Stimulation of central D1 dopamine receptors reverses reserpine-induced hypothermia in mice.

In mice rendered poikilothermic by a prior (18 h) subcutaneous administration of reserpine (3 mg/kg) the injection of the D1 dopamine agonist SKF 38393 in doses of 1 mg/kg or more increased dose-dependently, the body temperature. The D1 dopamine antagonist SCH 23390, administered subcutaneously, antagonized, with an ID50 of 16 micrograms/kg, the reversal by SKF 38393 of reserpine-induced hypothermia. The intracerebroventricular administration of 1 microgram per mouse of SKF 38393 was sufficient to elevate by about 7 degrees C the temperature of reserpinized mice.

Role of endogenous enkephalins in locomotion and nociception studied with peptidase inhibitors in two inbred strains of mice (C57BL/6J and DBA/2J).

Acetorphan, a parenterally active enkephalinase inhibitor, induced dose-dependently a naloxone-reversible analgesia on the hot-plate jump test in DBA/2J (DBA2) mice but was devoid of effects in C57BL/6J (C57) mice. By contrast, acetorphan increased locomotion in both strains; however, the DBA2 strain was much more sensitive than C57 mice to the locomotor stimulant effect. The increased locomotion was antagonized by naloxone in both strains.

Time course of postmortem modifications in synaptosomal [3H]dopamine uptake and [3H]GBR 12783 binding to the dopamine uptake complex in the rat striatum.

The present study focuses on the changes of two biochemical markers of the striatal dopaminergic innervation evaluated after different postmortem storage periods of rat heads either at room temperature (21 degrees C) or at 4 degrees C: (i) the uptake of [3H]dopamine (DA) into striatal synaptosomes and (ii) the specific binding of [3H]GBR 12783, a selective ligand for the neuronal dopamine uptake sites, to a striatal membrane fraction. The uptake of [3H]DA was completely abolished after 24 and 72 h storage of the tissue at 21 degrees C and 4 degrees C, respectively, whereas in the same conditions, the binding of [3H]GBR 12783 was slightly decreased. The Km and Kd of these two processes were virtually unchanged after the different storage periods considered, whereas the Vmax and Bmax were markedly decreased.

Correlation between (3H)dopamine specific uptake and (3H)GBR 12783 specific binding during the maturation of rat striatum.

The development of the specific uptake of dopamine in the rat striatum during the early postnatal period is compared with the ontogenetic changes of the specific binding of (3H)GBR 12783 to the site of uptake inhibition. During maturation, the increase in the specific binding of (3H)GBR 12783 parallels the increase in the specific uptake of dopamine. (3H)GBR 12783 specific binding sites increase in number from day 1 postpartum until 40 days, when they reach the adult level.

Characteristics of the dopamine receptors involved in the anorectic effects of apomorphine in mice.

In food-deprived mice apomorphine injected SC induced a brief (15-30 min) dose-dependent (30-150 micrograms/kg) reduction in food intake. This effect occurred in naive mice as well as in mice habituated to a food deprivation procedure. The anorectic effect of apomorphine (150 micrograms/kg SC) was antagonized by sulpiride (ID50 = 8.

Appearance of a stereotyped apomorphine-induced climbing in unresponsive DBA2 mice after subchronic manipulations of brain dopamine transmission.

DBA2 mice show an erratic spontaneous climbing which is reduced by increasing doses of direct dopamine agonists (apomorphine up to 5 mg/kg, piribedil up to 20 mg/kg). Sustained stereotyped climbing occurs when animals are treated with L-dopa plus benserazide and dexamphetamine. In this strain, which is spontaneously insensitive to apomorphine-induced climbing, this behaviour progressively appeared in a stereotyped manner after repeated administrations of apomorphine (5 mg/kg).

In vivo and in vitro autoradiographic labelling of central dopaminergic systems with [3H]GBR12783 in rodents.

Labelling of central dopaminergic systems with the dopamine uptake inhibitor [3H]GBR12783 was performed in vivo in mice by i.v. injection of a tracer dose of the ligand (40 microCi) 1 h before sacrifice.

Potent inhibition of cerebral aminopeptidases by carbaphethiol, a parenterally active compound.

We designed phethiol (1-amino-1-benzyl-2-mercaptoethane) as a potent and selective inhibitor of Zn-containing aminopeptidases. This compound inhibited purified aminopeptidase M (EC.3.

Acute effects of direct dopamine agonists in the mouse behavioral despair test.

All the dopamine agonists (apomorphine, dipropylamino-5,6-dihydroxytetrahydronaphtalene, piribedil, bromocriptine, CBM 36-733) tested in the 'behavioral despair' test performed in mice had a dose-dependent anti-immobility effect, with the exception of the D-1 dopamine agonist, SKF 38393. This effect occurred at doses that reduced locomotor activity and decreased colonic temperature. A profound hypothermia of the same amplitude resulted from the immersion in water of the control and apomorphine (Apo)-treated mice.

Hypothermic effect of neuromedin N in mice and its potentiation by peptidase inhibitors.

The intracerebroventricular administration of neuromedin N (from 50 ng to 5 micrograms) elicited a dose- and time-dependent hypothermia in mice. Two aminopeptidase inhibitors, bestatin (50 micrograms) and puromycin (50 micrograms), the endopeptidase 24.11 inhibitor, thiorphan (10 micrograms), and the angiotensin-converting enzyme inhibitor, captopril (50 micrograms), were tested for their ability to potentiate the neuromedin N-induced hypothermia.

[Pharmacological and molecular aspects of the regulation of eating behavior. With special reference to the role of catecholamines and effects of amphetamine].

Among the numerous endogenous substances involved in the regulation of feeding behaviours, the catecholamines are in the front rank. The numerous studies devoted to this aspect of catecholamines emphasize the importance and complexity of their intervention. Depending on the cerebral structures on which they act and on whether noradrenaline or dopamine are concerned, orexigenic or anorexigenic effects have been described.

Ionic requirements for the specific binding of [3H]GBR 12783 to a site associated with the dopamine uptake carrier.

At 0 degrees C, when Na+ was the only cation present in the incubation medium, increasing the Na+ concentration from 3 to 10 mM enhanced the affinity of [3H]1-[2-(++di-phenylmethoxy)ethyl]-4-(3-phenyl-2-propenyl)piperaz ine [( 3H]GBR 12783) for the specific binding site present in rat striatal membranes without affecting the Bmax. For higher Na+ concentrations, specific binding values plateaued and then slightly decreased at 130 mM Na+. In a 10 mM Na+ medium, the KD and the Bmax were, respectively, 0.

Potentiation by thiorphan and bestatin of the naloxone-insensitive analgesic effects of neurotensin and neuromedin n.

Neurotensin induced significant antinociceptive activity as measured in a variety of nociceptive tests 10 and 30 min following intracerebroventricular (i.c.v.

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice, evidenced by antidepressants.

The intracerebroventricular (i.c.v.

Naloxone-reversible antidiarrheal effects of enkephalinase inhibitors.

Thiorphan and acetorphan, two potent inhibitors of enkephalinase (EC 3.4.24.

Role of endogenous enkephalins in locomotion evidenced by acetorphan, an "enkephalinase" inhibitor.

To investigate whether endogenous enkephalins modulate locomotion we studied the effect of the systemic administration of acetorphan, a parenterally active "enkephalinase" inhibitor. Locomotor activity in mice and rats was considered as an index to the activity of mesolimbic dopaminergic neurons. Acetorphan injected i.

Analgesic effects of metapramine and evidence against the involvement of endogenous enkephalins in the analgesia induced by tricyclic antidepressants.

In several pain models, tricyclic antidepressants (TCAs) have been shown to reduce nociception. In the present study, we evaluated the antinociceptive effect of metapramine (META) in 4 nociception tests: (1) the hot plate test; (2) the phenylbenzoquinone-induced writhing; (3) the tail flick test; and (4) the test of electrical stimulation of the tail. We further analysed, using META and clomipramine (CLOM), the eventual role of endogenous opioids in analgesia induced by TCAs.

Enantiomers of thiorphan and acetorphan: correlation between enkephalinase inhibition, protection of endogenous enkephalins and behavioral effects.

The relationships between various properties of inhibitors of enkephalinase (membrane metalloendopeptidase, EC 3.4.24.

In vivo binding of [3H]GBR 12783, a selective dopamine uptake inhibitor, in mouse striatum.

[3H]GBR 12783 (1,2-(diphenylmethoxy)ethyl-4-(3-phenyl-2-propenyl)-piperazine), a specific dopamine uptake inhibitor, was tested for in vivo central binding in mice. The difference between the striatal and cerebellar levels of radioactivity was maximal 1 hour after the i.v.

Sodium independence of the binding of [3H]GBR 12783 and other dopamine uptake inhibitors to the dopamine uptake complex.

When Na+ was the only cation present in the incubation medium used for the determination of the specific binding of [3H]GBR 12783 in rat striatal membranes, the Na+-dependence between 10 and 210 mM Na+ was not observed. In media with low (10 mM) or high (130 mM) Na+ concentration, mazindol and nomifensine competed with [3H]GBR 12783 for its specific binding site with the same affinities. With the exception of amineptine, all the tested catecholamine uptake inhibitors were equally potent to compete with [3H]GBR 12783 when Na+ concentration was decreased from 130 to 10 mM.

Interactions of amineptine with the neuronal dopamine uptake system: neurochemical in vitro and in vivo studies.

The effects of amineptine on 3H-dopamine uptake and 14C-dopamine release have been studied simultaneously in double labelling test performed on rat striatal synaptosomes. 3H-dopamine uptake was completely inhibited at 10 microM amineptine, a concentration which produced only a weak 14C-DA release (13% of the 14C-radioactivity stored). The IC 50 for the inhibition of 3H-DA uptake was not modified by a previous treatment with reserpine whereas the IC 50 of (+) amphetamine and the IC 50 of clomipramine were decreased 9 fold and increased two fold, respectively.

Naloxone-insensitive potentiation of neurotensin hypothermic effect by the enkephalinase inhibitor thiorphan.

The hypothermic effect of neurotensin (0.1 microgram) injected i.c.

High-affinity [3H]GBR 12783 binding to a specific site associated with the neuronal dopamine uptake complex in the central nervous system.

We labelled the neuronal dopamine uptake system by using the potent dopamine uptake inhibitor GBR 12783 in its tritiated form (18.3 Ci/mmol). The binding of [3H]GBR 12783 to rat striatal membranes was saturable and specific with a Kd of 1.

Pharmacological properties of acetorphan, a parenterally active "enkephalinase" inhibitor.

Acetorphan, i.e. N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]-glycine, benzyl ester, is a lipophilic derivative of Thiorphan, a potent inhibitor of "enkephalinase" (EC 3.