Interaction between mianserin, an antidepressant drug, and central H1- and H2-histamine-receptors: in vitro and in vivo studies and radioreceptor assay.

Mianserin bimodally inhibited the stimulation of cyclic AMP accumulation mediated by histamine H1- and H2-receptors in slices from guinea-pig hippocampus with Ki values of 0.003 and 4 microM, respectively. Various treatments with mianserin were undertaken to determine whether the drug significantly interacted with cerebral histamine receptors in vivo in such a way that the response of the slice preparation could be modified. In hippocampal slices from animals treated with mianserin, the H2-receptor-mediated effect was estimated by constructing concentration-response curves to impromidine, a highly selective agonist, and that mediated by H1-receptors was measured by use of 0.5 mM 2-thiazolylethylamine (a predominantly H1-receptor agonist) in the presence of a maximal concentration of impromidine. After an acute treatment (10 mg/kg), the response mediated by H1-receptors was abolished whereas the response to impromidine in increasing concentrations was unchanged. After 1 week of drug administration (10 mg/kg twice daily), a 44% reduction in the response to 2-thiazolylethylamine was observed with no change in the response mediated by H2-receptors. When a dose of mianserin equivalent to a clinical dose (1 mg/kg, twice daily) was administered for 21 days, a partial but not significant decrease of the responsiveness to the H1-receptor agonist was accompanied by a significant increase of the maximal response to impromidine. Plasma levels of mianserin were estimated by a sensitive radioreceptor assay based upon inhibition of [3H]mepyramine binding. A good correlation was found between the concentration of mianserin in plasma and the tentative estimation of an equivalent concentration of mianserin in slices.

Histamine-stimulated cyclic AMP formation in the chick pineal gland: role of protein kinase C.

The role of protein kinase C (PKC) in histamine (HA)-stimulated cyclic AMP formation in intact chick pineal glands was investigated. In the pineal gland of chick HA, 2-methylHA, 4-methylHA, and N alpha, N alpha-dimethylHA potently increased cyclic AMP accumulation in a concentration-dependent manner. Treatment of intact glands with PKC inhibitors, i.e. chelerythrine and stautosporine, reduced the stimulatory effect of the HA-ergic compounds on cyclic AMP formation. HA, 2-methylHA, 4-methylHA, and N alpha, N alpha-dimethylHA significantly increased inositol-1,4,5-trisphosphate (IP3) levels in intact chick pineal glands, indicating their activities on phospholipase C and 1,2-diacylglycerol formation. The stimulatory effect of HA on IP3 levels was antagonized by aminopotentidine, a potent blocker of H2-like HA receptors in avian pineal gland. Preincubation of chick pineal glands with a PKC activator, 4 beta-phorbol 12, 13-dibutyrate (4 beta-PDB), enhanced the accumulation of cyclic AMP elicited by HA, 2-methylHA, 4-methylHA, and N alpha, N alpha-dimethylHA. On the other hand, 4 beta-phorbol, inactive on the PKC, was ineffective. Our results point to the possibility that PKC is involved in the regulation by HA of cyclic AMP synthesis in the pineal gland of chick. Furthermore, the cyclic AMP response to pineal HA receptor stimulation can be positively modulated by a concomitant activation of the PKC pathway.

Serotonin N-acetyltransferase (NAT) activity in hen retina and pineal gland: in vivo pharmacological induction at noon and antagonism of the light-evoked suppression at night.

In vivo effective pharmacological procedures are described which markedly increase activity of serotonin N-acetyltransferase (NAT), the key regulatory enzyme in melatonin biosynthesis, during the daytime (in light) and counteract suppressive effects of light on NAI activity at night in the hen retina and pineal gland. Of the tested compounds, and their combinations, the most effective were: "aminophylline + spiroperidol + alpha-methyl-p-tyrosine" for the retina, and "aminophylline + yohimbine (+ alpha-methyl-p-tyrosine)" for the pineal gland. The results give strong support to the concept that the dopaminergic (C(2)-receptor) and noradrenergic (alpha(2)-adrenergic receptor) mechanisms control NAT activity, and melatonin synthesis, in the hen retina and pineal gland, respectively.

The origin and fate of histamine in the rabbit retina.

The rabbit retina contained histamine, showed well expressed histamine-methyltransferase activity and marginal histidine decarboxylase activity. Slices of the rabbit retina and hypothalamus took up [(3)H]histamine against a concentration gradient in a temperature-dependent process. [(3)H]Histamine uptake by the rabbit retina was inhibited by ouabain, and was unaffected by imipramine, fluoxetine, nisoxetine and nomifensine (all at 10 ?M concentration). [(3)H]Histamine taken up by the retina was metabolized to tele-methylhistamine and methylimidazoleacetic acid. It is suggested that histamine in the retina may be of some functional importance.

Regulatory mechanisms in melatonin biosynthesis in retina.

The vertebrate retina produces melatonin in a light-dependent rhythmic fashion, synchronized with, but independent from the rhythm of the hormone formation in the pineal gland. This review summarizes the current status of our knowledge on regulatory mechanisms involved in controlling the retinal melatonin biosynthesis. Special emphasis is given to the role and mode of action of dopamine and GABA, two established retinal neurotransmitters, as well as that of second messengers (cyclic AMP, calcium ions). Comparisons are made between lower vertebrates and mammals.

Dopamine receptor regulating serotonin N-acetyltransferase activity in chick retina represents a D4-like subtype: pharmacological characterization.

The dopamine (DA) receptor regulating serotonin N-acetyltransferase (NAT) activity in chick retina was characterized pharmacologically. Intraocular (i.o.) administration of DA significantly decreased the nighttime NAT activity of chick retina. The effect of DA was antagonized by blockers of the D2 family of DA receptors, spiroperidol, YM-09151-2 and clozapine, and it was not affected by SCH23390, a selective antagonist of D1 DA receptor. Several agonists of D2 family of DA receptors given i.o. suppressed the nighttime NAT activity of the chick retina with quinpirole (D3/D4 receptor selective) and bromocriptine (D2/D3 receptor selective) being the most and the least potent drugs, respectively. The rank-order potency of antagonists of D2 family of DA receptors to block the inhibitory effect of quinpirole on the enzyme activity (with clozapine being relatively very potent, and (+)-butaclamol, raclopride and remoxipride-ineffective) match the characteristics of the D4 DA receptor. Moreover, although sulpiride effectively prevented the quinpirole-induced decline in the nighttime NAT activity of the chick retina, there was no marked stereoselectivity in its action. It is suggested that DA receptor regulating NAT activity in chick retina represents a D4-like subtype.

Melatonin and its generating system in vertebrate retina: circadian rhythm, effect of environmental lighting and interaction with dopamine.

Retinas of rats, rabbits, chicks and carp possess enzymes, i.e. serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), which convert serotonin (5-HT) to melatonin, NAT activity and melatonin levels, but not HIOMT activity, show distinct circadian rhythms, with peak values occurring during the dark (night) phase of the 12 h light-dark cycle. Exposure of the animals to light at night inhibited the night-stimulated NAT activity. Treatment of rats and rabbits with the dopaminergic agonist, apomorphine, inhibited the retinal NAT activity. Dopamine levels in the rabbit retina showed diurnal variations, with higher contents seen during the light phase of both the 12 h light-dark cycle with lights on between 06:00-18:00, and that with reversed periods of illumination (lights on between 18:00-06:00). Melatonin potently inhibited the electrically-evoked calcium-dependent release of [(3)H]dopamine from pieces of retina from both albino and pigmented rabbits. Our results indicate that the light-regulated melatonin-generating system does operate in the vertebrate retina. The present data, together with other findings, suggest that in the retina there is an antagonistic interplay between melatonin and dopamine. Thus, melatonin inhibits dopamine synthesis in, and release from, the retinal dopaminergic cells, whilst dopamine inhibits the night (dark)-stimulated melatonin formation by decreasing NAT activity. Since light increases metabolic activity of the retinal dopaminergic cells (it enhances the amine synthesis, levels and release), it seems likely that the retinal dopamine plays a role of a "light" messenger in the inhibition of melatonin synthesis. It is suggested that an interplay between melatonin and dopamine in the retina is responsible for regulation of those retinal events which follow circadian rhythmicity, and/or are dependent on light-dark conditions.

Activation of D2 dopamine receptors in hen retina decreases forskolin-stimulated cyclic AMP accumulation and serotonin N-acetyltransferase (NAT) activity.

Dopamine (DA; 1-100 ?M) alone did not significantly stimulate cyclic AMP accumulation in the hen retina; however, in the presence of 0.3 ?M spiroperidol, it clearly increased it. DA, in a concentration-dependent manner, enhanced the stimulatory effect of forskolin (1 and 10 ?M), both in the absence and presence of a phosphodiesterase (PDE) inhibitor IBMX (0.5 mM). A selective D1-receptor blocker such as SCH 23390 antagonized the activating effect of DA when used at 1 ?M, and reversed the amine action from a stimulatory into an inhibitory effect when applied at 3 or 10 ?M concentration. Addition of 0.3 ?M spiroperidol further enhanced the DA action on cyclic AMP accumulation evoked by forskolin; however, spiroperidol used at 5 ?M concentration antagonized the potentiating effect of the amine. Selective agonists of DA D2-receptors such as quinpirole (LY 1715550; 0.01-10 ?M) and bromocriptine (1-100 ?M) decreased both basal levels and forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner in the absence and presence of 0.5 mM IBMX. Under daylight conditions, dibutyryl-cyclic AMP (1 mM) and a combination of 50?M forskolin and 0.1 mM IBMX (these drugs applied separately were only weakly active) significantly enhanced the activity of serotonin N-acetyltransferase (NAT) activity (the key regulatory enzyme in melatonin biosynthesis) in pieces of the hen retina. Quinpirole (0.001-10 ?M) inhibited the effect of forskolin (combined with IBMX) in a concentration-dependent and spiroperidol-sensitive manner, and did not modify the action of dibutyrylcyclic AMP. It is concluded that the hen retina possesses both types of DA receptors, i.e. D1 and D2, whose stimulation respectively increase and decrease cyclic AMP levels. These D2-receptors, which are negatively coupled to adenylate cyclase, seem to be involved in the regulation of NAT activity in the retina, and their activation leads to the inhibition of the enzyme induction.

Does histamine stimulate cyclic AMP formation in the avian pineal gland via a novel (non-H1, non-H2, non-H3) histamine receptor subtype.

The effects of histamine (HA) and selective HA H1-, H2 and H3-receptor agonists on cyclic AMP formation were investigated in intact chick and duck pineal glands HA potently stimulated the pineal cycle AMP formation. The effect of HA was mimicked fully by N alpha-methylated histamines, and partially by several histaminergic drugs: 2-thiazolylethylamine (H1) amthamine (H2) and R alpha-methyl-histamine (H3). Dimaprit, another selective H2-agonist showed marginal activity. Forskolin highly potentiated the action of HA, and only weakly affected the effects of 2-thiazolylethylamine and amthamine. In the chick pineal, the stimulatory effects of HA and the tested histaminergic drugs were not blocked by mepyramine and thioperamide (H1- and H3-blockers, respectively), but they were antagonized by H2-receptor selective compounds ranitidine and aminopotentidine, which, however, acted in a noncompetitive manner. Another H2-selective blocker zolantidine antagonized the HA effect only when used at very high (30-100 microM) concentrations. In the duck pineal, the stimulatory effect of HA on cyclic AMP production was unaffected by mepyramine (H1), thioperamide (H3), and ranitidine (H2), and only partially inhibited by the H2-blocker aminopotentidine. Electrophysiological experiments revealed that HA is capable of evoking inward currents in most of the tested cells acutely isolated from chick pineal gland. The present findings further indicate that the pharmacological profile of the avian pineal HA receptor, whose stimulation leads to activation of cyclic AMP production, is different from any known HA receptor type (H1, H2, H3), and suggest the existence of either an avian-specific HA receptor, or a novel HA receptor subtype. Electrophysiological data suggest that the pineal HA receptor may be somehow linked to activation of an ionic channel.

Dopamine-dependent cyclic AMP generating system in chick retina and its relation to melatonin biosynthesis.

Stimulation of a D4-like dopamine (DA) receptors inhibits a cAMP-dependent increase in serotonin N-acetyltransferase activity and melatonin biosynthesis in the chick retina. In order to gain more insight into the molecular mechanisms underlying this suppressive action of DA, the effects of selective stimulation of the D2-family of DA receptors (including the D4-subtype) on cAMP formation were examined in chick retina using two experimental approaches: measurements of adenylyl cyclase activity in retinal homogenates, and cAMP accumulation in eye cup preparation prelabeled with [3H]adenine. The DA-sensitive adenylyl cyclase system is well expressed in chick retina. DA increased both basal and forskolin-stimulated adenylyl cyclase activity. This effect of DA was antagonized by SCH 23390 (a blocker of D1-family of DA receptors) and not affected by sulpiride (a D20-family blocker). Incubation of retinal homogenates with quinpirole (a predominant agonist of D3/D4 DA receptor subtypes) did not produce any major changes in adenylyl cyclase activity. On the other hand, activation of D4-like DA receptor subtype by quinpirole decreased forskolin-stimulated cAMP formation in intact chick retina maintained in "eye-cup" preparations. It is suggested that D4-like DA receptors regulating melatonin biosynthesis in chick retina may be indirectly linked to the cAMP generating system.

Arylamine and arylalkylamine N-acetyltransferases in retina, pineal gland, brain and liver of chicks: a comparative study.

Regulation of arylamine N-acetyltransferase (A-NAT) and arylalkylamine N-acetyltransferase (AA-NAT) was examined in retina, pineal gland, brain and liver of chicks. Enzyme activities were determined using as substrates p-phenetidine and procainamide for A-NAT, tryptamine and phenethylamine for AA-NAT. The activity of A-NAT in all tissues studied does not appear to be regulated by a light-dark cycle. On the other hand, AA-NAT showed distinct light-dark dependent changes (with high values at night) in the retina and pineal gland, but not in brain and liver. The nocturnal increase of retinal and pineal AA-NAT activity was prevented by cycloheximide; the drug did not affect A-NAT activity in these tissues. Treatment of light-adapted chicks with aminophylline significantly increased AA-NAT activity of the retina and pineal gland, without altering the enzyme activity in brain and liver. In these animals, the activity of A-NAT (procainamide) did not change in any tissue studied, whereas the enzyme activity measured using p-phenetidine as a substrate did decrease but only in the retina. A similar pattern of changes in retinal A-NAT and AA-NAT activities was observed after intraocular injection of d,b-cAMP. The rate of inactivation at 4 degrees C was significantly slower for AA-NAT than A-NAT. NATs from brain and liver displayed the highest and lowest, respectively, liability in the cold. The results indicate that the chick retina contains both A-NAT and AA-NAT. The two enzymes have distinct characteristics and the regulation of their activities is different. The retinal A-NAT is similar to A-NAT present in other tested tissues; however, AA-NAT can be induced at night only in the retina and pineal gland. It is suggested that there are two forms of retinal A-NAT, and that, under specified conditions, the activity of one form (A-NAT; p-phenetidine) may be regulated in an opposite manner to AA-NAT activity.

Dark-induced supersensitivity of dopamine D-1 and D-2 receptors in rat retina.

Light deprivation of rat retina leads to a rapid (within 6 h) development of a state of supersensitivity (upregulation) of dopamine D-1 receptors (positively coupled to adenylate cyclase), which are essentially involved in the modulation by light of the electrical activity and communication between horizontal cells. In contrast, the supersensitivity of D-2 receptors (negatively coupled to cAMP generating system) appears to develop only after 2 days (better after 4 days) of dark adaptation, although these receptors are linked to multiple light-dependent retinal functions. These results suggest the existence of different mechanisms of sensory adaptation for these two subtypes of dopamine receptors.

Rapid desensitization of presynaptic dopamine autoreceptors during exposure to exogenous dopamine.

When nomifensine is employed to inhibit neuronal uptake, exposure to dopamine (DA) (0.1-0.3 microM) or apomorphine (0.01-0.1 microM) inhibited, in a concentration-dependent manner, the electrically evoked release of [3H]dopamine from slices of the rabbit caudate nucleus. Apomorphine inhibited transmitter release independently of the time of exposure to the drug (6-32 min). On the other hand, the inhibitory effect of exogenous dopamine occurred only if a short period (4-12 min) of exposure was employed. In studies on the electrically evoked release of [3H]acetylcholine in slices of the rabbit caudate nucleus there was no evidence for desensitization to apomorphine or exogenous dopamine at the level of the dopamine receptors that inhibit [3H]acetylcholine release. These results indicate that the dopamine autoreceptors modulating [3H]dopamine release in the caudate nucleus become subsensitive after a few minutes of exposure to exogenous dopamine. This effect does not occur at the level of the dopamine receptors which inhibit the release of [3H]acetylcholine.

PACAP-induced formation of cyclic AMP in the chicken brain: regional variations and the effect of melatonin.

We have studied the effects of pituitary adenylate cyclase-activating polypeptide (PACAP27 and PACAP38) on cyclic AMP formation in chick brain, and the action of melatonin upon the PACAP-evoked effects. PACAP stimulated cyclic AMP production in the hypothalamus>cerebral cortex>pineal gland>optic lobes. In the hypothalamus and cerebral cortex, the rank-order of both PACAP forms and VIP in evoking the cyclic AMP response was: PACAP38 approximately PACAP27>>VIP, suggesting the presence in the tested tissues of PAC1 receptors. Melatonin suppressed (IC50=19.8 nM) the PACAP27 (0.1 microM)-induced cyclic AMP response in the hypothalamus, but not in the cerebral cortex. Melatonin also suppressed the hypothalamal cyclic AMP synthesis stimulated by forskolin, but not that evoked by histamine or isoprenaline. Our observations show that PACAP is capable of potently stimulating cyclic AMP formation in some regions of the chick brain, and suggest that the hypothalamus may be a site for a functional interaction between PACAP and the pineal hormone melatonin.

Interaction of histamine H2-receptor blocking drugs with the noradrenergic system in rat brain and heart.

The i.v.t. injection of burimamide (BUR), 50 micrograms, or cimetidine (CIM), 250 micrograms, decreased significantly the hypothalamic noradrenaline (NA) content by 32 and 21%, and significantly increased the whole brain 3-methoxy-4-hydroxyphenylglycol level by 46 and 28%, respectively. The i.p. administration of BUR or metiamide (MET), at a dose of 50 mg/kg, caused a decrease in the rat heart NA content by 34 and 21%, respectively; CIM had no effect at doses up to 100 mg/kg i.p., whether given acutely or chronically.

Influence of histamine on the serotonergic system of rat brain.

Both histamine and 4-methylhistamine, after intraventricular injection into normal rats, reduced the levels of serotonin and increased those of 5-hydroxyindoleacetic acid in hypothalamus; after injection into tranylcypromine-treated rats, head twitches were induced which were blocked by antiserotonin agents. 2-Pyridylethylamine, an agonist of histamine H1 receptors, neither influenced serotonin level in hypothalamus nor evoked behavioural changes. It is concluded that injected histamine may release serotonin from the hypothalamus and that this produces the behavioural changes.

Direct or indirect action of histamine on dopamine metabolism in the rat striatum?

Intraventricular administration of 500 microgram of 2-pyridylethylamine, an agonist of the histamine (Hi) H1-receptor, produced a 20% increase of striatal HVA in the rat while the Hi H2-receptor agonist 4-methylhistamine had no influence on HVA and DOPAC levels. L-Histidine (1.5 g/kg) or amodiaquine (60 mg/kg) given i.p. increased HVA and DOPAC levels to the same extent as did pyridylethylamine. Histidine combined with tremorine had an additive effect with respect to the increase of DA acidic metabolites while mepyramine slightly attenuated the tremorine-induced rise of HVA.

An interaction of histamine H2-receptor antagonists with the noradrenergic system in rat brain.

Intraventricular administration of 50 microgram of burimamide or 250 microgram of either metiamide or cimetidine decreased the NA concentration in rat hypothalamus by nearly 30%. Cimetidine did not significantly influence either DA or DOPAC levels in striatum. Cimetidine and metiamide significantly potentiated locomotor activity of tranylcypromine-treated rats and this effect was antagonized by phentolamine. It is concluded that the three histamine H2-receptor antagonists released NA in rat brain.

Vasoactive intestinal peptide-stimulated adenosine 3',5'-cyclic monophosphate formation in cerebral cortex and hypothalamus of chick and rat: comparison of the chicken and mammalian peptide.

Chicken and mammalian (human/porcine/rat) vasoactive intestinal peptides (VIP; 0.01-3 microM), whose structures differ by four amino acid residues in 11, 13, 26 and 28 positions, were compared with respect to their ability to stimulate adenosine 3',5'-cyclic monophosphate (cyclic AMP) formation in the hypothalamus and cerebral cortex of chick and rat. In four tested biological systems, the chicken VIP appeared to be significantly more potent in evoking cyclic AMP response than its mammalian counterpart, the differences were more pronounced in the chick tissues, particularly in the hypothalamus, where the mammalian peptide produced only weak (but significant) effect at the highest used dose, i.e. 3 microM. Pituitary adenylate cyclase-activating polypeptide, a VIP-like peptide, applied as a reference drug at 0.1 microM, strongly stimulated cyclic AMP formation in all tested systems. The data demonstrate significant quantitative differences in biological activity between mammalian and non-mammalian peptides tested in brain tissue of chicks and rats, indicating that usage of the mammalian VIP in at least 'avian' studies may lead to some false conclusions.

Intravitreal application of membrane-permeable analogs of cyclic GMP increases serotonin N-acetyltransferase (NAT) activity in retinas of light-exposed chicks: comparison with the effect of cyclic AMP analogs and darkness.

Intravitreal administration of membrane-permeable analogs of cGMP and cAMP markedly enhanced serotonin N-acetyltransferase (NAT) activity in retinas of light-exposed chicks. The effects of cGMP analogs were usually weaker than the actions of cAMP analogs, however, they were more pronounced than the effects of non-cyclic derivative of GMP (i.e., 8-bromo-GMP). Combined treatment with dibutyryl-derivatives of cGMP and cAMP yielded NAT values that were similar to the values produced by the compounds administered separately, whereas NAT activity in chicks receiving a combination of db-cGMP and aminophylline was higher than the enzyme activity produced by the drugs individually. Neither db-cGMP nor aminophylline affected hydroxyindole-O-methyltransferase (HIOMT) activity in retinas of light-exposed chicks. It is hypothesized that cGMP analogs enhance the retinal NAT activity indirectly, via cAMP.