The activation of D2-like receptors by intranasal dopamine facilitates the extinction of contextual fear and prevents conditioned fear-induced antinociception.

Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD.

Bromocriptine inhibits salsolinol-induced prolactin release in male goats.

The secretion of prolactin (PRL) is under the dominant and tonic inhibitory control of dopamine (DA); however, we have recently found that salsolinol (SAL), an endogenous DA-derived compound, strongly stimulated the release of PRL in ruminants. The aim of the present study was to clarify the inhibitory effect of DA on the SAL-induced release of PRL in ruminants. The experiments were performed from late June to early July. Male goats were given a single intravenous (i.v.) injection of SAL (5mg/kg body weight (BW)), a DA receptor antagonist (sulpiride, 0.1mg/kg BW), or thyrotropin-releasing hormone (TRH, 1µg/kg BW) before and after treatment with a DA receptor agonist (bromocriptine), and the effect of DA on SAL-induced PRL release was compared to that on sulpiride- or TRH-induced release. Bromocriptine completely inhibited the SAL-induced release of PRL (P<0.05), and the area under the response curve (AUC) for a 120-min period after the treatment with bromocriptine was 1/28 of that for before the treatment (P<0.05). Bromocriptine also completely inhibited the sulpiride-induced release (P<0.05). The AUC post-treatment was 1/17 that of pre-treatment with bromocriptine (P<0.05). Bromocriptine also inhibited the TRH-induced release (P<0.05), though not completely. The AUC post-treatment was 1/3.8 that of pre-treatment (P<0.05). These results indicate that DA inhibits the SAL-induced release of PRL in male goats, and suggest that SAL and DA are involved in regulating the secretion of PRL. They also suggest that in terms of the regulatory process for the secretion of PRL, SAL resembles sulpiride but differs from TRH.

Histamine H(3) receptor-mediated inhibition of depolarization-induced, dopamine D(1) receptor-dependent release of [(3)H]-gamma-aminobutryic acid from rat striatal slices.

1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

Antagonistic effects of beta-phenylethylamine on quinpirole- and (-)-sulpiride-induced changes in evoked dopamine release from rat striatal slices.

To assess the role of beta-phenylethylamine in aspects of dopamine release, we measured the level of beta-phenylethylamine in the rat striatum after killing the rats by microwave irradiation. We then investigated the effect of beta-phenylethylamine on electrically evoked dopamine release from rat striatal slices in vitro. The striatal beta-phenylethylamine level was 46.5 +/- 3.5 ng/g wet tissue, equivalent to 0.3 micromol/l. Superfusion with low concentrations of beta-phenylethylamine up to 1 micromol/l had no effect on spontaneous or electrically evoked dopamine release from striatal slices. Quinpirole reduced the evoked dopamine release from slices in a concentration-dependent manner. The quinpirole-induced reduction of evoked dopamine release was attenuated 30% by superfusion with 0.3 micromol/l beta-phenylethylamine. Moreover, the (-)-sulpiride (0.1 micromol/l)-induced increase in evoked dopamine release was also attenuated by superfusion with 0.3 micromol/l beta-phenylethylamine. These data indicate that submicromolar levels of beta-phenylethylamine could modify the dopamine autoreceptor mediated changes in evoked dopamine release from rat striatal slices.

Tamoxifen prevents sulpiride-induced weight gain in female rats.

To evaluate its potential utility in counteracting neuroleptic-induced obesity, the effects of long-term administration of tamoxifen (TAM) on body weight (BW) and food intake (FI) of gonadally intact and sulpiride-treated (SUL) female rats were assessed. In addition, estradiol and prolactin serum levels were measured in rats treated with SUL. SUL plus TAM and SUL plus bromocriptine (BR). TAM, at doses of 10, 50 and 100 micrograms, significantly decreased BW gain: FI was significantly reduced at the doses of 50 and 100 micrograms. In addition, doses of TAM ranging from 5-100 micrograms completely prevented SUL-induced BW gain and hyperphagia. BR also prevented SUL effects on BW and FI. In contrast to BR, concomitant administration of TAM did not prevent SUL-induced hyperprolactinemia. Estradiol levels were not modified by SUL alone or SUL plus BR, but they were significantly increased in the animals treated with TAM plus SUL. Neuroleptic-induced obesity in female rats might be related to an alteration in gonadal steroid balance secondary to hyperprolactinemia. While BR might counteract neuroleptic-induced weight gain by preventing hyperprolactinemia, TAM might directly interact with estrogen receptors, or indirectly increase estradiol levels. The use of TAM in preventing neuroleptic-induced obesity in humans warrants further investigation.

Antagonistic effects of OPC-14597, a novel antipsychotic drug, on quinpirole- and (-)-sulpiride-induced changes in evoked dopamine release in rat striatal slices.

The effects of a newly synthesized quinolinone derivative, 7-[4-(4-(2,3-dichlorophenyl)-1-piperazinyl) butoxy)-3,4-dihydro-2-(1H)-quinolinone (OPC-14597), a novel antipsychotic drug, on electrically evoked dopamine release in rat striatal slices were investigated. OPC-14597 (0.1-10 microM) had no effect on the dopamine release evoked in the striatal slices. The decrease induced by quinpirole, a dopamine receptor agonist, in evoked dopamine release was attenuated by superfusion with OPC-14597 (1 and 10 microM) which by itself had no effect on evoked dopamine release. The increase induced by (-)-sulpiride, a dopamine receptor antagonist, in evoked dopamine release was, moreover, also attenuated by 1 and 10 microM OPC-14597. These findings indicate that OPC-14597 antagonizes both dopamine agonist- and antagonist-induced changes in evoked dopamine release in striatal slices in rats.

ATP-sensitive K+ channel openers block sulpiride-induced dopamine release in the rat striatum.

In vivo brain microdialysis was used to investigate the role of ATP-sensitive K+ (KATP) channel openers in dopamine release regulated by dopamine autoreceptors in the rat striatum. Local infusion of two KATP channel openers, nicorandil (10(-5)-10(-3) M) and cromakalim (10(-5)-10(-3) M), into the striatum thorough the dialysis membrane produced dose-dependent decreases in extracellular concentrations of dopamine. Local application of the dopamine D2 receptor antagonist, (-)-sulpiride (10(-5) M), produced significant increases in extracellular concentrations of dopamine. Both nicrorandil (10(-5) M) and cromakalim (10(-4) M) blocked significantly (-)-sulpiride (10(-5) M)-induced increases in dopamine levels in the striatum. These results suggest that activation of KATP channels in the striatum causes decreases in endogenous dopamine release in vivo. Furthermore, the sulpiride-induced increases in dopamine levels caused by blocking the tonic activation of dopamine autoreceptors were inhibited by activation of KATP channel. These data indicate that KATP channels may be present in nigrostriatal dopaminergic terminals and that striatal dopamine autoreceptors inhibit dopamine release tonically by activation of KATP channels.

N-ethyl-carboxamide adenosine inhibits perioral dyskinesias induced by sulpiride + SKF 38393 in rabbits.

A pattern of perioral dyskinesia was induced in adult male rabbits by concomitant stimulation of dopamine D1 receptors (SKF 38393) and blockade of dopamine D2 receptors (sulpiride). Rabbits treated with sulpiride (6 and 12.5 mg/kg i.v.) then, 90 min thereafter, with SKF 38393 (0.1, 1 and 10 mg/kg i.v.) showed a pattern of perioral dyskinesia characterized by compulsive and repetitive sniffing, licking and vacuous chewing. These effects were completely prevented by the administration of N-ethylcarboxamide adenosine (NECA), an A2 > A1 adenosine receptor agonist. The present results confirm that perioral dyskinesia is dependent on the activation of dopamine D1 receptors. They also show that, in order to induce perioral dyskinesia in rabbits, a concomitant blockade of dopamine D2 receptors is required. Finally, the antagonistic effect of NECA on the appearance of perioral movements confirms that adenosine receptors play a key role in the control of dopamine-mediated effects.

Sulpiride anxiogenic-like effect inhibition by a D1 dopamine receptor antagonist.

The increased latency to explore a white compartment from a black one into which a mouse has been introduced, appears to be correlated with its anxiety level. In this test, the D2 specific dopamine receptor antagonist (+/-) sulpiride dose dependently (5-40) mg kg-1 i.p.) increased this latency. This effect was suppressed by the D1 specific dopamine receptor antagonist SCH 23390 (25 micrograms kg-1 s.c.) which intrinsically displayed an apparent anxiolytic effect.

Evidence for a dopaminergic involvement in the inhibitory effect of alpha human natriuretic peptide on prolactin in man.

Recently, it has been suggested that Atrial Natriuretic Peptides (ANP), as well as peripheral hormones, may have a role as central neurotransmitters or neuromodulators, and in humans it has been observed that alpha human ANP inhibits prolactin secretion. In this study, on 12 normal adult males, we evaluated the effects of ANP on the prolactin release induced by TRH and by the dopaminergic blocker sulpiride. Alpha-hANP administration was followed by a significant fall of prolactin plasma levels but did not influence TRH-induced prolactin response. Nevertheless, sulpiride-induced prolactin secretion was significantly lower after Alpha-hANP administration than after placebo pre-treatment (p values ranging between 0.01 and 0.001). Our results suggest that in man Alpha-hANP has no direct influence on lactotrope cells in inhibiting prolactin secretion, but seems to involve activation of the hypothalamic dopaminergic system.

D-Trp6-luteinizing hormone-releasing hormone inhibits sulpiride-induced hyperprolactinemia in normal men.

The effect of a potent agonistic analog of LHRH, D-Trp6-LHRH, on hyperprolactinemia induced by sulpiride was studied in normal men. Six men received sulpiride (100 mg, twice daily, orally) for 44 days. D-Trp6-LHRH was given sc during the last 2 weeks of sulpiride administration; the dose was 500 micrograms on the first day and 100 micrograms daily for the subsequent 14 days. All men had high serum PRL levels before D-Trp6-LHRH administration (mean +/- SEM, 56 +/- 9 ng/mL), which decreased significantly after the first dose of the analog (45 +/- 5 ng/mL; P = 0.031) and also after 15 days of analog administration (41 +/- 6 ng/mL; P = 0.016). These data demonstrate that administration of LHRH agonist can inhibit the hyperprolactinemic effect of sulpiride, suggesting a direct action of the analog on the pituitary gland to modulate PRL secretion.

Naloxone antagonizes the hyperdipsic effect of sulpiride in a salt-preference test in male and female rats.

The consumption of saline and water in a two-bottle test of salt-preference was measured after the administration of sulpiride, a dopamine receptor antagonist and of naloxone, an antagonist at opiate receptors. The two drugs were injected alone, or in combination. Three concentrations of saline (0.125, 0.6 and 1.7% NaCl solutions) were used and the tests were carried out using both male and female, water-deprived rats. When the rats were allowed the choice between a highly-preferred 0.125% NaCl solution and water, sulpiride (30 mg kg-1, i.p.) produced an increase in the intake of the two fluids. When naloxone (1 mg kg-1, s.c.) was given alone, it had no effect in this test of salt preference, but when given in combination, completely eliminated the hyperdipsic effect of sulpiride, providing behavioural evidence of a significant interaction between sulpiride and naloxone. When choices of either 0.6 or 1.7% NaCl solutions and water were given, the baseline levels of the consumption of the fluids were increased. Under these circumstances, sulpiride did not significantly increase the consumption of fluids; instead, naloxone significantly reduced the level of fluid consumption. In a further experiment, apomorphine, at dose levels which stimulate dopamine autoreceptors, had no effect on either fluid intake or saline preference in water-deprived male rats. Biochemical data showing that dopamine inhibits the release of beta-endorphin in the hypothalamus through the dopamine D-2 receptor, suggests a possible mechanism for a blockade of sulpiride-induced hyperdipsia by naloxone.

Prolactin lowering effect of dihydroergokryptine in rat and in man.

The prolactin lowering activity of dihydroergokryptine was investigated both in rats and in humans. The drug was administered orally at the doses of 0.2, 1 and 5 mg/Kg to intact or reserpinized male rats. Nine male adult volunteers were given 300 mg cimetidine iv 90 min after receiving 2, 3 or 4.5 mg of dihydroergokryptine and 3, 4.5 and 6.75 mg of dihydroergocristine or placebo per os in a randomized, cross-over design. Eight young adult males were injected im with 10 mg sulpiride 120 min after randomly receiving dihydroergokryptine 2.5 and 5 mg or placebo in a cross-over manner. Finally, five healthy young women were given dihydroergokryptine 2.5 and 5 mg, bromocriptine 2.5 mg and placebo in a cross-over design. Dihydroergokryptine caused a strong, long-lasting, dose-dependent fall of plasma prolactin concentrations in both rats and humans. Moreover, it inhibited the reserpine-induced rise of plasma prolactin in rats, as well as the cimetidine-or sulpiride-induced hyperprolactinemia in humans. Dihydroergokryptine proved twice as potent as dihydroergocristine and about half as potent as bromocriptine. Effective doses of both dihydrogenated ergot alkaloids were much better tolerated than bromocriptine.

Enhanced TSH stimulating effect of TRH by sulpiride in man.

Sulpiride, a specific dopaminergic blocker, was administered im to 6 normal male volunteers (100 mg) alone or in association with L-DOPA (500 mg per os, 90 min before sulpiride) or with TRH (400 micrograms iv in bolus, 30 min after sulpiride) and blood samples were obtained for TSH radioimmunoassay at various intervals before and after the treatments. Sulpiride alone produced a slight increase of plasma TSH levels which was inhibited by L-DOPA pre-treatment. The previous administration of sulpiride resulted in a marked increase of the TSH response to TRH. It is suggested that dopamine and TRH may interact to modulate pituitary secretion of both TSH and prolactin, though the hypophyseal thyrotrophs and lactotrophs show a different sensitivity to the common stimulatory and inhibitory substances.

Interaction of sulfpride and ergot derivatives on rat brain DOPAC concentration and prolactin secretion in vivo.

Sulpiride, which differs from classical neuroleptics by not producing major extrapyramidal side effects, is a potent antiemetic agent and stimulates prolactin secretion in both laboratory animals and man. In parallel it increases dopamine synthesis in both striatum and nucleus accumbens. Bromocriptine and metergoline are two effective agents in suppressing prolactin release and postulated to stimulate dopamine receptors. The interactions of these two ergot derivatives with sulpiride have been investigated on prolactin release and on striatal and limbic DOPAC accumulation. Bromocriptine at all doses tested was able to suppress the increased in vivo prolactin secretion observed after sulpiride administration. Metergoline antagonized the sulpiride-induced prolactin increase only at low doses; on the contrary higher doses potentiated it. High concentrations of bromocriptine suppressed the sulpiride-induced increased of DOPAC levels in striatum and n. accumbens, while metergoline potentiated the sulpiride-induced accumulation of brain DOPAC.

Differential behavioral effects of sulpiride in the rat and squirrel monkey.

Despite its clinical efficacy as an antipsychotic agent, sulpiride differs from other neuroleptics in that it has been reported to exert erratic effects in several animal models. The effects of sulpiride were investigated on Sidman avoidance responding by the rat and squirrel monkey. At 100 mg/kg i. p. or orally, sulpiride failed to impair rat Sidman avoidance responding appreciably while exerting marginally toxic effects, but at 30 mg/kg orally, this drug strongly impaired Sidman avoidance responding by the squirrel monkey. This effect, which manifested delayed onset, was reversed by benztropine, indicating that dopamine receptor blockade was most likely responsible for the impairment of responding. The gross behavioral effects of sulpiride in the squirrel monkey resembled those of haloperidol, and dyskinetic postures induced by haloperidol could be mimicked by sulpiride in some instances. It is concluded that the behavioral effects of sulpiride in the rat may not be representative of its action in primates or in the clinic.

[The relevance of anticholinesterase properties to toxicity and neuromuscular effects of sulpiride (author's transl)]. / Die Bedeutung der cholinesterasehemmendren Eigenschaften für Toxizität und neuromuskuläre Wirkungen von Sulpirid

N-[(1-Ethyl-pyrrolidin-2-yl)-methyl]-2-methoxy-5-sulf-amoyl-benzamide (sulpiride, Dogmatil) inhibits acetylcholinesterase of rat brain in a mixed-type manner (Ki 0.3 mM; Ki 1.8 mM) as well as serum cholinesterase of the rat competitively (Ki 0.37 mM). Using acetylthiocholine in concentrations below 0.1 mM and purified enzyme from Electrophorus, reaction becomes first-order kinetics. At 35 micronM sulpiride doubles half-life and is without effects below 3.5 micronM. Hydrolysis of acetylthiocholine in homogenates of stomach muscle from rats is not affected by sulpiride up to 20 micronM. Pretreatment of mice with 5 mg atropine/kg i.p. decreases i.p. LD50 of sulpiride to 67% of controls. The conclusion is drawn that neither toxicity nor hypermotility of stomach seen after sulpiride by other authors is due to the cholinesterase inhibiting properties of sulpiride.