Miljana Simonovic

The effect of phencyclidine on dopamine synthesis and metabolism in rat striatum

Previous behavioral and neurochemical studies indicate that phencyclidine (PCP), a potent psychotomimetic agent, interacts with central dopaminergic systems. We have examined the effects of PCP on the rate of accumulation of 3,4-dihydroxyphenylalanine (DOPA) after the inhibition of L-aromatic amino acid decarboxylase and on the levels of dopamine (DA) metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum. PCP, in doses from 2.5 to 50 mg/kg, decreased the rate of striatal DOPA accumulation. PCP did not antagonized the increase in the rate of striatal DOPA formation caused by haloperidol, reserpine or gamma-butyrolactone (GBL). When given alone, PCP decreased striatal levels of DOPAC and HVA, while it greatly potentiated the haloperidol-induced rise in striatal levels of these two metabolites. PCP is considerably less effective than d-amphetamine in promoting the release of 3H-DA from preloaded striatal slices in vitro. Our results are consistent with the interpretation that PCP potentiates the synaptic effects of endogenous DA. Its mechanism of action appears to be closely related to that of a category of drugs known as non-amphetamine stimulants, which, among others, includes methylphenidate, amfonelic acid and cocaine.

Effect of 8-hydroxy-2-(di-n-propylamino) tetralin on rat prolactin secretion.

8-OH-DPAT (8-hydroxy-2-[di-n-propylamino] tetralin) is a novel aminotetralin derivative which has been proposed to be a serotonin (5-HT) agonist devoid of dopamine agonist effects. We now report that the administration of 8-OH-DPAT, like known 5-HT agonists, produced a rapid elevation of serum prolactin concentrations in male rats. The prolactin response to 8-OH-DPAT, like that induced by other 5-HT agonists, was greatly potentiated in animals pretreated with the tryptophan hydroxylase inhibitor, para-chlorophenylalanine. However, the 8-OH-DPAT-induced elevation of serum prolactin cocentrations in untreated rats was not dose-dependent and was modest in magnitude compared to that produced by known 5-HT agonists. In contrast to the stimulatory effects of 8-OH-DPAT on prolactin secretionin vivo 8-OH-DPAT suppressed the secretion of prolactin from anterior pituitary tissuein vitro, and this effect was blocked by haloperidol. The results of the present study are supportive of the view that 8-OH-DPAT has dopamine agonist, as well as 5-HT agonist, properties.

Effect of antidepressants, lithium and electroconvulsive treatment on rat serum prolactin levels

The ability of antidepressant drugs, electroconvulsive treatment (ECT), or lithium chloride (LiCl), to modify prolactin secretion in the rat was studied. Chlorimipramine, citalopram, fluoxetine, imipramine and zimelidine potentiated the low dose 5‐hydroxytryptophan (5‐HTP)‐induced increase in prolactin secretion, suggesting inhibition of serotonin (5‐HT) uptake by these drugs. Amitriptyline, doxepin, iprindole, mianserin and trazadone inhibited the prolactin stimulating effects of high doses 5‐HTP and quipazine, suggesting that these drugs have 5‐HT receptor blocking properties. Tandamine inhibited only 5‐HTP‐induced increase in prolactin secretion. Chronic administration of imipramine, potentiated the effect of low dose S‐HTP significantly more than an acute dose. Amitriptyline, produced similar inhibition of the 5‐HTP‐induced increase in prolactin secretion after both acute and chronic administration. The ability of bupropion and mazindol to inhibit alpha‐methylparatyrosine‐induced prolactin secretion, and of nomifensine to inhibit reserpine‐induced prolactin secretion, is consistent with other evidence that these agents are indirect dopamine (DA) agonists. Desipramine, acutely, had no effect on any of the above paradigms but after chronic administration, potentiated the effect of low dose 5‐HTP on prolactin secretion. Nortriptyline had no effect on prolactin secretion after acute or chronic treatment. ECT for 10 days did not affect the ability of a 5‐HT agonist or d‐amphetamine to modify prolactin secretion. However, chronic, but not acute, treatment with LiCl markedly enhanced the prolactin response to 5‐HT agonists and reserpine while shifting the dose response curve for d‐amphetamine and apomorphine to the right. These results are discussed in light of current theories of the role of 5‐HT and DA in depression.

Effects of enkephalin analogues on prolactin release in the rat

Abstract The effects of nineteen enkephalin analogues on the circulating levels of prolactin in the male rat following intraventricular injection of the peptides were determined and compared with that of Met- and Leu-enkephalin. Eleven of the 19 analogues stimulated prolactin secretion. It was found, in general, that the structure activity relationship for enkephalin stimulation of prolactin secretion was similar to that for opiate receptor activity. Analogues which contained a [DAla 2 ] substitution were generally effective in stimulating prolonged prolactin release. Some, but not all analogues containing [DTrp 2 ] or [DLeu 5 ] were active. Analogues containing the [DTrp 1 ], [DPhe 4 ] or [DMet 5 ] substitutions were ineffective. The prolactin releasing effect of intravenous Tyr-DAla-Gly-Phe-DLeu was reversed by naloxone. Naloxone had no effect on the haloperidol- and alpha-methylparatyrosine induced increases in plasma prolactin levels. The results of these studies are discussed in the light of the suggestion that the enkephalins may function as neuroendocrine modulators.

Effects of pirenperone and ketanserin on rat prolactin secretion in vivo and in vitro

Pirenperone, which is chemically related to ketanserin, has been reported to be a selective serotonin2 (5-HT2) antagonist and a specific d-LSD antagonist. We now report that pirenperone markedly stimulates prolactin (PRL) secretion in vivo at low doses and blocks the dopamine (DA)-induced inhibition of PRL release from rat pituitary glands in vitro, suggesting it acts as an antagonist at DA2 receptors in the anterior pituitary gland. Ketanserin, also a purported selective 5-HT2 receptor blocker, has no effect on rat PRL secretion in vivo or in vitro, but at high doses, it inhibits the increase in serum PRL levels produced by the two 5-HT agonists, quipazine and 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT). It had a weak ability to antagonize the PRL-releasing effect of the 5-HT precursor, 5-hydroxytryptophan. These results suggest that serotonergic stimulation of rat PRL secretion by quipazine and 5-MeODMT may be partially mediated by 5-HT2 receptors. The inability of ketanserin to effectively block the effect of 5-HTP suggests its mechanism of stimulating PRL secretion is more complicated than that of the direct acting agonists.

A comparison of the effects of anti-psychotic drugs on pituitary, striatal and limbic system post-synaptic dopamine receptors.

Abstract Dopamine (DA) antagonists promote the secretion of prolactin (PRL) from the anterior pituitary gland by blocking the effects of DA at receptors in the pituitary itself. Thus, comparison of the properties of these receptors with DA receptors in the striatal, meso-limbic and meso-cortical regions is of interest. Evidence is presented that clozapine, RMI-81, 582 (a morphanthridine derivative), trebenzomine (CI-686, a chromanamine derivative) and sultopride (a benzamide) have much weaker effects on human and rat PRL secretion than would be predicted by their anti-psychotic potency. The reverse is true of two other benzamides, sulpiride and metoclopramide. Classical neuroleptics of the phenothiazine, butyrophenone and thioxanthene types appear to affect rat and human PRL secretion in a manner which is mainly but not entirely consistent with their known effects on striatal and meso-limbic/meso-cortical postsynaptic DA receptors. Preliminary studies indicate presynaptic receptors which affect prolactin secretion are not present in rats. Supersensitivity may develop in the tubero-infundibular (TI) system after chronic neuroleptic treatment but altered sensitivity of these receptors was not found in schizophrenics given apomorphine.

Effect of buspirone on rat plasma prolactin levels and striatal dopamine turnover

Buspirone, an effective antianxiety compound, produced a dose-dependent, relatively prolonged increase in rat plasma prolactin (PRL) levels. The stimulation of PRL secretion by buspirone was additive with the effect of α-methyl-p-tyrosine (AMPT) or γ-butyrolactone. In vitro, buspirone itself had no effect on the release of PRL from rat pituitary glands but it blocked the inhibitory action of dopamine (DA). Buspirone also increased DA turnover in the striatum as measured by the AMPT-induced depletion of striatal DA levels. These results demonstrate the ability of buspirone to block pituitary and striatal DA receptors.

Interaction of (+)- and (−)-3-PPP with the dopamine receptor in the anterior pituitary gland

The interaction of the enantiomers of the novel dopamine agonist, 3-PPP (3-hydroxyphenyl)-N-n-piperidine) with the dopamine receptor in the anterior pituitary gland was examined. Both (+)- and (-)-3-PPP were effective in suppressing the elevation in serum prolactin (PRL) concentrations in rats treated with alpha-methyl-paratyrosine, an inhibitor of dopamine synthesis. The (+)-enantiomer was slightly more potent than the (-)-enantiomer in this regard. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by both isomers of 3-PPP, with (+)-3-PPP being approximately 10 times more potent than (-)-3-PPP. Both (+)- and (-)-3-PPP displaced 3H-(-)-N-n-propylnorapomorphine (3H-NPA) and 3H-spiperone from bovine anterior pituitary membranes. The Hill coefficients of (+)- and (-)-3-PPP for the displacement of 3H-spiperone were 0.6 and 0.7, respectively. These results are consistent with the view that the (+)- and (-)-enantiomer exhibit dopamine agonist effects at dopamine receptor sites in the anterior pituitary gland. However, (+)-3-PPP demonstrated marked differences in affinity for 3H-NPA- and 3H-spiperone labeled-sites, whereas (-)-)3-PPP showed the same order of affinity for these two sites. In view of these results and the fact that (-)-3-PPP has also been characterized as a dopamine antagonist at postsynaptic receptor sites in the striatum, (-)-3-PPP might be best described as a partial agonist at pituitary dopamine receptors. Moreover, these data are suggestive of a similarity, at least on a pharmacological basis, between dopamine autoreceptors and dopamine receptors in the anterior pituitary gland.

Stimulation of rat prolactin secretion by indolealkylamine hallucinogens

The hallucinogenic indoleamine drugs N,N-dimethyltryptamine (N,N-DMT), psilocybin, bufotenin, 5-methoxy-N,N-dimethyltryptamine, and N-methyltryptamine, increased rat plasma prolactin (PRL) levels. The increase in plasma PRL produced by N,N-DMT, psilocybin, and bufotenin was inhibited by methysergide, a serotonin receptor blocker. Parachlorophenylalanine (PCPA), an inhibitor of serotonin synthesis, significantly potentiated the increase in PRL produced by N,N-DMT, and psilocybin. Parachloroamphetamine, a relatively selective toxin for serotonin neurons, also stimulated the increase in PRL produced by N,N-DMT. These results suggest that the indole hallucinogens stimulate PRL secretion by a serotonergic agonist mechanism. Bufotenin has been reported to pass the blood-brain barrier poorly, but of the indoles studied it had the most potent effect on PRL secretion. This raises the possibility that the serotonin receptors which promote PRL secretion may be outside the blood-brain barrier or that the central 5-HT receptors which mediate PRL secretion may be especially responsive to bufotenin.

Lysergic acid diethylamide: evidence for stimulation of pituitary dopamine receptors.

Lysergic acid diethylamide (LSD), 0.05 mg/kg and 0.20 mg/kg, significantly decreased plasma prolactin (PRL) levels in male rats. LSD, 0.20 mg/kg, also inhibits the increase in plasma PRL levels produced by chlorpromazine (CPZ), 5 mg/kg, and alpha-methylparatyrosine (AMPT), 50 mg/kg, both of which interfere with dopaminergic inhibition of PRL secretion. LSD was more potent than methysergide, a serotonin receptor blocker, in lowering plasma PRL levels and more potent than apomorphine, a known direct acting dopamine agonist, in blocking the increase in plasma PRL produced by quipazine, a 5-HT agonist. These results suggest LSD has potent dopamine agonist properties on the rat pituitary or hypothalamic dopamine receptors which directly or indirectly inhibit PRL secretion.