H3 receptor-mediated inhibition of noradrenaline release: an investigation into the involvement of Ca2+ and K+ ions, G protein and adenylate cyclase.

The present study was aimed at the identification of mechanisms following the activation of histamine H3 receptors. Mouse brain cortex slices preincubated with 3H-noradrenaline were superfused and the (H3 receptor-mediated) effect of histamine on the electrically evoked tritium overflow was studied under a variety of conditions. The extent of inhibition produced by histamine was inversely related to the frequency of stimulation used to evoke tritium overflow and to the Ca2+ concentration in the superfusion medium. An activator (levcromakalim) and blocker (glibenclamide) of ATP-dependent K+ channels did not affect the electrically evoked tritium overflow and its inhibition by histamine. A blocker of voltage-sensitive K+ channels, tetraethylammonium (TEA), increased the evoked overflow and attenuated the inhibitory effect of histamine. TEA also reduced the inhibitory effect of noradrenaline and prostaglandin E2 on the evoked overflow. When the facilitatory effect of TEA on the evoked overflow was compensated for by reducing the Ca2+ concentration in the superfusion medium, TEA did no longer attenuate the effect of histamine. Exposure of the slices to the SH group-alkylating agent N-ethylmaleimide increased the evoked overflow and attenuated the inhibitory effect of histamine; both effects were counteracted by the SH group-protecting agent dithiothreitol, which, by itself, did not affect the evoked overflow and its inhibition by histamine. Mouse brain cortex membranes were used to study the effect of the H3 receptor agonist R-(-)-alpha-methylhistamine on the basal cAMP accumulation and on the accumulation stimulated by forskolin or noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Time course of the effects of histamine, thioperamide and EEDQ on H3 receptors in the mouse brain.

The effects of histamine, thioperamide and EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) at the noradrenaline release-modulating H3 receptor in the mouse brain were examined. In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the inhibitory effect of histamine on the electrically (0.3 Hz) evoked tritium overflow was virtually identical when the time of exposure was 30, 80 or 130 min; after withdrawal of histamine, the evoked overflow recovered within 80 min. The attenuation of the effect of histamine by thioperamide was reversible within 50 min after withdrawal of the antagonist, whereas the attenuation produced by EEDQ remained constant for at least 80 min. In conclusion, the effects of histamine and thioperamide at the H3 receptor are readily reversible, whereas EEDQ appears to be an irreversible antagonist; desensitization of the H3 receptor does not occur.

The 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide facilitates noradrenaline release by blockade of alpha 2-adrenoceptors in the mouse brain cortex.

We analyzed the facilitatory effect of the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (mCPBG) on the electrically evoked noradrenaline release in superfused mouse brain tissue. In addition, we determined the affinities of mCPBG and two other 5-HT receptor ligands, namely 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; also a 5-HT3 receptor agonist) and 5-carboxamidotryptamine (5-CT; a 5-HT1 receptor agonist) for alpha 2 binding sites. The latter two 5-HT receptor agonists were included because of the claimed involvement of alpha 2-adrenoceptors in their effects on noradrenaline release. In superfusion experiments on mouse brain cortex slices preincubated with 3H-noradrenaline, tritium overflow evoked by 2-min periods of electrical field stimulation (3 Hz) was facilitated by mCPBG and, in addition, by rauwolscine (alpha 2-adrenoceptor antagonist) and tetraethylammonium (K+ channel blocker) (which were examined for comparison). The effect of mCPBG was not affected by the 5-HT3 receptor antagonist tropisetron or by desipramine but was abolished by rauwolscine. In slices superfused with medium containing desipramine, the concentration-response curve of unlabelled noradrenaline for its inhibitory effect on the electrically (0.3 Hz) evoked overflow was shifted to the right by mCPBG and rauwolscine (apparent pA2 5.35 and 7.88, respectively). In another series of superfusion experiments, 4 electrical pulses, administered at 100 Hz, were used to evoke tritium overflow. Tritium overflow evoked by this stimulation procedure (under which an endogenous tone of noradrenaline does not develop) was not affected by mCPBG and rauwolscine but still increased by tetraethylammonium.(ABSTRACT TRUNCATED AT 250 WORDS)

Nordimaprit, homodimaprit, clobenpropit and imetit: affinities for H3 binding sites and potencies in a functional H3 receptor model.

We determined the affinities of nordimaprit, homodimaprit, clobenpropit and imetit for H3 binding sites (labelled by 3H-N alpha-methylhistamine) in rat brain cortex homogenates and their potencies at presynaptic H3A receptors on noradrenergic nerve endings in mouse brain cortex slices. 3H-N alpha-Methylhistamine bound saturably to rat brain cortex homogenates with a Kd of 0.70 nmol/l and a Bmax of 98 fmol/mg protein. Binding of 3H-N alpha-methylhistamine was displaced monophasically by dimaprit (pKi 6.55), nordimaprit (5.94), homodimaprit (6.44), clobenpropit (9.16), imetit (9.83), R-(-)-alpha-methylhistamine (8.87) and histamine (8.20), and biphasically by burimamide (pKi high 7.73, pKi low 5.97). In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the electrically (0.3 Hz) evoked tritium overflow was inhibited by imetit (pIC35 8.93), R-(-)-alpha-methylhistamine (7.87) and histamine (7.03). The effect of histamine was attenuated by nordimaprit, homodimaprit, clobenpropit and N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ); EEDQ (but not nordimaprit, homodimaprit and clobenpropit) attenuated the effect of histamine also in slices pre-exposed to the drug 60-30 min prior to superfusion. The concentration-response curve of histamine was shifted to the right by homodimaprit and clobenpropit; Schild plots yielded straight lines with a slope of unity for both drugs (pA2 5.94 and 9.55, respectively). Nordimaprit depressed the maximum effect of histamine (pD'2 5.55) and also slightly increased the concentration of histamine producing the half-maximum effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors.

In superfused mouse striatal slices preincubated with [3H]dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 mumol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [3H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H3 agonist R-(-)-alpha-methylhistamine; it was not affected by the H1 antagonist dimetindene and the H2 antagonist ranitidine but abolished by the H3 antagonist thioperamide. Tritium overflow evoked by Ca2+ ions (introduced into Ca(2+)-free, K(+)-rich medium containing tetrodotoxin) was not affected by histamine 10 mumol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H3 receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H3 receptor-mediated inhibition of dopamine release.

[Is there a subgroup of hyperkinetic children with emotional disorders? Results of a pilot study]. / Gibt es eine Untergruppe hyperkinetischer Kinder mit emotionalen Störungen? Ergebnisse einer Pilot-Studie.

Child psychiatric classification systems make no provision for a regular association between the Hyperkinetic Syndrome and emotional disorders. However, such an association could be demonstrated in 9.3% of 464 in- and outpatients seen at our child psychiatric unit for treatment of hyperkinesis. Based on the differences found between the subjects with both the Hyperkinetic Syndrome and emotional problems and those without emotional problems, four pathogenetic models were discussed. An experimental design is proposed for hypothesis testing.

[Computer tomography, electroencephalography and neurologic findings in child and adolescent psychiatric syndromes]. / Computertomographische, elektroencephalographische und neurologische Befunde bei kinder- und jugendpsychiatrischen Syndromen.

Computed tomographic brain scan (CT) findings in 239 inpatients seen at a child psychiatry unit were rated in terms of type, location, and severity of brain damage. The rate of abnormalities found was 42%, which is consistent with the figures reported in the literature. There was only a small overlap between abnormal CT findings and abnormal findings in the electroencephalographic (EEG) or neurological examinations. Although abnormal CT findings were more frequent in children with certain diagnoses, i.e. those with psychoses or anorexia nervosa, no CT findings were characteristic of any group, thus indicating a quantitative rather than a qualitative difference. The fact that there was little overlap between CT scans and EEG or neurological findings suggests the need for more studies on diagnosing brain damage and on the relationship of brain damage to psychiatric symptoms.

[Epilepsy, anticonvulsive treatment and child psychiatric conspicuousness]. / Epilepsie, antikonvulsive Behandlung und kinderpsychiatrische Auffälligkeit.

Seventy-nine children suffering from epileptic seizures who were seen at a clinic for child and adolescent psychiatry for behavior disorders were compared with a control group from the same clinic matched by age, sex and IQ. Significant differences were found between the two groups in the percentages diagnosed as having "no psychiatric disorder", "neurotic or emotional disorder" and "specific disorder following brain damage". Neither the type nor the frequency of epileptic seizures was found to have an influence on the type of psychiatric disturbance. Only a small proportion of the children with epilepsy (12%) had psychiatric symptoms, which if present were compatible with the diagnosis "organic psychosyndrome". No abnormal psychosocial situations were found to be specific for epilepsy, but the type of medication (especially barbiturates) had a significant influence on the incidence of conduct disorders.

[Combined treatment of autism]. / Kombinierte Autismusbehandlung--ein Fallbericht.

In this detailed case report we describe the inpatient treatment of an eight-year-old boy with infantile autism. A multiple modality approach was used that included holding therapy as recommended by Prekop (1983), educational therapy and lithium treatment. The aim of holding was two-fold: to achieve interpersonal contact with the child and to improve his ability to concentrate on learning tasks. The educational therapy also served to increase his attention span and, later to initiate language acquisition. Lithium treatment resulted in better control of behavior and in improvement of mood.