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Biomedical subjects

O Gandolfi

Publications and source records attributed to O Gandolfi.

At least 55 records · Page 3Linked to original sources
PubMed1986

Behavioral differentiation between pharmacokinetic and pharmacodynamic components of the interaction of antidepressants or neuroleptics with methamphetamine.

This study proposes a method capable of separating the pharmacodynamic from the pharmacokinetic component in the methamphetamine (MA) hyperactivity potentiation induced by antidepressants. Several antidepressants and neuroleptics, other centrally-acting drugs and the inhibitor of hepatic drug metabolism SKF 525-A were studied. The motility counts taken between 10 and 20 min after MA injection were considered as an index of pharmacodynamic interaction and the whole duration of the hyperactivity syndrome as an index of pharmacokinetic interaction. The duration of MA effect was prolonged by some of the drugs studied and left unchanged by the others regardless of their clinical classification. On the contrary, our evaluation of the intensity of MA effect produced a sharp differentiation between classical neuroleptics and typical antidepressants: the former antagonized and the latter potentiated MA peak intensity. Only the D-2 blocking neuroleptics sulpiride and tiapride potentiated MA intensity. Regarding the specificity of our model, none of the compounds known to be devoid of clinical antidepressant or antipsychotic activity interacted with MA in such a way as to be included in either category. As to the sensitivity of the test, two "false negatives" were obtained: the neuroleptic clozapine and the antidepressant mianserin. Such exceptions were discussed taking into account their peculiar mechanisms of action.

Animals↗
PubMed1986

Involvement of different dopamine receptors in rat diphasic motility response to apomorphine.

A critical dose of apomorphine (300 micrograms/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (-)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity.

Animals↗
PubMed1985

Different effects of serotonin antagonists on 3H-mianserin and 3H-ketanserin recognition sites.

In minces prepared from the frontal cortex of rats treated with ketanserin (10 mg/kg i.p.) or mianserin (5 mg/kg i.p.) twice daily for 21 days, the Vmax of the adenylate cyclase stimulated by NE (100 microM) is attenuated, suggesting that ketanserin and mianserin share with a number of antidepressants the ability to attenuate the adenylate cyclase stimulation by NE. Ketanserin, given with the above mentioned dose schedule for 7 consecutive days, reduced the Bmax of 5HT2 recognition sites but failed to change either the Bmax or the apparent Kd of H-mianserin binding. A significant decrease in the Bmax of 5HT2 binding sites is elicited also by a single injection of mianserin (1). This drug also down-regulates its own binding when given twice daily for 3 weeks. From this and other information (2,3), it is concluded that ketanserin and mianserin bind to distinct recognition sites. The possibility that 5HT2 and mianserin recognition sites are functionally related and that serotonergic synapses are modulated by multiple chemical signals might be considered.

Animals↗
PubMed1984

On the neurotoxicity of chlordecone: a role for gamma-aminobutyric acid and serotonin.

Rats receiving the chlorinated insecticide, chlordecone (80 mg/kg i.p.), exhibit hyperexcitability, exaggerated startle response and tremors within a few hours after the injection. Since the chlordecone-elicited tremors are relieved by injections of muscarinic receptor blockers, acetylcholine has been implicated indirectly in the mechanism of chlordecone toxicity. Our studies on acetylcholine steady-state levels and turnover in several brain structures failed to detect evidence for an involvement of cholinergic presynaptic mechanisms in the chlordecone toxicity. We then investigated whether GABA is involved by measuring the rate of its accumulation following intraventricular injection of gabaculine. Chlordecone reduced the rate of GABA accumulation in striatum, but not in cerebellum, brainstem or hippocampus. Such inhibition appeared 4 h after drug injection thereby preceding the onset of tremors. Since tremors elicited by chlordecone are attenuated by the administration of serotonin receptor blockers and since chlordecone increases serotonin (5-HT) turnover, we studied whether 5-HT recognition sites are modified following chlordecone administration. We have found a reduction of the Bmax of 5-HT1 receptors in striatum and hippocampus without any modification in the kinetic characteristics of 5-HT2 receptors. We have also shown that the temporal relationship between down regulation of 5-HT1 recognition sites, reduction of striatal GABA turnover and tremors caused by chlordecone allows one to consider these 3 phenomena as reciprocally dependent. In conclusion our results favor the possibility that tremors may result from a decrease in the striatal GABergic tone which probably is elicited by an increase of serotonergic activity caused by chlordecone by a yet unknown mechanism.

Acetylcholine↗
PubMed1984

The (-)-deprenyl actions on beta-adrenergic receptors require the integrity of brain serotonergic axon terminals.

In rats receiving (-)-deprenyl (1 mumol/kg, s.c.) twice daily for 3 weeks, the Bmax of imipramine binding sites located in crude synaptic membranes prepared from frontal cortex increases while the NE stimulation of cAMP accumulation in minces prepared from frontal cortex is attenuated. The presence of intact 5HT axon terminals is an absolute requirement for the down-regulation of the beta-adrenergic receptor function by repeated injections of (-)-deprenyl. These and other lines of evidence suggest that the increase in the Bmax of [3H]imipramine binding sites and the attenuation of beta-adrenergic receptor function elicited by (-)-deprenyl might be causally related.

5,7-Dihydroxytryptamine↗
PubMed1984

Antidepressant versus neuroleptic activities of sulpiride isomers on four animal models of depression.

The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness ( FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4. (-)-Sulpiride worked in a similar way to haloperidol in all tests. (+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential "antidepressant" activity of (+)-sulpiride which merits further investigation.

Animals↗
PubMed1984

Comparison of iprindole, imipramine and mianserin action on brain serotonergic and beta adrenergic receptors.

Iprindole in vitro displaces mianserin from specific recognition sites (IC50 3 microM). Daily doses (5 mg/kg i.p.) of iprindole repeated for 3 weeks attenuate the norepinephrine stimulation of adenylate cyclase studied in brain slices. Whereas the attenuation of noradrenergic receptor function elicited by imipramine can be antagonized by lesions of serotonergic axons, the inhibition of norepinephrine-induced stimulation of adenylate cyclase elicited by iprindole or mianserin is not inhibited by serotonin axon lesions. Iprindole given daily repeatedly reduces the maximal number of binding sites of [3H]mianserin and [3H]ketanserin; both actions are unchanged by lesions of central serotonergic axons.

Animals↗
PubMed1983

(-)-Deprenyl a selective MAO "B' inhibitor, increases [3H]imipramine binding and decreases beta-adrenergic receptor function.

In rats, a selective inhibition for 3 weeks of monoamineoxydase (MAO) type B elicited by daily doses of pargyline (2.5 mumol/kg) or (-)-deprenyl (1 mumol/kg) attenuated the NE dependent stimulation of cortical adenylate cyclase and reduced the number of brain recognition sites for beta-adrenergic receptor ligands. Similar actions were not elicited by a comparable dose regimen of (+)-amphetamine. Hence the inhibition of MAO B mimicks responses that are typically elicited by antidepressants. The molecular nature of the mechanisms involved cannot be understood, however, these mechanisms may not be identical for pargyline and (-)-deprenyl because this drug but not pargyline increased the number of [3H]imipramine recognition sites. Even high daily doses of pargyline (100 mumol/kg, for 3 weeks) failed to change [3H]imipramine binding though they still down regulated beta-adrenergic recognition sites, the NE stimulation of adenylate cyclase and the Bmax of [3H]mianserin and [3H]spiroperidol binding.

Animals↗
PubMed1983

Time course of rat motility response to apomorphine: a simple model for studying preferential blockade of brain dopamine receptors mediating sedation.

The present work proposes a simple behavioral method for studying the ability of certain neuroleptics to block preferentially dopamine receptors subserving sedation. The model is based on the temporally biphasic motor response induced in rats by a single critical dose of apomorphine. It was chosen from a preliminary apomorphine dose-response study which showed that the same doses between 6.25 and 625 micrograms/kg affected rat motility differently according to whether the animals were "naive" or "familiarized" to the apparatus for 90 min before administering the drug. When the motility response of naive rats to 300 micrograms/kg of apomorphine was recorded immediately after SC injection, an initial (1--5 min) inhibition and a subsequent (20--45 min) stimulation of motility were obtained. (--)-Sulpiride (1.25--50 mg/kg) was found to be approximately 6-fold more effective in counteracting the apomorphine inhibition than stimulation of locomotion. Haloperidol (0.005--0.1 mg/kg) incompletely antagonized apomorphine inhibition and markedly blocked stimulation, which suggests that it has no preferential activity on dopamine receptors subserving sedation. The results were in accordance with those obtained by other authors with different paradigms, and indicated that the time course of the rat motility response to a single dose of apomorphine may constitute a useful model for detecting selective influences on different dopamine receptors.

Animals↗
PubMed1983

Daily bupropion injections for 3 weeks attenuate the NE stimulation of adenylate cyclase and the number of beta-adrenergic recognition sites in rat frontal cortex.

In rats receiving daily doses (50 mg/kg i.p. twice daily) of bupropion HCI (WellbutrinR) repeated for 21 days the Bmax of the beta-adrenergic receptor recognition sites located in the frontal cortex is reduced. This decrease is not associated with a decrease of the apparent affinity of these recognition sites. However the Vmax of the cAMP (cyclic AMP) generating system stimulated by NE is reduced suggesting that similarly to other antidepressants bupropion down regulates beta-adrenergic receptors located in the frontal cortex. Bupropion neither inhibits MAO (monoamine oxidase) nor releases biogenic amines but only weakly inhibits monoamine uptake in vitro.

Adenylyl Cyclases↗
PubMed1983

Differences in the regulatory adaptation of the 5HT recognition sites labelled by 3H-mianserin or 3H-ketanserin.

In crude synaptic membranes prepared from rat brain the sites occupied by 3H-spiroperidol that are displaced by microM concentrations of serotonin (5HT) have been termed 5HT2 receptors (Peroutka and Snyder, 1980). Since the 3H-spiroperidol displaced by 5HT is also displaced very effectively (IC50 in the nM range) by ketanserin and mianserin it was suggested that spiroperidol, mianserin and ketanserin are labelling 5HT2 receptors. Data are presented showing that the 3H-ketanserin and 3H-mianserin bound to crude synaptic membrane in the presence of a H1 receptor blocker are not labelling the same recognition site. Hence from this standpoint the recognition site marked by 3H-mianserin and 3H-ketanserin is not identical. The possibility that allosteric effects are operative in some of these ligand displacements should be entertained.

Animals↗
PubMed1983

Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites.

Imipramine inhibits the serotonin uptake by binding with high affinity to regulatory sites of this uptake located on axons that release serotonin. The number of imipramine recognition sites located on crude synaptic membrane preparations is reduced by two daily injections of imipramine or desmethylimipramine for 3 weeks. When the binding sites for [3H]imipramine are down-regulated the Vmax of the neuronal uptake of serotonin is increased. Moreover, in minces prepared from the brain hippocampus of rats receiving imipramine in a dose regimen that reduces the number of [3H]imipramine recognition sites, the efficiency of imipramine as a blocker of the serotonin uptake is diminished. Hence the high-affinity binding sites for [3H]imipramine may have a physiological role in modulation of serotonin reuptake. Probably this is mediated by an endogenous effector of these regulatory sites. A nonpeptidic constituent of rat brain capable of displacing [3H]imipramine from its high-affinity binding site and of inhibiting the serotonin uptake in a dose-related manner has been extracted and its partial purification is described.

Animals↗
PubMed1983

Simultaneous modulation of hippocampal cholinergic activity and extinction by intraseptal muscimol.

The relationship between regulation of acetylcholine metabolism in the septal-hippocampal pathway and extinction of a food reinforced lever press response was investigated by comparing the turnover rate of acetylcholine (TRACh) in the rat hippocampus with the amount of responding during extinction after intraseptal injection of the gamma-aminobutyric acid receptor agonist muscimol. Doses (0.3-3.0 nmol) which decreased the TRACh in the hippocampus also increased the responding during extinction over that of saline controls. Responding during the continuous reinforcement schedule before extinction was also increased, but to a lesser extent. Higher doses (10-30 nmol) further decreased the TRACh in the hippocampus, decreased it in the cortex and were accompanied by irregular responding and sedation. The TRACh in the hippocampus was also measured in drug-free rats undergoing extinction after training on a continuous reinforcement or variable interval 60 sec reinforcement schedule. Although the variable interval 60 sec reinforcement schedule rats responded more than the continuous reinforcement rats during extinction, there were no differences between the TRACh in the hippocampus. The present results indicate that the decrease in the hippocampal TRACh which is produced by intraseptal muscimol is accompanied by an increase in the response rate during extinction, but that operantly induced differences in this behavior are not accompanied by detectable changes in hippocampal TRACh.

Acetylcholine↗
PubMed1982

Differential enhancement of behavioral sensitivity to apomorphine following chronic treatment of rats with (-)-sulpiride and haloperidol.

Rat exploratory activity as well as apomorphine-induced hypermotility and stereotyped behavior were assayed following acute (60 min before) or chronic (21 days) administration of sulpiride stereoisomers and haloperidol. Parallel groups of rats were assayed for their hypermotility and stereotyped responses to challenging doses of apomorphine 7 and 21 days after discontinuation of chronic treatments. Following its acute administration, (-)-sulpiride fully antagonized apomorphine-induced hypermotility without affecting the level of animal spontaneous activity and partially counteracted stereotyped behavior. Haloperidol completely suppressed both apomorphine responses and also depressed exploratory activity. Some tolerance to the anti-apomorphine effect of (-)-sulpiride groups exhibited enhanced behavioral sensitivity to apomorphine only with respect to hypermotility, whereas haloperidol groups were supersensitive with respect to both hypermotility and stereotyped responses. The results are discussed in terms of differential dopamine receptor supersensitivity arising from prolonged administration of butyrophenone and substituted benzamide.

Animals↗
PubMed1981

Behavioral supersensitivity to methamphetamine following chronic treatment with (--)-sulpiride in the rat.

Hyperactivity induced by methamphetamine (4 mg/kg i.p.) was actographically evaluated in rats chronically treated with sulpiride stereoisomers and haloperidol. The trial was repeated with half dose of the stimulant after 8 days of neuroleptic withdrawal. (--)-Sulpiride and haloperidol antagonized the response to the full dose of methamphetamine and induced behavioral supersensitivity to the challenging dose. (+)-Sulpiride strongly enhanced the effect of 4 mg/kg of methamphetamine, but no relevant changes in dopaminergic sensitivity followed.

Animals↗
PubMed1981

[Diphasic action of apomorphine on motility of the rat. I. Dose-effect relationship in exploratory and basal motility].

The effect of 8 doses of apomorphine HCl (0 - 6.25 - 13.46 - 29.01 - 62.5 - 134.65 - 290.1 - 625.0 microgram/kg, s.c. 15 min before) upon rat 30-min locomotor activity was evaluated in naive animals and in rats habituated to the actometer for 90 min. The doses of 29.01 - 62.5 - 134.65 significantly inhibited the exploratory activity of naive rats and the higher doses did not significantly influence such elevated baseline motility. On the contrary, low baseline motility of habituated rats resulted unaffected by the lower doses of apomorphine, whereas it was greatly stimulated by the doses of 290.1 and 625.0. It was concluded that suitable baselines of rat motility are required for the appearance of apomorphine stimulating effects at pre- and post-synaptic dopamine receptor levels.

Animals↗