Dopamine Antagonist Sulpiride Research Articles

Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans.

Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366.

Preliminary Evaluation of Treatment With Long-Acting Estradiol Cypionate and Sulpiride for Advancing First Ovulation of Year in Postpartum Acyclic Mares

Two preliminary trials were performed to evaluate the efficacy of long-acting estradiol cypionate plus sulpiride treatment for hastening the first ovulation in postpartum acyclic mares. In 2010 (year 1) and 2012 (year 2), mares that had foaled in January or February and that were ≥7 ± 1 day postpartum were teased to a stallion to detect estrus and examined by transrectal ultrasonography 3 times weekly. Mares identified as acyclic were alternately assigned to treatments as follows: year 1—group ECP-SUL (n = 5)—same day intramuscular (IM) injection of 50-mg long-acting estradiol cypionate (ECP) plus 1.5-g long-acting sulpiride (SUL), or CON (n = 5)—control; year 2—ECP-SULX2 (n = 4)—IM injection of 100-mg ECP, followed 2 and 7 days later with IM injection of 1.5-g SUL, or CON (n = 5). When a follicle ≥35 mm in diameter, prominent uterine edema and a relaxed cervix were detected, an ovulation-inducing agent was administered. Examinations continued at 2- to 3-day intervals until ovulation was detected. Median (range) interval to ovulation did not differ in year 1 between SUL-ECP (76 days; 31–90 days) and CON mares (74 days; 35–98 days; P = 1.00), or in year 2 between ECP-SULX2 (48 days; 36–66 days) and CON mares (39 days; 39–71 days; P = .91). The injection of the dopamine antagonist sulpiride in a sustained release form in conjunction with the estrogen ECP failed to shorten the interval to the first ovulation of the year in these two groups of postpartum acyclic mares.

The antipsychotic drug sulpiride induces insulin intolerance but does not affect body weight in adult male mice

Research studies have shown that chronic administration of some antipsychotic drugs induces obesity in female but not in male. To explore the mechanisms involved in this effect, we administrated the dopamine antagonist sulpiride (40 mg/kg) or vehicle intraperitoneally to adult male mice during 45 days and then the glucose tolerance and serum levels of insulin, serum, and testicular testosterone and prolactin, and blood estrogen levels were evaluated. Chronic sulpiride administration did not affect body weight. However, prolactin levels and the area under the glucose and insulin curves were significantly elevated. Sulpiride significantly decreased testosterone and increased estrogen levels (p < 0.05). After prolonged administration, sulpiride did not affect body weight, so this lack of effect may be related to the impairment of insulin sensitivity which prevents body weight gain and deals with other effects of sulpiride that cause adiposity promotion such as hyperprolactinemia. Future studies must evaluate other neurotransmitters involved in food intake regulation such as histamine and serotonin.

Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, the mechanism of action is still unknown. Previous evidence showed that DA can inhibit pituitary vascular endothelial growth factor expression (VEGF), that may be involved in pituitary tumor growth. The aim of our study was to clarify whether VEGF secretion modulation might mediate the effects of DA agonists on cell proliferation in human NFA. We assessed DA receptor subtype 2 (DR2) expression in 20 NFA primary cultures, where we also investigated the effects of a selective DR2 agonist, cabergoline (Cab), on VEGF secretion and on cell viability. All NFA samples expressed α-subunit and DR2 was expressed in 11 samples. In DR2 expressing tumors, Cab significantly reduced cell viability (-25%; P<0.05) and VEGF secretion (-20%; P<0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. Cab antiproliferative effects were blocked by VEGF. Our data demonstrate that Cab, via DR2, inhibits cell viability also by reducing VEGF secretion in a selected group of NFA, supporting that DA agonists can be useful in the medical therapy of DR2 expressing NFA.

Dopamine Modulates the Voltage Response of Human Rod Photoreceptors by Inhibiting thehCurrent

The h current (I(h)) is a hyperpolarization-activated current that plays important roles in the physiological functions of different types of cells. In the retina of lower vertebrates, I(h) contributes to the rod responses to light stimuli by bringing the membrane potential back to the dark level in the presence of continuous light. The purpose of this study was to determine how dopamine modulates I(h) in human rods and regulates voltage responses. A patch-clamp recording technique was used on surgically excised human retinas to investigate the effects of dopamine on the I(h) of isolated rods. Dopamine was applied in the superfusate. Dopamine reversibly decreased the amplitude of the I(h) induced by hyperpolarizing voltage steps from a holding potential of -60 mV. At a voltage step of -100 mV, 20 μM dopamine decreased the amplitude of I(h). The D2 dopamine agonist quinpirole inhibited I(h), but the D1 agonist SKF-38393 had no effect. Dopamine-induced reduction of I(h) amplitude was blocked by the D2 dopamine antagonist sulpiride. Under current-clamp conditions, an injection of hyperpolarizing current steps to rods produced voltage responses that exhibited a gradual decay. Adding dopamine to the superfusate inhibited the decay in the voltage responses. Quinpirole also inhibited the voltage decay, whereas SKF-38393 was ineffective. Dopamine reduced I(h) through a D2 receptor and inhibited the gradual decay in the voltage response through a D2 receptor, indicating that dopamine slows the recovery phase of responses to light stimuli by inhibiting I(h) in human rods.

Clinical use of dopamine antagonist sulpiride to advance first ovulation in transitional mares

Artificial photoperiod treatment is currently the best method to hasten the first ovulation of the breeding season in winter anoestrus mares. However, this is not easy to apply in large herds of mares and, to be effective, has to be planned in the northern hemisphere in December at the latest. Pharmacological treatments have been proposed as alternatives: GnRH agonists, progesterone or its synthetic agonist Altrenogest, and dopamino-antagonists, as pherphenazine, domperidone or sulpiride. Dopamino-antagonists protocols, beginning at a given day of the year, gave controversial results in terms of hastening ovulation. The aim of this study was to evaluate the efficacy of an up-to-21-d long dopamine antagonist (sulpiride) treatment on mares at the beginning of the spring transition for its ability to hasten estrous cyclicity. In Study 1, 49 seasonally-acyclic standardbred mares, maintained in paddocks under natural photoperiod, were treated with 1 mg/kg/d sulpiride at the evidence of the first follicle with of 25 mm in diameter until ovulation for a maximum of 21 d (Group S 1; n = 34) or left untreated (Group C 1; n = 15). Group S 1 and C 1 mares showed a follicle of 35 mm in diameter after 8 and 22 d (median; P < 0.05) and ovulated after 18 and 43 d, respectively (median; P < 0.05). Twenty-two/26 and 6/15 mares of the Group S 1 and C 1 ovulated within 30 d from the beginning of the treatment, respectively (P < 0.05). All the mares of the study cycled until Autumn, unless they became pregnant. In Study 2, pregnancy rates after the first ovulation of the year of 22 acyclic standardbred mares maintained in paddocks under natural photo-period, treated following the same protocol as Study 1 (S 2), and 47 untreated mares (C 2) were compared. In Groups S 2 and C 2, 63.6% and 61.7% of the mares became pregnant after the first cycle (P > 0.05) and 50.0% and 61.1% of the remaining became pregnant in the following cycles (P > 0.05), respectively. Beginning with sulpiride treatment when follicles were 25 mm in diameter resulted in a significant advancement of cyclicity in non-photo-stimulated mares. Pregnancy rates after artificial insemination of treated mares were similar to those of untreated animals.

Hypothalamic Prolactin Receptor Messenger Ribonucleic Acid Levels, Prolactin Signaling, and Hyperprolactinemic Inhibition of Pulsatile Luteinizing Hormone Secretion Are Dependent on Estradiol

Hyperprolactinemia can reduce fertility and libido. Although central prolactin actions are thought to contribute to this, the mechanisms are poorly understood. We first tested whether chronic hyperprolactinemia inhibited two neuroendocrine parameters necessary for female fertility: pulsatile LH secretion and the estrogen-induced LH surge. Chronic hyperprolactinemia induced by the dopamine antagonist sulpiride caused a 40% reduction LH pulse frequency in ovariectomized rats, but only in the presence of chronic low levels of estradiol. Sulpiride did not affect the magnitude of a steroid-induced LH surge or the percentage of GnRH neurons activated during the surge. Estradiol is known to influence expression of the long form of prolactin receptors (PRL-R) and components of prolactin's signaling pathway. To test the hypothesis that estrogen increases PRL-R expression and sensitivity to prolactin, we next demonstrated that estradiol greatly augments prolactin-induced STAT5 activation. Lastly, we measured PRL-R and suppressor of cytokine signaling (SOCS-1 and -3 and CIS, which reflect the level of prolactin signaling) mRNAs in response to sulpiride and estradiol. Sulpiride induced only SOCS-1 in the medial preoptic area, where GnRH neurons are regulated, but in the arcuate nucleus and choroid plexus, PRL-R, SOCS-3, and CIS mRNA levels were also induced. Estradiol enhanced these effects on SOCS-3 and CIS. Interestingly, estradiol also induced PRL-R, SOCS-3, and CIS mRNA levels independently. These data show that GnRH pulse frequency is inhibited by chronic hyperprolactinemia in a steroid-dependent manner. They also provide evidence for estradiol-dependent and brain region-specific regulation of PRL-R expression and signaling responses by prolactin.

Dopamine-mediated actions of ephedrine in the rat substantia nigra

Although ephedrine is a centrally active stimulant, its effect on midbrain dopamine neurons is not known. To study the effect of ephedrine on dopamine-containing cells, current-clamp microelectrode recordings were made from substantia nigra pars compacta (SNC) neurons in horizontal brain slice preparations. Ephedrine (100–1000 μM) slowed spontaneous firing and produced a modest concentration-dependent hyperpolarization of membrane potential (EC 50 279 μM), with a concomitant net decrease in membrane resistance. These effects were blocked by the D 2-like dopamine antagonist sulpiride (1 μM). Electrically evoked inhibitory synaptic potentials mediated by GABA B receptors were reduced 28% by ephedrine. However, ephedrine did not reduce fast synaptic potentials mediated by GABA A or ionotropic glutamate receptors. Inhibition of the GABA B response appeared to be mediated by a postsynaptic mechanism because ephedrine also reduced baclofen-induced hyperpolarization by 28%. Both ephedrine-induced hyperpolarization and inhibition of baclofen-induced hyperpolarization were abolished when slices were superfused with the tyrosine hydroxylase inhibitor α-methyl- para-tyrosine (AMPT). Despite perfusion with AMPT, the ability of ephedrine to cause hyperpolarization was restored after perfusing the slice with dopamine (30 μM). Taken together, these results suggest that ephedrine causes hyperpolarization and suppresses GABA B receptor-mediated effects by releasing endogenous dopamine. However, the high concentrations required to observe these effects in vitro suggest that biologically relevant central effects of ephedrine are more likely to be mediated either by non-dopamine systems, such as those involving noradrenaline, or by dopamine systems outside the SNC.

Rapid Dopaminergic Signaling by Interneurons That Contain Markers for Catecholamines and GABA in the Feeding Circuitry of Aplysia

Consummatory feeding behaviors in Aplysia californica are controlled by a polymorphic central pattern generator (CPG) circuit. Previous investigations have demonstrated colocalization of markers for GABA and catecholamines within two interneurons, B20 and B65, that participate in configuring the functional output of this CPG. This study examined the contributions of GABA and dopamine (DA) to rapid synaptic signaling from B20 and B65 to follower cells that implement their specification of motor programs. Pharmacological tests did not substantiate the participation of GABA in the mediation of the excitatory postsynaptic potentials (EPSPs) from either B20 or B65. However, GABA and the GABA(B) receptor agonist baclofen were found to modify these signals in a target-specific manner. Several observations indicated that DA acts as the neurotransmitter mediating fast EPSPs from B20 to two radula closer motor neurons B8 and B16. In both motor neurons, application of DA produced depolarizing responses associated with decreased input resistance and increased excitation. B20-evoked EPSPs in both follower cells were occluded by exogenous dopamine and blocked by the DA antagonist sulpiride. While dopamine occlusion and sulpiride block of convergent signaling to B8 from B65 resembled that of B20, both of these actions were less potent on the rapid signaling from B65 to the multifunctional and widely acting interneuron B4/5. These findings indicate that dopamine mediates divergent (B20 to B16 and B8) and convergent (B20 and B65 to B8) rapid EPSPs from two influential CPG interneurons in which it is colocalized with GABA-like immunoreactivity.

Dopaminergic contributions to modulatory functions of a dual-transmitter interneuron in Aplysia

The feeding central pattern generator of Aplysia produces motor programs that can differ in the degree to which they are ingestive or egestive. A number of pattern-generating interneurons that play an important role in shaping motor programs have been identified. One of these interneurons, B65, is unusual in that it contains two classical neurotransmitters, dopamine and γ-aminobutyric acid. Here, we study the role of one of these transmitters, dopamine, using a combination of pharmacological and electrophysiological means. We show that B65 uses dopamine to elicit fast synaptic potentials in several follower neurons. Furthermore, we demonstrate that the dopamine antagonist sulpiride mimics the effect of bilateral B65 hyperpolarization on egestive motor programs. Thus our data suggest that dopaminergic transmission serves to increase the degree of egestiveness of motor programs, and decrease the duration of the protraction phase.

Evidence that estrogen receptor alpha, but not beta, mediates seasonal changes in the response of the ovine retrochiasmatic area to estradiol.

In ewes, anestrus results from a reduction in LH pulsatility due to an increased sensitivity of the hypothalamic estradiol negative feedback system. Considerable evidence has implicated the A15 group of dopaminergic neurons in the retrochiasmatic area in this seasonally dependent estradiol effect. Moreover, estradiol administered to the retrochiasmatic area in ovariectomized anestrous ewes inhibits LH secretion. However, A15 neurons do not appear to contain the classical estrogen receptors (ERalpha). Therefore, we tested the hypothesis that beta-estrogen receptors mediate the action of estradiol in the retrochiasmatic area by comparing the effects of estradiol and genistein, a selective ERbeta agonist. We also examined whether there are seasonal changes in response of the retrochiasmatic area to these agonists and if these effects are mediated by dopamine. To test these hypotheses, ovariectomized ewes were implanted with bilateral guide cannulae targeting the retrochiasmatic area. Crystalline agonists were administered via microimplants inserted down the cannulae. Blood samples taken before and 4 days after microimplant insertion were analyzed for LH concentrations, pulse frequency, and amplitude. Genistein treatment produced no significant change in LH levels in either season. Estradiol treatment decreased both mean LH concentrations and pulse frequency in anestrous but not breeding-season ewes. Administration of the dopamine antagonist sulpiride to ovariectomized ewes with estradiol microimplants in the retrochiasmatic area returned LH pulse frequency to levels indistinguishable from controls. From these data, we hypothesize that estradiol acts on local ERalpha-containing neurons in this area to stimulate a dopaminergic pathway that inhibits LH secretion during anestrus.

Dopaminergic and opioidergic regulation of gonadotropin and prolactin release in stallions.

In the non-breeding season, LH release is reduced via dopaminergic systems in the ram. On the other hand, our previous studies demonstrated an opioidergic inhibition of LH release in stallions outside the breeding season. Thus, in the present study we investigated the dopaminergic regulation of LH and prolactin secretion in stallions, considering interactions between dopamine and opioids. To achieve this, stallions (n=8) were treated with the dopamine antagonist sulpiride (0.6 mg/kg), the opioid antagonist naloxone (0.5 mg/kg), sulpiride plus naloxone or saline in December, March and June. Two hours after the respective treatments, they received a GnRH agonist. Sulpiride induced a significant prolactin release which was most pronounced in December, indicating seasonal variations in the inhibition of prolactin secretion by dopaminergic systems. Prolactin concentrations were not changed by naloxone. Neither during nor outside the breeding season, a dopaminergic regulation of LH release could be demonstrated. In contrast, naloxone caused a significant (p < 0.05) LH release, confirming an opioidergic inhibition of LH release. In conclusion, opioidergic regulation of LH and dopaminergic inhibition of prolactin secretion undergo seasonal changes. Neither during nor outside the breeding season, dopaminergic effects on LH release exist in the stallion.

The antipsychotic drug sulpiride does not affect bodyweight in male rats. Is insulin resistance involved?

Previous studies have shown that prolonged administration of antipsychotic drugs induces obesity in female but not in male rats. To explore the mechanisms involved in this sex-dependent effect, we administered the dopamine antagonist sulpiride (20 mg/kg i.p.) or vehicle (0.1 N HCl) to adult male rats during 21 days and daily assessed bodyweight and food intake. Then, we evaluated the glucose tolerance and the serum levels of insulin, leptin, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S), thyroid hormones and blood lipids. In another experiment, food intake and water intake were assessed after acute injections of sulpiride or vehicle into the perifornical lateral hypothalamus. Lastly, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) in the lateral hypothalamus were assessed by in vivo microdialysis after acute systemic injections of sulpiride and vehicle. Chronic sulpiride administration did not affect bodyweight gain and food intake. However, prolactin levels and the area under the glucose and insulin curves were significantly elevated. Acute sulpiride significantly increased food intake, water intake, DOPAC and HVA levels. The acute effects of sulpiride show that this drug is active at the perifornical lateral hypothalamus, which is a brain area where blockade of dopamine receptors stimulates feeding. However, after prolonged administration, sulpiride did not affect body weight. This lack of effect may be related to the impairment of insulin sensitivity, which may prevent body weight gain, and counteract other effects of sulpiride that promote adiposity such as hyperprolactinemia. These findings noticeably contrast with those observed in sulpiride-treated female rats that appear to display enhanced insulin sensitivity. The changes in insulin sensitivity do not appear related to a decrease in androgenic activity, because testosterone and DHEA-S levels were not affected by sulpiride. However, these results should be considered as preliminary because other relevant endocrine variables such as free testosterone, steroid binding globulin and pituitary gonadotrophin levels were not evaluated. Since the same sex-dependent effect on body weight and food intake in rats has been observed during administration of risperidone, which has a different pharmacological profile than sulpiride, future studies must evaluate other neurotransmitters involved in food intake regulation such as serotonin, noradrenaline and histamine.

Short-term modulation of prolactin secretion by melatonin in anestrous ewes following dopamine- and opiate receptor blockade.

This study tested the hypothesis that the dopaminergic and opioidergic systems are not involved in the short-term stimulatory action of melatonin (MLT) on the secretion of prolactin in anestrous ewes. Thus, MLT should stimulate prolactin release after blockade of either dopamine (DA) or opiate receptors with specific antagonists at the level of the pituitary gland and central nervous system (CNS), respectively. During afternoon intracerebroventricular (icv.) infusion of MLT, the mean plasma prolactin concentration increased significantly (P < 0.001) as compared with the concentrations noted before and during the infusion of the vehicle (veh.). As a result of subcutaneous (s.c.) injection of sulpiride (SULP, DA antagonist), an increase in plasma prolactin concentration was observed, followed by a gradual decrease during the icv. infusion of the vehicle. MLT infused icv. significantly increased (P < 0.001) the secretion of prolactin in SULP + MLT-treated ewes, as compared with the concentration of prolactin noted during infusion of the vehicle in SULP + veh.-treated ewes. Naloxone (NAL, opioid antagonist) infused icv. did not significantly affect the secretion of prolactin, however, a significant (P < 0.01) increase in the concentration was observed after the infusion. In MLT + NAL-treated ewes, the plasma prolactin concentration increased significantly (P < 0.001) during the infusion, as compared with the concentration noted before and that in NAL-alone infused ewes. These results demonstrate that melatonin stimulates prolactin release after the pharmacological exclusion of the dopaminergic input with the DA antagonist sulpiride and also despite the presence of DA activity in the hypothalamus after NAL treatment. Secondly, endogenous opioid peptides are not a major component of this melatonin action.

A method to evaluate the diffusion rate of drugs from a microdialysis probe through brain tissue

For interpretation of microdialysis experiments in which compounds are applied retrodialysis, it is important to have information about the migration rate of the infused compounds. Here we describe a dual-probe microdialysis method that can be used to evaluate the penetration rate of the infused drug. The basic idea is that not the drug itself is assayed, but that its pharmacological effect is recorded by a second probe positioned at a fixed distance (1 mm) of the infusion probe. Using this approach several compounds, each known to induce specific changes in the extracellular levels of dopamine, were infused into the striatum of the rat. The results indicate that the penetration rate of the pharmacological effect of infused compounds differed widely. No effects were seen at the second probe when high potassium chloride was infused. Apparently dopamine was not able to migrate into brain tissue over a distance of 1 mm. Low penetration rates were observed for the dopamine antagonist sulpiride, the dopamine agonist LY17 155, and for amphetamine and nomifensine. A very high penetration rate was observed in case of tetrodotoxin. The fast effects of TTX could also be explained by remote inhibition of neurons passing along the infusion probe. The present study showed that most of the compounds have rather slow infusion rates, indicating that relatively high infusion concentrations are needed (1–10 mM) to reach substantial brain concentrations at a distance of 1 mm from the infusion probe.

Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test.

It has been shown recently that the fraction IIIc of a crude extract of Hypericum perforatum, (St. John's wort) that contained both hypericin (1) and pseudohypericin (2), was remarkably active in the rats forced swimming test (FST) after Porsolt. However, neither of the naphthodianthrones isolated from this fraction were sufficiently effective when administered suspended in water. The solubility of 1 and 2 is remarkably increased in the presence of a fraction containing procyanidins, especially procyanidin B2, which is present also in the active Hypericum fraction IIIc. The cooperative effect of procyanidins significantly increased the in vivo effects of 1 and 2, which exhibited inverted U-shaped dose response curves, in the FST. The anti-immobility effect of solubilized 1 and 2 was antagonized by the dopamine antagonist sulpiride. These data indicate that naphthodianthrones are antidepressant constituents of H. perforatum and suggest that the dopaminergic system is involved in their action.

Sulpiride-induced increases in serum prolactin levels in female rats exposed prenatally to alcohol

We examined the impact of prenatal alcohol exposure on serum prolactin levels and on the ability of the D 2 dopamine antagonist sulpiride to stimulate prolactin release in Long-Evans rats. Pregnant rats were intubated with alcohol (0, 3, or 5 g/kg/day) from gestational day 8 (GD8) to GD20. Adult female offspring were screened for estrous cycle stage. At diestrus, the rats were challenged with a single dose of sulpiride (0, 10, or 40 μg/kg) and trunk blood was collected 20 min later. After prenatal exposure to either dose of alcohol, mean basal serum levels of prolactin were about 65% less than the 0 g/kg group, and the 35–40% mean differences from an untreated control group were not significant. Sulpiride produced dramatic dose-dependent increases in serum prolactin levels in all prenatal treatment groups. Across all doses of sulpiride, the group given the higher dose of prenatal alcohol (5 g/kg/day) had significantly lower serum prolactin levels than all other groups. There was no significant interaction between prenatal treatment and sulpiride dose. Neither prenatal alcohol exposure nor sulpiride injections had significant effects on serum corticosterone levels in this study. Although the current results are unclear regarding a baseline decrease in prolactin levels after prenatal alcohol exposure, the overall results suggest that prenatal alcohol exposure decreases prolactin levels but there is no evidence that it does so by altering dopaminergic tone in hypothalamus of female rats.

Feeding stimulants activate an identified dopaminergic interneuron that induces the feeding motor program in Helisoma.

The neurotransmitter dopamine is shown to play a fundamental role in the generation of the feeding motor pattern and resultant feeding behavior in Helisoma. Application of exogenous dopamine triggered the fictive feeding motor pattern in the isolated CNS and triggered feeding movements in semi-intact preparations. Application of feeding stimulants to the oral cavity excited the putatively dopaminergic buccal interneuron N1a, and depolarization of interneuron N1a triggered the production of the fictive feeding motor pattern. The ability of dopamine superfusion and of interneuron N1a stimulation to activate the fictive feeding motor pattern was blocked by the dopamine antagonist sulpiride. The phase of the fictive feeding motor pattern was reset by brief hyperpolarization of interneuron N1a, demonstrating that interneuron N1a is an integral component of the buccal central pattern generator (CPG). During spontaneous fictive feeding patterns, prolonged hyperpolarizations of interneuron N1a inhibited the production of patterned activity. Exogenous dopamine maintained the fictive feeding motor pattern in the absence of interneuron N1a activity. Interneuron N1a was labeled by the formaldehyde-glutaraldehyde histochemical technique, which is indicative of the presence of dopamine in mollusks. These data suggest that interneuron N1a is an endogenous source of the neuromodulator dopamine, intrinsic to the buccal CPG, and that interneuron N1a has a prominent role in the sensory-motor integration triggering the consummatory response.

The role of the frontal cortex in the mouse in behavioral sensitization to amphetamine

Pharmacological studies have shown that a variety of neuroeffectors are involved in behavioral sensitization to amphetamine-induced stereotypy. In the present work, the effect of some of these drugs on sensitization was studied after intracortical administration in order to determine the role of the cortex in mediating their systemic effects. The dopamine antagonists sulpiride and spiperone were both ineffective against the acute response to amphetamine; nevertheless, both blocked the induction of sensitization, suggesting that the mesocortical dopamine pathway is not involved in the acute response but is necessary for the induction of sensitization. Both CPP, an NMDA receptor antagonist, and THIP, a GABA A agonist, blocked the acute response and the induction of sensitization to amphetamine. On the other hand, mecamylamine, the nicotinic cholinergic antagonist, failed to affect either the acute response or the induction of sensitization, which suggests that the cortex is not a locus of its activity. Anisomycin, an inhibitor of protein synthesis, and diltiazem, a calcium-channel blocker, were both ineffective against the acute response, but both blocked induction. All of the drugs, except CPP and THIP, were ineffective against the expression of sensitization; therefore, the ability of the other drugs to block expression must reside within another locus. Bicuculline injected intracortically in non-convulsant doses produced a stereotypy indistinguishable from that induced by amphetamine; and the effect was readily antagonized by CPP administered either systemically or intracortically. In contrast, sulpiride by either route of administration failed to block the bicuculline-induced stereotypy; we conclude, therefore, that the stereotypic effect of bicuculline is not mediated by dopamine. These results imply that amphetamine-induced stereotypy is mediated in the cortex by the removal of the inhibitory control of the excitatory system. The data also suggest that cortical dopamine, as well as the NMDA and GABA A systems, is important in sensitization to amphetamine. In general the data demonstrate that different neuroeffectors involved in sensitization exert their effects at different brain loci.

Dopaminergic regulation of adrenocorticotrophic hormone, alpha-melanocyte-stimulating hormone and cortisol secretion in the ovine fetus.

During ovine fetal development there is a progressive maturation of the hypothalamo-pituitary-adrenal axis which culminates in the onset of birth. The role and regulation of the intermediate lobe of the fetal pituitary gland in relation to this maturational process remains controversial. To test the hypothesis that the pars intermedia of the ovine fetal pituitary is under tonic inhibitory dopaminergic control we treated fetal sheep at day 131 of gestation with a 3-day intravenous infusion of one of the following: the dopamine antagonist sulpiride (0.3 mg/ 0.5 ml/h; n = 12), the dopamine agonist bromocriptine (0.03 mg/0.5 ml/h; n = 7) or vehicle (0.1 M tartaric acid in saline; n = 8) alone. Fetal plasma concentrations of alpha-MSH were significantly (P < 0.01) increased by treatment with sulpiride and decreased (P < 0.05) by bromocriptine. The increase in alpha-MSH after sulpiride was characterised by an increase in the amplitude of alpha-MSH pulses whereas bromocriptine virtually abolished all pulses of alpha-MSH. Immunoreactive ACTH (IR-ACTH) concentrations were significantly (P < 0.05) elevated after sulpiride but were unaffected by bromocriptine. There were no changes in the pulsatile characteristics of IR-ACTH secretion. Cortisol concentrations were unchanged by either treatment. We conclude that fetal alpha-MSH and IR-ACTH are secreted in a pulsatile fashion and are tonically inhibited by dopaminergic pathways. The lack of an effect of endogenously raised alpha-MSH on plasma cortisol concentrations provides evidence that this POMC-derived peptide is not responsible for the regulation of cortisol biosynthesis and/or secretion.