Tuberoinfundibular Dopamine Neurons Research Articles

Responsiveness of tuberoinfundibular dopamine neurons in the aged female rat to the stimulatory actions of prolactin.

The autoregulatory feedback control of prolactin, which is mediated by tuberoinfundibular dopamine (DA) neurons, is altered in the aged rat; this is evidenced by increased circulating concentrations of prolactin and decreased activity of these neurons. In the present study the action of prolactin on tuberoinfundibular DA neurons in young and aged female rats was estimated by measuring the rate of DA synthesis (dopa accumulation following the administration of a decarboxylase inhibitor) in the median eminence. The rate of dopa accumulation in the median eminence of the aged (26 months) rat was reduced to 50-60% of that in the young (3 months) rat. The acute systemic administration of haloperidol, a DA antagonist which increases serum concentrations of prolactin or intracerebroventricular infusions of prolactin increased the rate of dopa accumulation in the median eminence of both young and aged rats by the same relative amount. The administration of haloperidol and prolactin increased the rate of DA synthesis to a greater extent in young than in aged rats. The administration of bromocriptine, a DA agonist which reduces serum concentrations of prolactin, decreased the rate of dopa accumulation in the median eminence of both young and aged rats. In young animals the intracerebroventricular administration of prolactin reversed the bromocriptine-induced decrease in DA synthesis in the median eminence after 4 h and caused a further increase after 12 h. Qualitatively similar effects were seen in the aged rats; however, prolactin-treated young rats had much higher levels of DA synthesis than aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of gonadal steroids on tuberoinfundibular and tuberohypophysial dopaminergic neuronal activity in male and female rats.

The activities of tuberoinfundibular and tuberohypophysial dopamine (DA) neurons were estimated by measuring the turnover of DA in terminals of these neurons in the median eminence and in the neural and intermediate lobes of the pituitary, respectively. The rate of DA turnover (alpha-methyltyrosine-induced decline of DA) in the median eminence was two to three times faster in females than in males, but no sexual differences in DA turnover rates were noted in the neural and intermediate lobes. Two weeks following gonadectomy the rate of DA turnover in the median eminence was increased in the male but decreased in the female. These effects were reversed by testosterone and estrogen replacement in gonadectomized males and females, respectively. Neither gonadectomy nor steroid replacement altered DA turnover in the neural or intermediate lobes of either males or females. These results indicate that estrogen stimulates and testosterone inhibits tuberoinfundibular DA neuronal activity while neither steroid affects tuberohypophysial DA neuronal activity.

Effects of different dopamine agonists and antagonists on post-menopausal hot flushes

The dopaminergic system seems to be involved in both pulsatile luteinizing hormone (LH) secretion and hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectiveness of dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessed scores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one of the following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergic agent, Liposom; the antidopaminergic drug, veralipride or the peripheral antidopaminergic agent, domperidone. All of these treatment regimens were effective in alleviating hot flushes, but the pharmacological agents proved to be more effective than the placebo. A direct dopaminergic action is hypothesized in the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through different indirect mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on tuberoinfundibular dopamine (TIDA) neurons with a secondary dopamine-like activity, or stimulation of the opioid system.

Activation of GABA receptors in the hypothalamus stimulates secretion of growth hormone and prolactin

Localized intracerebral microinjections of GABA, muscimol, picrotoxin and bicuculline were made in the anterior and basal hypothalamus to determine possible sites of action of GABA in the regulation of prolactin and growth hormone (GH) secretion. Studies were carried out in unanesthetized male rats with chronic indwelling atrial cannulae and intracerebral guide cannulae which permitted stress free blood sampling and intrahypothalamic injections, respectively. Preoptic/anterior hypothalamic area (PO/AHA) injection of muscimol (0.16 nmol) stimulated both prolactin and GH secretion. GABA (1600 nmol) stimulated prolactin. Bicuculline (0.016 and 0.16 nmol) inhibited GH secretion. Medial basal hypothalamic (MBH) injection of muscimol (0.1 and 1.0 nmol) and GABA (1000 nmol) stimulated prolactin but had no effect on GH secretion. Picrotoxin and bicuculline did not stimulate GH. These findings indicate that activation of PO/AHA GABAergic receptors facilitates secretion of GH and prolactin and activation of MBH GABAergic receptors stimulates secretion of prolactin. It is proposed that GABA inhibits somatostatin neurons in the PO/AHA to facilitate GH and inhibits tuberoinfundibular dopamine or GABA neurons in the MBH to stimulate prolactin.

Hypothalamic Monoamine Metabolism in Mice: Evaluation of Drug Challenges and Neurotoxic Insult

Hypothalamic monoamine metabolism was evaluated in male and female mice that were administered monosodium glutamate (MSG, 4 mg/g) on postnatal day 4. Hypothalamic dopamine (DA) content was reduced approximately by 22% across all experiments and pituitary DA content was also significantly decreased. Despite reductions in hypothalamic DA levels, MSG-treated mice did not exhibit significant reductions in the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Hypothalamic monoamine and metabolite profiles in MSG-treated and control mice were examined after the administration of pargyline (PAR), alpha-methyl-p-tyrosine (MPT) or reserpine (RES). DA turnover as indexed by PAR and MPT techniques were not as conclusive as the metabolite measures in suggesting an accelerated DA utilization. MSG-treated mice were more resistant to the DA-depleting actions of reserpine than were the controls. No alterations were found in hypothalamic norepinephrine metabolism in MSG-treated mice, however, after drug challenges, alterations were found in serotonin metabolism. These results indicate the extent and nature of the changes that occur in hypothalamic monoamine metabolism after neonatal MSG treatment. The DA neurons that survive MSG treatment appear to exhibit neurochemical characteristics dissimilar to those of tuberoinfundibular DA neurons. Additionally, the neuropharmacological actions of MPT, PAR and RES are discussed as they relate to hypothalamine monoamine metabolism in the mouse.

Studies on neuropeptide Y-catecholamine interactions in the hypothalamus and in the forebrain of the male rat. Relationship to neuroendocrine function

Neuropeptide Y-catecholamine interactions have been analyzed within the hypothalamus and in the forebrain of male rats by means of immunocytochemistry in combination with morphometry, quantitative histofluorimetry on catecholamine fluorescence in discrete catecholamine nerve terminal systems, biochemical analysis of catecholamines as well as by studies on serum levels of adenohypophyseal hormones vasopressin, adrenocortical hormones and angiotensin II using radioimmunoassay determinations. (1) Morphologic and morphometrical evidence indicates the existence of separate populations of neuropeptide Y and tyrosine hydroxylase immunoreactive nerve cell bodies in the parvo- and magnocellular components of the arcuate nucleus respectively. In addition, a significant codistribution of NPY immunoreactive nerve terminals and tyrosine hydroxylase immunoreactive nerve cell bodies were demonstrated in the ventrolateral part of the magnocellular component of the arcuate nucleus. (2) Immunocytochemical studies on the distribution of tyrosine hydroxylase, phenyl ethanolamine- N-methyltransferase and neuropeptide Y immunoreactive nerve terminal networks in the peri- and paraventricular hypothalamic nucleus indicated that these types of immunoreactive nerve terminals densely innervate the medial and anterior parvocellular part of the paraventricular hypothalamic nucleus and anterior periventricular hypothalamic nucleus. From studies on the pattern of terminal distribution results have been obtained compatible with the view that neuropeptide Y or a neuropeptide Y related peptide can be a comodulator in noradrenaline and adrenaline nerve terminal networks of these regions. (3) Acute intraventricular injections of neuropeptide Y (1.25 nmol) do not change dopamine and noradrenaline levels in any hypothalamic and telencephalic dopamine and noradrenaline nerve terminal system analyzed with the exception of the anteromedial frontal cortex, in which area a significant increase in the dopamine levels was observed as revealed biochemically. (4) By means of the tyrosine hydroxylase inhibition method it was possible to show that acute intraventricular injection of NPY (1.25 nmol) increased dopamine utilization in the medial and lateral palisade zone of the median eminence and in the anteromedial frontal cortex and reduced noradrenaline utilization in the parvocellular part of the paraventricular hypothalamic nucleus, while dopamine utilization was not influenced in the nucleus caudatus putamen, nucleus accumbens or in the tuberculum olfactorium. (5) In the intraventricular experiments reported above neuropeptide Y (1.25 nmol, 1 h) reduced the serum levels of thyreotropin stimulating hormone, prolactin and luteinizing hormone and increased serum corticosterone, adrenocorticotrophin, vasopressin, angiotensin II and aldosterone levels. The presence of the tyrosine hydroxylase inhibitor by itself, increased corticosterone, adrenocorticotrophin and aldosterone serum levels and reduced serum luteinizing hormone levels. Neuropeptide Y together with the tyrosine hydroxylase inhibitor further enhanced the adrenocorticotrophin, angiotensin II and aldosterone serum levels seen with the inhibitor, but could no longer produce its excitatory and inhibitory effects on serum corticosterone and luteinizing hormone levels, respectively. Vasopressin serum levels were increased to the same extent in the absence or presence of tyrosine hydroxylase inhibition. The present morphological, neurochemical and functional studies indicate that neuropeptide Y given intraventricularly inhibit the secretion of prolactin, luteinizing and thyreotropin stimulating hormones probably by activation mainly of neuropeptide Y receptors located in the somadendritic region of the arcuate DA cell bodies, leading to increased activity in inhibitory tubero-infundibular dopamine neurons. In addition, it is suggested that the ability of neuropeptide Y to increase adrenocorticotrophin and corticosterone secretion is at least in part related to its ability to reduce noradrenaline turnover in the parvocellular part of the paraventricular hypothalamic nucleus, rich in corticotrophin releasing factor immunoreactive nerve cell bodies. It is speculated that neuropeptide Y as a comodulator in the noradrenaline nerve terminals in this area may enhance the excitatory actions of noradrenaline on the corticotrophin releasing factor immunoreactive nerve cells. Such an action will lead to increases of corticotrophin releasing factor neuronal activity and of adrenocorticotrophin hormone secretion producing a feedback response, which may reduce noradrenaline turnover exclusively in this nucleus as was observed in the present experiments. The increase in aldosterone may be induced by the increased adrenocorticotrophin serum levels but the increase in vasopressin secretion and in angiotensin II serum levels may be secondary to the hypotensive activity of neuropeptide Y. Finally, it is suggested that neuropeptide Y mechanisms can increase dopamine synthesis and release in the anteromedial frontal cortex. Thus, neuropeptide Y mechanisms may participate in the control of cortical functions at least partly by regulating the cortical dopamine neurotransmission.

Acute effects of morphine on neurochemical estimates of activity of incertohypothalamic dopaminergic neurons in the male rat

The effects of an acute injection of morphine on the activities of mesotelencephalic, tuberoinfundibular and incertohypothalamic dopamine (DA) neurons was estimated by measuring: (1) the rate of turnover of DA (decline after α-methyltyrosine); and (2) the concentration of the DA metabolite, dihydroxyphenylacetic acid (DOPAC), in brain regions containing cell bodies or terminals of these neurons (i.e. nucleus accumbens, striatum, median eminence and various hypothalamic nuclei). The rate of turnover of DA and the concentration of DOPAC were increased in nucleus accumbens and striatum and decreased in the median eminence 60 min after the administration of morphine (10 mg/kg, s.c.). Morphine increased the rate of turnover of DA and the concentration of DOPAC in brain regions containing both cell bodies (periventricular nucleus and medial zona incerta) and terminals (medial preoptic, preopticosuprachiasmatic and dorsomedial nuclei) of incertohypothalamic DA neurons. The effects of morphine in all brain regions were blocked by pretreatment with naltrexone. These results indicate that incertohypothalamic DA neurons are stimulated by the acute administration of morphine, and in this respect they resemble the extrahypothalamic mesotelencephalic DA neurons rather than hypothalamic tuberoinfundibular DA neurons.

Strain differences in pituitary prolactin content: Relationship to number of hypothalamic dopamine neurons

BALB/cJ mice have more tuberoinfundibular dopamine neurons, and thus greater tyrosine hydroxylase activity, than CBA/J mice. Strain differences in the synthesis and release of prolactin would also be predicted since dopamine released from the tuberoinfundibular neurons is the prolactin inhibitory factor which plays a role in the regulation of both prolactin synthesis and release. As expected, CBA/J mice, with fewer dopamine neurons, synthesized and released significantly more prolactin than BALB/cJ mice; that is, both pituitary and serum prolactin concentrations were greater in CBA/J mice. To determine if there were more cells containing prolacting prolactin or more prolactin per cell, pituitaries were stained with antibodies to prolactin and densitometric analysis made of both the average staining per unit area and total staining per pituitary. For both indices CBA/J mice had more staining than BALB/cJ mice. Using these criteria the difference in staining was attributed to more prolactin-stained lactotrophs in the CBA/J strain. Although no differences in the number of acidophils demonstrated by Pearse Trichrome method were observed, acidophils from BALB/cJ mice appeared smaller and contained less cytoplasm than those from CBA/J mice. We conclude that strain differences in the number of tuberoinfundibular dopamine neurons are inversely related to the number of immunocytochemically demonstrable prolactin-containing cells in the anterior pituitary.

Mecamylamine pretreatment counteracts cigarette smoke induced changes in hypothalamic catecholamine neuron systems and in anterior pituitary function.

We have studied the effects of acute, intermittent exposure to tobacco smoke on discrete hypothalamic CA nerve terminal networks and on neuroendocrine function by means of quantitative histofluorimetrical determinations of catecholamine (CA) fluorescence in sections of rat brain and by radioimmunoassay procedures for hormones. Acute intermittent exposure to cigarette smoke induced a lowering of NA levels and increased NA turnover in discrete hypothalamic nerve terminal regions. This exposure also induced increases in DA turnover in the median eminence. The cigarette smoke lowered TSH, prolactin, LH and FSH serum levels, but induced an increase in serum corticosterone concentrations. To determine if the above mentioned changes in neuroendocrine function were nicotine mediated, a cholinergic nicotine-like blocking agent, mecamylamine, was administered prior to exposure to cigarette smoke. Pretreatment with mecamylamine (1.0 mg kg-1) counteracted the cigarette smoke induced changes in CA levels and turnover in all hypothalamic CA nerve terminal regions as well as the changes in serum levels of the pituitary hormones and corticosterone. It is suggested that acute intermittent exposure to cigarette smoke, via its nicotine component, lowers TSH, prolactin, LH and FSH secretion at least in part through activation of the tubero-infundibular DA neurons. Furthermore, the nicotine component of the cigarette smoke is suggested to induce the increase in corticosterone serum levels via increasing NA turnover in the paraventricular hypothalamic nucleus.

The effect of long-term diethylstilbestrol treatment or hyperprolactinemia on the response of the tuberoinfundibular dopamine neurons to elevated prolactin

Adult male rats were rendered hyperprolactinemic by two different methods. Some animals received subcutaneous implants of diethylstilbestrol (DES) or empty capsules. After 2 months the capsules were removed. Other rats received 3 anterior pituitary homografts under the kidney capsule or had sham surgery. The DES-treated rats were killed 8 months after capsule removal, while pituitary-grafted rats were killed 4 or 12 months after surgery. The DES-treated rats had hyperplastic anterior pituitaries, and both the DES-treated rats and the rats with anterior pituitary homografts were hyperprolactinemic. The activity of the TIDA neurons, as evidenced by dopamine (DA) synthesis in the median eminence (ME), was markedly and comparably elevated in both of these experimental groups of rats when compared to their respective controls. These data: (1) show that the maintenance of hyperplastic pituitaries 8 months after DES withdrawal is not due to impaired function of the TIDA neurons; and (2) provide no evidence for a neurotoxic effect of prolonged hyperprolactinemia on the response of the TIDA neurons to elevated PRL.

Rapid effects of hyperprolactinemia on basal prolactin secretion and dopamine turnover in the medial and lateral median eminence.

Subcutaneous injections of ovine PRL (oPRL; 4 mg/kg) were used to study the negative feedback of PRL on its own secretion in the adult male rat. A single injection of oPRL significantly suppressed the endogenous secretion of rat PRL within 3-4 h, an effect that persisted until the oPRL was substantially cleared from the circulation some 4-6 h later. In rats injected every 8 h, rat PRL levels were suppressed for 48 h, while LH titers increased significantly at some time points, and FSH levels varied in the same direction as LH. LHRH concentrations in 10 brain structures containing cell bodies, axons, and terminal boutons were not affected by 48 h of oPRL treatment. Dopamine turnover in both medial and lateral aspects of the median eminence increased as early as 2 h after the first oPRL injection and remained elevated after 10 and 26 h of oPRL exposure. The results are consistent with the hypothesis that the tuberoinfundibular dopamine neurons mediate the negative feedback action of PRL on its own secretion. Further, under these experimental conditions, neurons projecting to both medial and lateral aspects of the median eminence are equally sensitive to elevated PRL levels.

Adenohypophysial dopamine content and prolactin secretion in the aged male and female rat.

In male rats the concentrations of dopamine (DA) in the adenohypophysis and of PRL in serum increase progressively with age. The increase in the DA content is not a consequence of reduced metabolism of DA, since the activities of the enzymes that deaminate (monoamine oxidase) and O-methylate (catechol-O-methyltransferase) this amine are not reduced in the anterior pituitary of aged male rats; indeed, both type A and B monoamine oxidase activities are increased in the pituitaries of aged rats. The increased DA present in the aged adenohypophysis is not in a static pool but, as in young rats, is rapidly decreased by pharmacological treatments that reduce the activity of tuberoinfundibular DA neurons (gamma-butyrolactone), reduce the synthesis of DA in these neurons (alpha-methyltyrosine), or block DA receptors (haloperidol) in the adenohypophysis. All of these treatments increased serum PRL levels and reduced DA concentrations in the adenohypophysis of both young and aged rats. Similarly, in female rats, where age-related differences in BW and body composition are minimized, serum PRL concentrations and DA concentrations in the adenohypophysis of both young and aged rats changed in the same way after the administration of a DA agonist (apomorphine) or a DA antagonist (haloperidol). Apomorphine reversed the alpha-methyltyrosine-induced increase in serum PRL concentrations and the decrease in anterior pituitary DA content in both young and aged rats, although the latter animals appear to be more responsive to this drug. Similarly, aged rats were more sensitive to the increase in serum PRL concentrations and the decrease in anterior pituitary DA content caused by haloperidol. The actions of acute and chronically administered haloperidol are reversible, with the reduced DA content of the adenohypophysis and the elevated serum concentrations of PRL returning to respective pretreatment levels in both young and aged rats once treatment stops. The time course for recovery of serum PRL levels and anterior pituitary DA contents after both the acute and chronic haloperidol treatment is of longer duration in the aged rat, which is consistent with a decreased rate of clearance of haloperidol in these animals. Twelve daily injections of bromocriptine, a DA agonist, reduced serum PRL and anterior pituitary DA concentrations in both young and aged rats, and these effects persisted for up to 7 days after the injections were stopped.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoprolactinemia induced by hypophysectomy and long-term bromocriptine treatment decreases tuberoinfundibular dopaminergic neuronal activity and the responsiveness of these neurons to prolactin.

The effect of long-term decreases in circulating concentrations of prolactin was determined on the responsiveness of tuberoinfundibular dopamine (DA) neurons to this hormone. The activity of these neurons in ovariectomized rats was estimated by measuring the rate of DA synthesis (DOPA accumulation after the administration of a decarboxylase inhibitor) in the median eminence at various times after serum concentrations of prolactin had been reduced by hypophysectomy or the chronic administration of a DA agonist (bromocriptine, 3 mg/kg/day). The concentration of DA in the median eminence, but not in striatum, declined progressively up to 12 days after hypophysectomy, but did not change at any time during bromocriptine treatment. On the other hand, norepinephrine concentrations in the median eminence were increased 12 days after both treatments. Within 24 h after hypophysectomy or the first injection of bromocriptine the rate of DA synthesis in the median eminence was decreased; this decrease was maintained for at least 12 days suggesting that tuberoinfundibular DA neuronal activity is normally maintained by endogenous prolactin. Intracerebroventricular (ICV) injections of prolactin (10 micrograms, 12 h prior to sacrifice) increased the rate of DA synthesis in the median eminence of control, 24-hour hypophysectomized and 24-hour bromocriptine-treated rats. After longer periods (6-12 days) of bromocriptine treatment or after hypophysectomy the responsiveness of tuberoinfundibular DA neurons to prolactin was reduced. Dose-response studies revealed that the sensitivity and magnitude of response to ICV prolactin was markedly reduced in 12-day hypophysectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential regulation of tuberohypophysial dopaminergic neurons terminating in the intermediate lobe and in the neural lobe of the rat pituitary gland.

In order to characterize the properties of tuberohypophysial dopaminergic neurons which terminate in the intermediate (IL) and neural (NL) lobes of the pituitary gland a technique was developed which permitted the selective dissection of the rat pituitary into its three distinct lobes (NL, IL and anterior lobe, AL). The success of the dissection was evaluated histologically and biochemically by measuring the distribution of peptide hormones characteristic of the dissected regions. As would be predicted, prolactin was found almost exclusively in the AL, arginine-vasopressin in the NL and alpha-melanotropin in the IL. Over two-thirds of total immunoreactive beta-endorphin was located in the IL and less than 30% was found in the AL. The concentration of dopamine (DA) was greater in the IL than in the NL, but the rate of turnover of the amine was approximately the same suggesting that the basal activity of tuberohypophysial DA neurons is similar in both regions. On the other hand, the turnover of DA in the IL, but not NL, was increased following the administration of a DA antagonist (haloperidol) and decreased following a DA agonist (bromocriptine). Thus, the activity of DA neurons terminating in the IL is regulated, at least in part, by DA receptor-mediated mechanisms and in this regard these neurons resemble DA neurons terminating in the nucleus accumbens and striatum. Since DA turnover in NL was not altered by the administration of haloperidol or bromocriptine it is proposed that these neurons lack DA receptor-mediated regulatory mechanisms and thus resemble tuberoinfundibular DA neurons terminating in the median eminence.

Effects of estradiol and prolactin on incertohypothalamic dopaminergic neurons in the male rat

The activity of incertohypothalamic, tuberoinfundibular, mesolimbic and nigrostriatal dopamine (DA) neurons was estimated by measuring the rate of turnover of DA (decline of DA after α-methyltyrosine) in brain regions containing the cell bodies and terminals of these neurons. Estradiol benzoate (25 μg/kg/day × 3; s.c.), markedly increased the concentration of prolactin in plasma and increased the rate of turnover of DA in median eminence, but failed to alter DA neuronal activity in the striatum or nucleus accumbens. An intracerebroventricular injection of prolactin (10 μg/rat, 12 h) mimicked the effect of estradiol on the turnover of DA in the median eminence. Within the incertohypothalamic DA system, both estradiol and prolactin increased DA turnover in the dorsomedial nucleus but decreased DA turnover in the rostral periventricular, medial preoptic and preoptico-suprachiasmatic nuclei. Hypophysectomy decreased the tonic activity of tuberoinfundibular DA neurons, but failed to alter the activity of incertohypothalamic DA neurons. The stimulatory effects of estrogen on DA turnover in the median eminence and dorsomedial nucleus, and the inhibitory effects of this hormone on rostral hypothalamus DA neurons were blocked by hypophysectomy. Taken together these results suggest that estradiol-induced changes in intact male rats are mediated by prolactin. Estradiol increased incertohypothalamic DA neuronal activity in the medial preoptic and preoptic-suprachiasmatic nuclei of hypophysectomized rats suggesting that in the absence of circulating prolactin, estradiol has a direct stimulatory effect on incertohypothalamic DA neurons in the rostral, periventricular hypothalamus. Thus, while incertohypothalamic DA neurons resemble the major ascending extrahypothalamic DA neurons in their responsiveness to DA agonists and antagonists, they differ from the mesolimbic and nigrostriatal DA neurons in that they are also responsive to estrogen and prolactin, and in this regard resemble tuberoinfundibular DA neurons.

Differential effects of mecamylamine on the nicotine induced changes in amine levels and turnover in hypothalamic dopamine and noradrenaline nerve terminal systems and in the secretion of adenohypophyseal hormones in the castrated female rat. Evidence for involvement of cholinergic nicotine-like receptors.

The effects of mecamylamine on the nicotine induced changes in hypothalamic catecholamine (CA) levels and turnover in female rats ovariectomized for one month have been evaluated using a quantitative microfluorimetric approach to measure CA levels in sections of brains treated according to the Falck-Hillarp procedure for the cellular demonstration of CA. In the same group of animals the serum prolactin, LH, FSH, TSH, GH and corticosterone levels were measured using radioimmunoassay procedures. The nicotine treatment induced a significant depletion of amine stores and an increase of amine turnover in dopamine (DA) and noradrenaline (NA) nerve terminals of the median eminence and of the peri- and paraventricular and dorsomedial NA systems of the hypothalamus using the tyrosine hydroxylase (TH) inhibition model. Mecamylamine (2 X 1 mg/kg) partly counteracted the nicotine induced reduction of amine stores in peri- (anterior part) and paraventricular NA nerve terminal systems as well as the nicotine induced increase of NA turnover in these systems, but not the action of nicotine on the CA systems of the median eminence. Nicotine (4 X 2 mg/kg) significantly and markedly reduced prolactin, LH, TSH, and GH secretion increased corticosterone secretin but did not influence FSH secretion. These effects were partly counteracted by mecamylamine (2 X 1 mg/kg) in the case of prolactin, LH and TSH secretion but not in the case of GH and corticosterone secretion. Taken together the results show that mecamylamine treatment (2 X 1 mg/kg) differentially counteract nicotine induced changes of amine levels and turnover in peri- (anterior part) and paraventricular NA nerve terminal systems indicating that the cholinergic nicotine-like receptors located in peri- (anterior part) and paraventricular areas may be more susceptible to the blocking activity of mecamylamine than those located in the median eminence area. Furthermore, the inhibitory effects of nicotine on prolactin, LH and TSH secretion are differentially counteracted by mecamylamine. In conclusion, other inhibitory systems than the tuberoinfundibular DA neurons in the MPZ and LPZ must also be involved in mediating the inhibitory effects of nicotine on prolactin, LH and TSH secretion and different types of cholinergic nicotine-like receptors may exist.

Function of Tuberoinfundibular Dopamine Neurons in Pargyline- and Reserpine-Treated Rats

The synthesis and release of dopamine within tuberoinfundibular neurons were studied in rats treated with reserpine and/or pargyline. The effect of reserpine to elevate the serum concentration of prolactin was accompanied by a 70-80% reduction in the concentration of dopamine in pituitary stalk plasma. When rats were given pargyline (75 mg/kg) prior to the administration of reserpine (2.5 mg/kg), the reserpine-induced alterations in serum prolactin and stalk plasma dopamine concentrations were completely prevented. Pargyline treatment alone resulted in a significant elevation of the concentration of dopamine in pituitary stalk plasma and a reduction in the serum concentration of prolactin. The effects of reserpine and pargyline on the synthesis of dopamine in the median eminence were found to be the opposite of their effects on the release of dopamine. Dopamine synthesis (as estimated by the accumulation of dihydroxyphenylalanine after inhibition of decarboxylase activity) was increased after reserpine and decreased after pargyline administration. Thus, these data serve to illustrate the point that, under certain conditions, the release of dopamine from tuberoinfundibular neurons can be dissociated from its rate of synthesis. More importantly, it appears the release of dopamine from these neurons is dependent upon intact dopamine storage function and monoamine oxidase activity, in addition to continued catecholamine synthesis.

Uptake and release of [ 3H]dopamine by the median eminence: Evidence for presynaptic dopaminergic receptors and for dopaminergic feedback inhibition

The accumulation and release of [ 3H]dopamine by the median eminence in vitro was studied after treatments with different pharmacological agents, to determine whether such a procedure would be useful for measuring neuronal activity in the tuberoinfundibular dopaminergic system. The accumulation of [ 3H]dopamine was temperature, time, and sodium dependent, and reduced by unlabelled dopamine and by a potent dopamine uptake blocker, nomifensine. The outflow of tritium was studied after blocking the oxidative deamination of dopamine by nialamide. The outflow of tritium was elicited consistently by biphasic square wave electrical pulses and by high molarity potassium ions. The response to electrical stimulation was dependent largely on calcium and partially on sodium. The response to high molarity potassium ions was reduced in the absence of calcium ions. The response to electrical stimulation was increased by nomifensine and by a dopaminergic antagonist, haloperidol, and was reduced by dopamine and by a dopaminergic agonist, piribedil. The inhibitory action of dopamine was antagonized by haloperidol. These results indicate the existence of uptake and release mechanisms in the tuberoinfundibular dopamine neurons, and suggest that dopamine may inhibit its own release via dopaminergic receptors. This in vitro method may be useful for measuring dopamine uptake and release by tuberoinfundibular dopaminergic neurons.

On the presence of autoreceptors on dopamine neurons in different brain regions.

The alpha-methyltyrosine-induced disappearance of dopamine was inhibited by the selective dopamine autoreceptor agonist B-HT 920 in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex, and the rostral part of the cerebral cortex of the rat. These inhibitory actions of B-HT 920 were almost completely reversed by the dopamine receptor antagonist haloperidol, indicating that they were caused by a stimulation of dopamine autoreceptors. In the caudal cortex and the cerebellum, the effects of B-HT 920 and haloperidol were less clear, perhaps due to a low concentration of dopamine and to the occurrence of this dopamine in both dopamine and noradrenaline neurons. In the hypothalamus, B-HT 920 and haloperidol did not change the alpha-methyltyrosine-induced disappearance of dopamine in agreement with previous findings that the tubero-infundibular dopamine neurons are not regulated via dopamine receptors.

Biphasic effect of 5-methoxy-N,N-dimethyltryptamine on rat prolactin secretion

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT), a potent serotonin (5-HT) receptor agonist, exerts a biphasic effect on rat prolactin (PRL) secretion. 5-MeODMT (2.5–10 mg/kg) produces a marked, dose-related but short-lasting (less than 30 min) rise in serum PRL levels. At intervals longer than 30 min, 5-MeODMT (1–15 mg/kg) inhibits the stimulation of PRL secretion by another 5-HT agonist, 5-methoxytryptamine (5-MeOT, 10 mg/kg), by α-methylparatyrosine (50 mg/kg) or by haloperidol (0.15 mg/kg). 5-MeODMT did not significantly alter the PRL-releasing effect of γ-butyrolactone (500 mg/kg) or a higher dose of haloperidol (1 mg/kg). The biphasic effect of 5-MeODMT on rat PRL secretion is shared by the centrally-acting 5-HT agonist quipazine, but not by 5-MeOT, an indole derivative excluded by the blood-brain barrier. The initial stimulation of PRL secretion by 5-MeODMT is probably due to its ability to activate postsynaptic 5-HT receptors. The subsequent inhibitory effect of 5-MeODMT appears to be due to increased functional activity of tuberoinfundibular dopamine neurons. The possible mechanisms underlying the inhibitory effect of 5-MeODMT on PRL release are discussed.