Opiate and alpha 1-adrenergic receptors in mice responding to morphine with sedation or with running fit.

Two subpopulations of Albino Swiss mice were selected on the basis of their response to a dose of 20 mg/kg ip of morphine: individuals in which the drug constantly produced sedation, and those which responded with running fit. Both subpopulations of mice had cerebral opiate delta and mu receptors (defined as [3H]DADLE and [3H]naloxone binding sites) of similar Bmax and KD values but mice responding with sedation showed lower density of alpha 1-adrenoceptors (defined as [3H]prazosin binding sites) as compared both with mice reacting with running fit or randomly selected animals. Chronic administration of imipramine resulted in a significant increase in the density of [3H]prazosin binding sites in the mice responding with sedation, but not in the animals responding with running fit.

Chronic electroconvulsive treatment counteracts cortical beta-adrenoceptor upregulation induced by morphine abstinence.

Morphine treatment (20 mg/kg for 7 consecutive days) did not affect the density of [3H]dihydroalprenolol ([3H]DHA) binding sites in the cortical membranes of the rat, but during naloxone-precipitated abstinence syndrome the density of these sites increased. Electroconvulsive treatment for 6 days, which by itself decreased the density of [3H]DHA binding sites, prevented the increase.

Antiserotonin activity of 9-methyl-2-[3-(4-phenyl-1-piperazinylpropyl)]-1,2,3,4-tetrahydro -beta-carbolin-1-one (B-193).

The effect of B-193 on the central and peripheral serotonin system was studied. B-193 antagonized the head-twitches responses induced by L-5-hydroxytryptophan (L-5-HTP) in mice (ED50 = 0.75 mg/kg ip and 6.6 mg/kg po) and lysergic acid diethylamide (LSD) in rats (ED50 = 1.54 mg/kg ip) and also counteracted forepaws clonic convulsions induced by tryptamine (ED50 = 3.07 mg/kg ip). B-193 (2.5-20 mg/kg ip) antagonized dose-dependently hyperthermia induced by fenfluramine or m-chlorophenylpiperazine (m-CPP) and in a dose of 1 mg/kg iv abolished the stimulation of the flexor reflex evoked by quipazine or fenfluramine. B-193 given in a concentration of 10(-7)-10(-5) mol/l competitively inhibited contractions of the rat stomach fundus strip induced by serotonin (5-HT) (pA2 = 6.5) and the increases in blood pressure induced by 5-HT in pithed rats (ED50 = 0.17 mg/kg iv). In receptor binding studies B-193 has shown distinct affinity to 5-HT2 receptors, and alpha 1-adrenoceptors much weaker affinity to 5-HT1 receptors and alpha 2-adrenoceptors but not to beta-adrenergic, GABA-ergic or benzodiazepine receptors. Our findings demonstrated that B-193 shows potent central and peripheral antiserotonin activity.

The effect of chronic imipramine and electroconvulsive shock treatment on [3H]DADLE binding to cortical membranes of rats pretreated with chronic reserpine or 6-hydroxydopamine.

Repetitive electroconvulsive shock treatment (for 8 days) or chronic administration of imipramine (10 mg/kg/day IP for 14 or 21 days) elevated the density of opioid delta receptors in the cerebral cortex of the rat. Electroconvulsive shock treatment produced a similar effect in rats treated subchronically with reserpine or receiving intraventricularly 6-hydroxydopamine, but these manipulations of central catecholamines prevented the action of imipramine.

Repeated treatment with antidepressant drugs does not affect the benzodiazepine receptors in preincubated membrane preparations from mouse and rat brain.

Repeated injections or oral administration of antidepressants: imipramine, amitriptyline and desmethylimipramine (10 mg/kg twice daily for 21 days) did not alter significantly [3H]flunitrazepam binding to frozen-thawed preincubated membranes from the brains of mice or rats.

Effects of chronically administered antidepressants and electroconvulsive treatment on cerebral neurotransmitter receptors in rodents with 'model depression'.

The aim of this study was to develop a model of depression in laboratory animals in which chronically administered antidepressant drugs and electroconvulsive treatment (ECT) would produce receptor effects similar to but more marked than those in normal animals. The models discussed in detail are reserpinized and centrally chemosympathectomized rats. Other models currently under investigation are albino Swiss mice that respond with motor inhibition to high doses of morphine and rats tolerant to morphine. The reserpine model seems to be of some value, because in reserpinized rats antidepressants and ECT lead to adrenoceptor changes the same as or more marked than those observed in normal animals. Central chemosympathectomy with 6-hydroxydopamine prevents several receptor actions of imipramine, though not of ECT. The 'opiate models', though apparently not very promising, need further study.

Increased low-affinity 3H-spiroperidol binding to rat cortical membranes after chronic antidepressant treatments.

Looking for receptor correlates of increased motor response to dopaminergic stimulation in rats after antidepressant treatments, we measured specific 3H-spiroperidol binding to membranes from various brain ureas in rats receiving chronically electroconvulsive shock (ECS), imipramine or trazodone. In all groups the low-affinity 3H-spiroperidol binding (KD approximately 3 nM) was increased in the cortex, but not in the subcortical areas.

Effect of electroconvulsive treatment on cerebral opioid receptors in the rat: changes in delta but not mu receptors.

The rats subjected to repetitive electroconvulsive treatment (ECT; 8 electroshocks within 9 days) the density of specific 3H-D-Ala2, D-Leu5-enkephalin (3H-DADLE) binding sites in the cortical membranes was enhanced by approx. 60%, while the density of specific 3H-naloxone binding sites remained unchanged. In the striatum of rats subjected to ECT the specific binding of 3H-DADLE was reduced by 15%, and no change in 3H-naloxone binding was observed. The density of specific binding sites for either radioligand in the rest of brain remained unaffected by ECT. The results suggest that ECT affects specifically the opioid delta receptors in some brain areas.

Chronic administration of antidepressant drugs increases the density of cortical [3H]prazosin binding sites in the rat.

Administration of antidepressants (imipramine, citalopram) or antidepressant neuroleptics (levomepromazine, chlorprothixene) for 14-24 days enhanced by 20-30% the density of [3H]prazosin binding sites in the membranes from the cerebral cortex of the rat, without significant change in their affinity.

Increase in rat cortical [3H]naloxone binding site density after chronic administration of antidepressant agents.

Given chronically, the first and second generation antidepressants imipramine and citalopram, and antidepressant neuroleptics levomepromazine and chlorprothixene, elevated moderately but significantly (by 15-30%) the density of [3H]naloxone binding sites in rat cerebral cortical membranes. There were only small non-significant changes in Kd values.

Alpha up-beta down adrenergic regulation: a possible mechanism of action of antidepressant treatments.

The presently reported findings: that spaced electroconvulsive treatment increases the density of alpha-1 adrenoceptor in the spinal cord as well as in the cerebral cortex of the rat, that treatment with various classes of antidepressant drugs, including antidepressant neuroleptics, affects in a similar manner alpha-adrenoceptors, elevating within 2 weeks the density of alpha-1, and depressing the density of alpha-2 subpopulation, and that prolonged imipramine treatment in investigated strains of rats does not depress the beta adrenoceptor density within 3 weeks, but only after 6-week-treatment such an effect is observed, are discussed together with our earlier results. It is suggested that the first effect of an antidepressant therapy may be a transient upregulation of alpha-2 adrenoceptors causing a decrease in noradrenaline utilization, but this is followed rapidly by an upregulation of alpha-1 adrenoceptors and depression of density of alpha-2 adrenoceptors. Eventually, adaptive beta adrenoceptor down-regulation follows. The final effect of an antidepressant therapy is a specific facilitation of neurotransmission regulated by alpha-1 adrenoceptors.

Electroshock-induced increase in [3H]prazosin binding to cortical membranes in reserpinized rats.

Chronic, spaced electroconvulsive shock (ECS, 6 treatments at 72 h intervals) produced a moderate (16%) increase in the density of [3H]prazosin binding sites to rat cerebral cortical membranes. The increase was of borderline significance (0.1 greater than P greater than 0.05) and KD was not affected. The effect was similar but much more pronounced (increase in Bmax by 38%, P less than 0.01) in rats receiving reserpine pretreatment (4 mg/kg i.p.) 24 h before each ECS. Reserpine produced a transient increase in [3H]prazosin binding 24 h but not 48 h after the last dose, at the time when the ECT effect was measured.

Chronic electroconvulsive treatment enhances the density of [3H]prazosin binding sites in the central nervous system of the rat.

Chronic electroconvulsive treatment (ECT) given daily for 10 days enhanced the density of [3H]prazosin binding sites in the membranes from the spinal cord and cerebral cortex of the rat 24 h after the last shock. Similar effect (investigated only in cortical membranes) was produced by spaced ECT (5 shocks at 72 h intervals). The effect was preceded by a decrease in the density of [3H]prazosin binding sites, observed 2 h after the last shock and disappeared within 48 h.

Dopamine receptors in the striatum and limbic system of various strains of mice: relation to differences in responses to apomorphine.

Dopamine receptors, defined as [3H]spiroperidol binding sites, had similar population parameters in the limbic forebrain of C57BL/6, Albino Swiss and DBA/2 mice, but the parameters of the striatal populations were different: not only the densities differed among themselves, but the KD value of the striatal dopamine receptors of DBA/2 mice was significantly higher than that in the two remaining strains. Behavioral responses of Albino Swiss mice to apomorphine: biphasic effect of apomorphine on locomotor activity and stereotypy characterized by high motility, frequent rearing and sharp, not very frequent bites, were similar to those described earlier for C57BL/6 mice, and differed from those reported for DBA/2 mice. The results suggest that the difference in responding to apomorphine in various strains of mice may be related to differences in their striatal dopamine receptors.

The effect of quipazine and LSD on monoamines in the rat striatum.

Rats given quipazine (5 mg/kg) or LSD (0.05 mg/kg), were decapitated at the time of maximum of behavioral effect of drugs (head twitches), resp. 30 and 15 min, or when the behavioral effects disappeared (resp. 60 and 30 min), and concentrations of dopamine (DA), noradrenaline (NA), serotonin (5HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed in the striatum. Quipazine significantly elevated the DA level at both periods tested. LSD at the peak of its action depressed the level of 5-HIAA, and in the next period produced a significant depression of striatal levels of NA, 5HT and 5-HIAA.

The effect of electric stimulation of caudate nucleus and nucleus accumbens septi on serotonergic neurons in the rat brain.

Nucleus caudatus--putamen (CP) or nucleus accumbens septi (A) were stimulated electrically for 30 min in free moving rats. Immediately or 30 min after the stimulation we studied the level of 5-HTP and DOPA accumulated in the mesencephalon+pons+medulla oblongata, after inhibition of activity of aromatic amino acids decarboxylase by NSD 1015, and intensity of histofluorescence of serotonin in the midbrain raphe nuclei. The electrical stimulation of either structure did not significantly change the content of 5-HTP and DOPA, but stimulation of nucleus accumbens depressed the level of serotonin in the neurocytes of dorsal and ventral raphe nuclei.