyphenylacetic acid (DOPAC) contents and tyrosine hydroxylase activity in the medial basal hypothalamus or the density of D2-dopaminergic receptors in the anterior pituitary. However, the administration of THC to estrogen-replaced ovariectomized rats that had been pretreated with two separately administered inhibitors of cytochrome P450, piperonyl butoxide or metyrapone, significantly increased DOPAC content in the medial basal hypothalamus, with no changes in the other parameters. Collectively, these results indicate that the metabolism of THC to inactive compounds might play a protective role in females, counteracting the effects of this cannabinoid on tuberoinfundibular dopaminergic activity because pharmacological inhibition of cytochrome P450-linked monooxygenase system elicited a significant stimulation of these neurons by THC.

Neuroendocrinological function in Alzheimer's disease.

The neuroendocrine function is regulated by several neurotransmitters (acetylcholine, dopamine, somatostatin and noradrenaline) known to be reduced in brains of patients with Alzheimer's disease (AD). Moreover, the hypothalamus also has pathological changes. In spite of these findings suggesting neuroendocrine dysfunctions, this function has seldom been investigated in AD patients so far. We have compared patients with clinically 'probable' AD of mild-to-moderate severity with nondemented age- and sex-matched controls. Plasma levels of prolactin (PRL), growth hormone (GH) and thyroid-stimulating hormone (TSH) were measured by commercially available radioimmunoassays (RIA) before and after stimulation with metoclopramide, l-dopa or thyrotropin-releasing hormone. Basal plasma levels of beta-endorphin and beta-lipotropin were measured by RIA after high-performances liquid chromatography. Basal and stimulated plasma levels of PRL, GH, TSH and beta-lipotropin were similar in the two groups. Basal lamina levels of beta-endorphin were significantly higher in the patient group. Of doubtful clinical importance, this might be attributed to decreased tuberoinfundibular dopaminergic activity and has also been seen in patients with Parkinson's disease.

Effect of electrical stimulation of the ventromedial nucleus and the dorsomedial nucleus on the activity of tuberoinfundibular dopaminergic neurons.

Perikarya and terminals of tuberoinfundibular dopaminergic (TIDA) neurons are located in the arcuate nucleus (ARN) and in the median eminence (ME), respectively. Dopamine (DA) released from TIDA terminals in the ME inhibits prolactin secretion from the anterior pituitary. Anatomical studies have described the sources of afferents to ARN and ME, but not to TIDA neurons per se. The ventromedial nucleus (VMN) and the dorsomedial nucleus (DMN) of the hypothalamus project to ARN and ME and have a role in prolactin regulation. In the present study, VMN and DMN were investigated as possible sources of TIDA afferents. Alterations in the activity of TIDA neurons were estimated by measuring plasma concentrations of prolactin and the rates of DA synthesis (3,4-dihydroxyphenylalanine - DOPA - accumulation after administration of the decarboxylase inhibitor NSD 1015) and metabolism (concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid - DOPAC) in the ME following electrical stimulation of ARN, VMN, and DMN in ovariectomized female rats. Thirty minutes of bilateral stimulation of ARN or DMN increased DOPA accumulation in the ME; stimulation of the VMN had no effect. 5-Hydroxytryptamine synthesis in the ME was unaffected by stimulation of any region. Plasma prolactin levels declined during DMN stimulation, varying with the frequency and duration of the electrical stimulus. DA metabolism within TIDA neurons increased with DMN stimulation, as evidenced by increased DOPAC concentrations in the ME. In females whose basal TIDA activity has been increased by haloperidol treatment or decreased by bromocriptine treatment, DMN stimulation was still able to increase DOPA accumulation in the ME. The present data suggest the presence of stimulatory TIDA afferents originating from or passing through the DMN.

Prolactin release and tuberoinfundibular dopaminergic neuronal activity following single and double injections of morphine

It is well established that opiate agonists alter tuberoinfundibular dopaminergic activity and consequently prolactin release. The purpose of this study was to characterize the effects of morphine on prolactin secretion and tuberoinfundibular dopaminergic neuronal activity with respect to time after administration. Additionally, the effect of an initial morphine injection on the response produced by a second injection of morphine was determined. The rate of depletion of median eminence dopamine content following synthesis inhibition byα-methyl- p-tyrosine was used as an index of dopaminergic neuronal activity. Male rats given a single injection of morphine sulfate (15 mg/kg, s.c.) showed a significant increase in circulating prolactin levels and had a lower rate of median eminence dopamine turnover 1 h after injection. Four hours after injection, circulating prolactin levels were similar to those in vehicle treated rats, while dopamine turnover was significantly higher than controls. When two injections of morphine sulfate (15 mg/kg, s.c.) were given 4 h apart, the stimulation of prolactin release produced by the second injection was significantly attenuated. Although this second injection caused a significant decrease in dopamine turnover, the turnover rate following this injection was significantly greater than that following the initial injection. The combination of fluoxetine and 5-hydroxytryptophan (FLX/5-HTP) caused an initial increase in prolactin secretion with plasma values returning to basal levels by 4 h. When rats were pretreated with FLX/5-HTP instead of morphine, the prolactin response to an injection of morphine 4 h later was not attenuated. Similarly a FLX/5-HTP pretreatment had no influence on a second injection of FLX/5-HTP administered 4 h later. The attenuation of a secretory response to a second morphine injection is specific to prolactin, since the growth hormone responses to the initial and the second injections of morphine were the same. These results indicate that the response of tuberoinfundibular dopaminergic neurons to morphine is biphasic. Following morphine administration, dopamine turnover is initially decreased but by 4 h turnover is increased above pretreatment rates. These alterations in dopamine turnover affect prolactin secretion such that release is initially stimulated, but 4 h later the response to a second morphine stimulation is attenuated.

Decline of tuberoinfundibular dopaminergic function resulting from chronic hyperprolactinemia in rats.

The effect of hyperprolactinemia on tuberoinfundibular dopaminergic (TIDA) neurons was studied after sc transplantation of a PRL-secreting pituitary tumor (MtT.W15) to young female rats. TIDA activity was determined by measuring the concentration of dopamine (DA) in pituitary stalk portal blood, the uptake and release of [3H]DA by the median eminence in vitro, and the presynaptic DA receptor activity. Eight weeks after transplantation of the tumor, serum PRL increased to approximately 100 times higher values than those in nontumor-bearing animals. Both the DA concentration and the content in pituitary stalk blood collected from rats bearing tumors for 6 weeks were significantly lower than those in nontumor-bearing rats. Injection of a DA uptake blocker, nomifensine, significantly increased stalk blood DA in nontumor-bearing rats, but did not increase DA release in tumor-bearing rats. The uptake of [3H]DA in vitro by the median eminence of rats bearing pituitary tumors for 8 weeks was lower than that in control rats. Basal and electrically induced release of [3H]DA from the median eminence in vitro from rats with tumors for 8 weeks were also significantly lower than in rats without tumors. Piribedil, a DA receptor agonist, reduced stimulated release of [3H]DA in vitro from the median eminence of rats without tumors, presumably by activating presynaptic DA receptors. However, piribedil had no effect on release of [3H]DA from the median eminence of rats with tumors. These results indicate that chronic elevation of PRL can produce a decline in TIDA function.