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Chronic haloperidol treatment at low dose enhances the increase of homovanillic acid in rat brain
Studies in Basic and Clinical Psychopharmacology
BIOL PSYCHIATRY 1989;25:42A-53A
43A
inic, muscarinic, nicotinic, adenosinic, GABAergic, glutaminergic, Ca channel, neurotensine, CCK-8, benzodiazepine, opiates, TRH, PCP, imipramine, desipramine, methylphenydate, and amphetamine sites. The effect on norepinephrine, serotonin, dopamine and choline uptake, were also tested. In another set of experiments, fipexide was given chronically (2 X 32 mg/kg/dayRl days, IP) and its effect on some receptors evaluated. In the in vitro experiments fipexide had no significant effect on any system tested. Administered chronically, fipexide decreased the B max values for 5-HT 2 receptors in the frontal cortex. Similar effects were observed with imipramine, paroxetine, buspirone. Fipexide decreases also the B max values for the beta-adrenergic receptors. These down-regulations suggest antidepressant properties.
88
COGNITIVE ENHANCEMENT PROPERTIES OF FIPEXIDE IN RODENTS C.J. Gouret, R. Porsolt, A. Lenegre, J.L. Junien Fresnes, France and Kremlin-Bicetre, France
Pharmacological studies have shown psychotropic properties of fipexide (Pierre and Gauthier, 1975). From in vitro binding studies, Missale and Al (1983) have proposed an interaction with the dopaminergic system in selected brain areas. David and Al (1985) and Spano and Al (1986) have reported cognitive activation with fipexide in scopolamine and chloramphenicol amnesia tests in rats. We have thus investigated the promnesic properties of fipexide in a series of tests classically used for evaluating nootropic agents in mice and rats. Amnesia was induced in a one-trial step-through passive avoidance test either by drugs (scopolamine, diazepam or PCP) in mice or by ECS or hypoxia in rats. Retention was measured 24 hours later by measuring the step through latency. Fipexide and piracetam (reference compound) were administered, PO, one hour before Sl. The effects of fipexide on the habituation of exploratory activity of in the stair case test on the acquisition of a food-rewarded lever-pressing response were also investigated. Fipexide dose dependently decreased memory loss induced by scopolamine in mice, by ECS treatment and exposition to CO2 in rats. The minimal effective dose for these tests was 32 mg/kg. Fipexide also significantly decreased the exploratory activity in the stair case test, this effect suggesting a memory facilitation. Piracetam was always active in the amnesia tests but at higher dose. Fipexide did not improve the memory deficit induced by diazepam or PCP and in contrast to amphetamine was inactive in the acquisition test. These results in rodents indicate that fipexide acts as a cognitive enhancer.
89
CHRONIC HALOPERIDOL TREATMENT AT LOW DOSE ENHANCES THE INCREASE OF HOMOVANILLIC ACID IN RAT BRAIN Wen-Ho Chang, Shu-Swei Jaw, Lacan Tsay Taipei, Taiwan, ROC
This study presents homovanillic acid (HVA) levels, determined by HPLCECD, in the striatum (S) and the prefrontal cortex (PC) of rats after single and repeated (10 times with 2-day intervals) injections of haloperidol (H) at doses from 0.01 to one mg/kg. H increased HVA levels in both brain regions after both acute and chronic
treatments at all doses used. The increases m HVA levels m the S were blunted after repeated H injections at doses of 0.5-l m&kg, suggesting that H pretreatment results in a decreased responsiveness to the drug at high doses (tolerance). Tolerance also developed to the action of long-term H treatment on HVA elevations in the PC at the highest dose used ( 1 mg/kg), suggesting that the differences in tolerance development ~ between S and PC, are not absolute and qualitative but relative and quantitative. However, repeated H injections at doses of 0.01-0.05 mg/kg can enhance the increases in HVA levels, suggesting that tolerance does not develop after chronic H treatment at low dosages. Decreased HVA concentration after withdrawal from chronic H treatment was also found (rebound decrease). However. this rebound decrease was much smaller than the tolerant HVA responsiveness, suggesting different mechanisms between them. Our results do not support the megadose H treatment in clinical settings.
90
CHRONIC IMIPRAMINE INCREASES PLATELET NON-CYANOIMIPRAMINE (CNIMI) BINDING BUT DECREASES CNIMI SPECIFIC BINDING Edward DeMet, Kate Bell, Robert Gerner, Christopher Reist, Aleksandra Chicz-DeMet Irvine, CA Two subclasses of 3H-IMI binding sites were distinguished using CNIMI inhibition. Sites specific for CNIMI are trypsin sensitive (proteinaceous), and Na-dependent, whereas non-CNIMI sites are not. Total 3H-IMI binding was better correlated with non-CNIMI than CNIMI binding although both correlations were significant. Both CNIMI and non-CNIMI binding were reduced in endogenous unipolar depressed patients relative to controls although only the former was significant. Chronic imipramine treatment (6 week) significantly increased total 3H-IMI binding. Even larger increases were found in non-CNIMI binding. In contrast, CNIMI specific binding was significantly reduced by imipramine treatment. Highly significant inverse correlations were found between post-treatment cortisol and total 3H-IMI binding and non-CNIMI specific binding, whereas post-treatment cortisol was not related to CNIMI binding. The results suggest that a CNIMI specific subclass of 3H-IMI binding sites may be a trait marker of depressive illness, whereas non-CNIMI binding may fluctuate with plasma cortisol levels.
91
AN AUTORADIOGRAPHIC STUDY OF MIANSERIN-INDUCED DOWN REGULATION OF SEROTONIN (5HTz AND 5HTlc) RECEPTORS Bryan L. Roth, Linda Decker, Miles Herkenham Stanford,
CA and Bethesda,
MD
Serotonin (5hydroxytryptamine; 5HT) selective uptake blockers (fluoxetine, zimelidine) as well as 5HT receptor antagonists (mianserin) are clinically useful antidepressants. Chronic treatment with these antidepressants in rats has caused downregulation of cortical 5HT2 receptors. Questions remain regarding: (1) the anatomical loci of the down- regulated receptors as well as (2) whether other 5HT receptor subtypes are similarly altered. Accordingly, we injected Sprague-Dawley rats with mianserin (10 mg/kg ip X 3 days) and after sacrifice prepared brains for receptor autoradiography
BIOL PSYCHIATRY 1989;25:42A-53A
43A
inic, muscarinic, nicotinic, adenosinic, GABAergic, glutaminergic, Ca channel, neurotensine, CCK-8, benzodiazepine, opiates, TRH, PCP, imipramine, desipramine, methylphenydate, and amphetamine sites. The effect on norepinephrine, serotonin, dopamine and choline uptake, were also tested. In another set of experiments, fipexide was given chronically (2 X 32 mg/kg/dayRl days, IP) and its effect on some receptors evaluated. In the in vitro experiments fipexide had no significant effect on any system tested. Administered chronically, fipexide decreased the B max values for 5-HT 2 receptors in the frontal cortex. Similar effects were observed with imipramine, paroxetine, buspirone. Fipexide decreases also the B max values for the beta-adrenergic receptors. These down-regulations suggest antidepressant properties.
88
COGNITIVE ENHANCEMENT PROPERTIES OF FIPEXIDE IN RODENTS C.J. Gouret, R. Porsolt, A. Lenegre, J.L. Junien Fresnes, France and Kremlin-Bicetre, France
Pharmacological studies have shown psychotropic properties of fipexide (Pierre and Gauthier, 1975). From in vitro binding studies, Missale and Al (1983) have proposed an interaction with the dopaminergic system in selected brain areas. David and Al (1985) and Spano and Al (1986) have reported cognitive activation with fipexide in scopolamine and chloramphenicol amnesia tests in rats. We have thus investigated the promnesic properties of fipexide in a series of tests classically used for evaluating nootropic agents in mice and rats. Amnesia was induced in a one-trial step-through passive avoidance test either by drugs (scopolamine, diazepam or PCP) in mice or by ECS or hypoxia in rats. Retention was measured 24 hours later by measuring the step through latency. Fipexide and piracetam (reference compound) were administered, PO, one hour before Sl. The effects of fipexide on the habituation of exploratory activity of in the stair case test on the acquisition of a food-rewarded lever-pressing response were also investigated. Fipexide dose dependently decreased memory loss induced by scopolamine in mice, by ECS treatment and exposition to CO2 in rats. The minimal effective dose for these tests was 32 mg/kg. Fipexide also significantly decreased the exploratory activity in the stair case test, this effect suggesting a memory facilitation. Piracetam was always active in the amnesia tests but at higher dose. Fipexide did not improve the memory deficit induced by diazepam or PCP and in contrast to amphetamine was inactive in the acquisition test. These results in rodents indicate that fipexide acts as a cognitive enhancer.
89
CHRONIC HALOPERIDOL TREATMENT AT LOW DOSE ENHANCES THE INCREASE OF HOMOVANILLIC ACID IN RAT BRAIN Wen-Ho Chang, Shu-Swei Jaw, Lacan Tsay Taipei, Taiwan, ROC
This study presents homovanillic acid (HVA) levels, determined by HPLCECD, in the striatum (S) and the prefrontal cortex (PC) of rats after single and repeated (10 times with 2-day intervals) injections of haloperidol (H) at doses from 0.01 to one mg/kg. H increased HVA levels in both brain regions after both acute and chronic
treatments at all doses used. The increases m HVA levels m the S were blunted after repeated H injections at doses of 0.5-l m&kg, suggesting that H pretreatment results in a decreased responsiveness to the drug at high doses (tolerance). Tolerance also developed to the action of long-term H treatment on HVA elevations in the PC at the highest dose used ( 1 mg/kg), suggesting that the differences in tolerance development ~ between S and PC, are not absolute and qualitative but relative and quantitative. However, repeated H injections at doses of 0.01-0.05 mg/kg can enhance the increases in HVA levels, suggesting that tolerance does not develop after chronic H treatment at low dosages. Decreased HVA concentration after withdrawal from chronic H treatment was also found (rebound decrease). However. this rebound decrease was much smaller than the tolerant HVA responsiveness, suggesting different mechanisms between them. Our results do not support the megadose H treatment in clinical settings.
90
CHRONIC IMIPRAMINE INCREASES PLATELET NON-CYANOIMIPRAMINE (CNIMI) BINDING BUT DECREASES CNIMI SPECIFIC BINDING Edward DeMet, Kate Bell, Robert Gerner, Christopher Reist, Aleksandra Chicz-DeMet Irvine, CA Two subclasses of 3H-IMI binding sites were distinguished using CNIMI inhibition. Sites specific for CNIMI are trypsin sensitive (proteinaceous), and Na-dependent, whereas non-CNIMI sites are not. Total 3H-IMI binding was better correlated with non-CNIMI than CNIMI binding although both correlations were significant. Both CNIMI and non-CNIMI binding were reduced in endogenous unipolar depressed patients relative to controls although only the former was significant. Chronic imipramine treatment (6 week) significantly increased total 3H-IMI binding. Even larger increases were found in non-CNIMI binding. In contrast, CNIMI specific binding was significantly reduced by imipramine treatment. Highly significant inverse correlations were found between post-treatment cortisol and total 3H-IMI binding and non-CNIMI specific binding, whereas post-treatment cortisol was not related to CNIMI binding. The results suggest that a CNIMI specific subclass of 3H-IMI binding sites may be a trait marker of depressive illness, whereas non-CNIMI binding may fluctuate with plasma cortisol levels.
91
AN AUTORADIOGRAPHIC STUDY OF MIANSERIN-INDUCED DOWN REGULATION OF SEROTONIN (5HTz AND 5HTlc) RECEPTORS Bryan L. Roth, Linda Decker, Miles Herkenham Stanford,
CA and Bethesda,
MD
Serotonin (5hydroxytryptamine; 5HT) selective uptake blockers (fluoxetine, zimelidine) as well as 5HT receptor antagonists (mianserin) are clinically useful antidepressants. Chronic treatment with these antidepressants in rats has caused downregulation of cortical 5HT2 receptors. Questions remain regarding: (1) the anatomical loci of the down- regulated receptors as well as (2) whether other 5HT receptor subtypes are similarly altered. Accordingly, we injected Sprague-Dawley rats with mianserin (10 mg/kg ip X 3 days) and after sacrifice prepared brains for receptor autoradiography