Diana Kelder

Long lasting attenuation of 8-OH-DPAT-induced corticosterone secretion after a single injection of a 5-HT1A receptor agonist

SummaryThe effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some other 5-hydroxytryptamine1A (5-HT1A) receptor agonists (buspirone, ipsapirone and flesinoxan) on corticosterone secretion in rats were studied. The 5-HT1A receptors mediating the corticosterone secretion appear to be postsynaptic to the 5-HT neurons, since the response to 8-OH-DPAT was not decreased but potentiated by depletion of 5-HT with p-chlorophenylalanine pretreatment of the animals. Rapid attenuation of the response was developed after a single dose of a 5-HT1A receptor agonist. Thus, 1 mg/kg s.c. of 8-OH-DPAT attenuated the response of a challenge dose (0.1 mg/kg s.c.) of this compound within 4 h lasting between 7 and 14 d. The development of the subsensitivity was antagonized by pretreatment of the rats with the 5-HT1A receptor antagonist S-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((−)-UH 301). This compound also antagonized the acute effect of 8-OH-DPAT in increasing serum corticosterone. The subsensitivity development was specific for the 5-HT1A receptor-mediated corticosterone secretion, since the increase in serum corticosterone produced by stimulation of other receptor systems, e.g. α2-adrenoreceptors (clonidine) or 5-HT2 receptors [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI)] was not affected.

N-Methyl-D-aspartate receptor antagonists counteract the long lasting 5-HT1A receptor-induced attenuation of postsynaptic responses in the rat in vivo

SummaryThe effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine and phencyclidine, the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP) and the antagonist at the glycine modulatory site of the NMDA receptor, 3-amino-l-hydroxy-2-pyrrolidone (HA-966) on the long lasting attenuation of some postsynaptic 5-HT1A receptor-mediated responses in rats (increased corticosterone secretion and inhibition of the cage leaving response) produced by a single injection of the 5-hydroxytryptamine1A 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied. It was found that these antagonists counter-acted the attenuation of these responses at dose levels known to block the NMDA receptor-ion channel complex in vivo. It is concluded that the long lasting attenuation of postsynaptic responses after a 5-HT1A receptor agonist is initiated through stimulation of glutamate NMDA receptors indicating a functional interaction between the 5-HT and glutamate systems in at least two different models.

Effect of veratridine on the fluxes of 3H-noradrenaline and 3H-bretylium in the rat vas deferens in vitro

SummaryThe effect of the depolarizing agent veratridine on the accumulation and release of 3H-noradrenaline and 3H-bretylium in the rat vas deferens in vitro was examined. Veratridine produced inhibition of the accumulation and induced marked release of the amines. in vas deferens from non-reserpinized rats the release of noradrenaline evoked by veratridine was partially antagonized by omission of Ca2+ in the incubation medium and partially inhibited by low concentrations of desipramine. In reserpinized vas deferens the release of noradrenaline like that of bretylium in normal vas was not affected by omission of Ca2+ but inhibited by low concentrations (3–5×10−7 M) of desipramine. Tetrodotoxin and the local anesthetics millicaine and lidocaine antagonized the effect of veratridine on the accumulation and release of the amines, probably due to prevention of the depolarization. High concentration (3×10−5 M) of desipramine had a similar effect on The release of noradrenaline in normal tissue in presence of external Ca2+. It is concluded that noradrenaline is released by veratridine from normal vas deferens by two mechanisms: 1) an exocytosis release, 2) a carrier mediated desipramine sensitive outward transport. In reserpinized tissue the second mechanism is solely responsible for the release of noradrenaline. Bretylium is only released by the second mechanism. It is suggested that the inhibition of the amine accumulation by veratridine is due to an equilibrium of the influx at a low tissue to medium ratio.

Forebrain projections of the ventral tegmentum as studied by axonal transport of [3H]dopamine in the rat

Twenty-four hours after [3H]dopamine ([3H]DA) injections into different parts of the ventral tegmentum the radioactivity recovered in the forebrain showed a highly regional distribution which corresponded to well-known DA projections. Selective degeneration of DA-neurons with 6-hydroxydopamine (6-OHDA) markedly reduced the axoplasmic transport after [3H]DA injections. The ventral tegmental area (VTA) was found to project primarily to the nucleus accumbens, olfactory tubercle and amygdala. The DA-innervation of the entorhinal cortex and the amygdala derive from cells widely distributed in the VTA and SN.

Effects of acute and repeated administration of amiflamine on mono amine oxidase inhibition in the rat

The inhibitory effect on monoamine oxidase (MAO) of the reversible MAO-A inhibitor (+)-4-dimethylamino-2,alpha-dimethylphenethylamine [amiflamine, FLA 336(+)] was evaluated in the rat after acute and repeated (twice daily for two weeks) oral treatment. MAO activity was measured ex vivo in slices from the hypothalamus and the duodenum for both MAO-A and MAO-B. Amiflamine selectively inhibited the A form of MAO after repeated as well as after acute treatment (ED50 approximately 7 mumoles/kg both acute and repeated). In the brain slices this inhibition corresponded to a decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA) and to an increase in the concentration of 5-HT in the hypothalamus, the hippocampus and the striatum. The concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) was decreased in the striatum to the same extent as the decrease in the 5-HIAA concentrations. The effect on the homovanillic acid (HVA) concentration was somewhat weaker as was the increase in the concentration of dopamine. No essential difference was found after acute and chronic treatment on the amine and metabolite levels. The MAO activity returned to normal 24 hours after final dosing. A large difference between the neuronal and the extraneuronal protection against the phenelzine-induced irreversible MAO inhibition in the hypothalamus was found after both acute and repeated treatment. The ED50 of the protection within the serotonergic neurons was 1.3 mumoles/kg p.o. (acute) and 0.75 mumoles/kg p.o. (repeated). Amiflamine was 3 times less potent within noradrenergic neurons than within serotonergic neurons. A brain to plasma ratio of about 20:1 was found for amiflamine and its metabolites. The plasma and the brain concentrations of the N-demethylated metabolite [FLA 788(+)] exceeded that of amiflamine after a single dose, whereas the N,N-demethylated [FLA 668(+)] was found in low concentrations. The effect on MAO-A correlated significantly with the plasma and the brain concentration of FLA 788(+).

Counteraction of the rapid tolerance to 8‐OH‐DPAT‐induced corticosterone secretion in rats by activation of the GABAA receptor‐chloride channel complex

1 The effect of various classes of compounds on the rapidly developed tolerance to 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT)‐induced corticosterone secretion was examined. 2 Compounds activating the γ‐aminobutyric acidA (GABAA) receptor‐chloride complex, i.e. muscimol (3 mg kg−1), diazepam (5 mg kg−1), flunitrazepam (1 mg kg−1), sodium pentobarbitone (10–30 mg kg−1) and chlormethiazole ethane disulphonate (50 mg kg−1) counteracted the development of tolerance when injected before or simultaneously with, but not 15 min after 8‐OH‐DPAT. 3 At these doses the compounds produced an acute increase in serum corticosterone but had, with the exception of muscimol, no effect on the response to the challenge dose of 8‐OH‐DPAT 24 h later. Muscimol significantly decreased the response. 4 The GABAA chloride channel antagonist, picrotoxin (1 mg kg−1, s.c.), but not bicuculline (1 mg kg−1, i.p.) potentiated the development of tolerance to 8‐OH‐DPAT‐induced corticosterone secretion. 5 A number of compounds with widely differing pharmacological actions were examined and found to have no effect on the development of tolerance to 8‐OH‐DPAT‐induced corticosterone secretion.

Selective inhibition by 4,α-dimethyl-m-tyramine (H77/77) and 4-methyl-α-ethyl-m-tyramine (H75/12) of the monoamine oxidase within serotonergic and noradrenergic neurons in the rat brain

Summary1. The inhibition of monoamine oxidase (MAO) by 4,α-dimethyl-m-tyramine (H77/77) and 4-methyl-α-ethyl-m-tyramine (H75/12), two amine releasing compounds, within monoaminergic neurons in the rat hypothalamus and striatum in vivo was determined. This was performed by measuring the protection of MAO by the test compound against the irreversible inhibition produced by phenelzine. The MAO activity inside and outside monoaminergic synaptosomes in homogenates of brain tissue was measured in the absence and presence of selective uptake inhibitors at low concentrations of 14C-labelled 5-hydroxytryptamine, noradrenaline or dopamine. 2. It was found that H77/77 and H75/12 produced a pronounced protection against phenelzine within the serotonergic and noradrenergic neurons, whereas much less effect was observed outside these neurons. 3. It was shown that the protection by H75/12 within the serotonergic neurons was somewhat reduced in 5-HT depleted reserpinized rats and that the protection outside these neurons was abolished. Some of the protection of MAO might therefore have been brought about by 5-HT molecules released by H75/12. 4. The marked inhibition of MAO within serotonergic and noradrenergic neurons was counteracted by amine uptake inhibitors and is accordingly brought about by the high concentrations of the accumulated compounds. 5. In contrast to other neuron selective MAO inhibitors, H75/12 decreased the 5-HT concentration in the hypothalamus showing that the releasing effect dominated over the MAO inhibitory effect.