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Effects of typical and atypical neuroleptics on dopamine release and metabolism in rat striatumin vivo: Systemic and local administration
THE ~ ' ~ C T OF 5-HTIA RECEPTOR LIGANDS IN THE CHRONIC MILD STRESS MODE~ OF DEPRESSION E. Przegali~ski, E. Moryl and M. Papp Institute of Pharmacology, Polish Academy of Sciences 12, Sa~tna St., PL 31-343 Krak6w, Poland.
STUDY OF THE ANTIDEPRESSANT-LIKE EFFECT O F RB 101, AN ENKEPHALIN CATABOLISM INHIBITOR, ON LEARNED HELPLESSNESS MODEL OF DEPRESSION P. Teiedor-ReaP, J.A. Mic6,t C.S. Smadja, M.C.Foumi4-Zaluski, B.P. Roques, J. Gibert-Rahola.t 1Dpt. Neurosciences, School Medicine, Cadiz, Spain. 2 Dpt. Organic Chemistry, Fac. Pharmaceutical Ski. Biol., Paris, France.
Antidepressant properties of 5-HTIA receptor ligands (the full agonist 8-OH-DPAT, the partial agonists buspirone and ipsapirone, and the selective and silent antagonist WAY 100135) were studied in a chronic mild stress model of depression. In that model, rats subjected to a variety of mild stressors for a prolonged period of time showed a substantial decrease in the consumption of a palatable sucrose solution (anhedonia), an effect sensitive to repeated treatment with antidepressant drugs. In the present study we found that the stress-induced deficit in sucrose intake %~s gradually reversed by chronic (3-5 weeks) treatment with buspirone (2.5 - 5 mg/kg i.p., b.i.d.) or WAY 100135 (10 mg/kg s.c., b.i.d.), but not with 8-OH-DPAT (0.5 mg/kg s.c., b.i.d.) or ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude of the effects of buspirone and ~i~Y 100135 and their time course were cc¢~oarable to those observed following similar administration of the antidepressants imipramine (10 mg/kg i.p.) or citalopram (10 mg/kg i.p.). The increase in sucrose intake following chronic trea~t with buspirone, WAY 100135, imipramJ_ne or citalopram was specific to stressed animals; the behaviour of non-stressed controls was unchanged by any of the drugs tested. The above results indicate that buspirone and WAY 100135 may have antidepressant properties. However, further experiments are necessary to evaluate possible links between the anti-anhedonic effect of these drugs and their interaction with 5-HTIA receptors.
The presence of opio[d peptides in the human brain and the observed euphorogenic, properties of opiates suggest the involvement of the endogenous opioidergic system in the pathogenesis of several mental disorders. In previous studies we have found that administration of enkephalins or enkephalin metabolism inhibitors (RB 38A, inhibitor of both aminopeptidase N and neutral endopeptidase, and RB 38B, inhibitor of neutral endopeptidase) to rats, previously subjected to inescapable shocks, exhibited an escape failure number decrease in the learned helplessness paradigm. The aim of this study was to investigate whether administration of RB 101, a new mixed enkephalin metabolism inhibitor able to cross the blood brain barrier, could reverse helplessness effects induced by inescapable shocks. Other purpose was to determine whether naltfindole could antagonize the effect of RB 101 in the same paradigm. Learned helplessness was chosen for this study because it has been shown to be of good validity for the screening of antidepressant therapies. Results showed that administration of RB 101 to rats previously exposed to inescapable shocks reduced dose-dependent the number of escape failure in the shuttle-box test. Interestingly, combined administration of both RB 101 and naltrindole showed that naltrindole was able to antagonize the effect of RB 101, suggesting the preferentially role of delta receptors in this effect. Enkephalin degrading enzyme inhibitors could be in the future a new strategy in the treatment of depressive states. This research has been supported by a BIOMED grant n ° PL 931721 and a DGICYT n° CE 94-0003.
PRESCRIBING PATTERNS OF NEUROLEPTIC DRUGS IN LONGSTAY HOSPITAL RESIDENT CHRONIC PSYCHIATRIC PATIENTS M. Cosentino, O. Leoni, L. Rispoli*, C. Pellegrini*, L. Finavera*, S. Lecchini and G.M. Frigo Department of Internal Medicine and Therapeutics, II Faculty of Medicine, University of Pavia, and *Psychiatric Unit, USSL n.1, Via O. Rossi n.9, 1-21100 Varese, Italy.
EFFECTS OF TYPICAL AND ATYPICAL NEUROLEPTICS ON DOPAMINE RELEASE AND METABOLISM IN RAT STRIATUM IN VIVO: SYSTEMIC AND LOCAL ADMINISTRATION RR.Gainetdinov. T.D.Sotnikova, T.V.Grekhova and K.S. Rayevsky Institute of Pharmacology Russian Academy of Medical Sciences, Baltiyskaya str., 8, Moscow , 125315, Russia
Surveys of drug utilization in psychiatric hospital practice have pointed out some concerns about psychotropic drug prescribing habits with particular regard to neuroleptics, namely polypharmacy, inappropriate prescribing, inadequate review of precdptions. As a part of a study devised to introduce pharmacoepidemiologic data collection into hospital routine, a drug prescription monitoring program was implemented in the psychiatric hospital of Varese (Italy), in collaboration with the hospital staff, Fifty female patients aged (mean+s.d.) 65+12,7 years permanently reside in the ward included in the program. Psychiatric diagnoses are (ICD 10): schizophrenia (n-25), mental retardation (13), affective disorders (10), personality disorders (4), vascular dementia (1). Details about neureleptic use have been retrieved from a computerized data base periodically updated with informations concerning all drug prescriptions. At the onset of the monitoring program, 42 patients were on neuroleptics. Haloperidol accounted for the majority of prescriptions (19), followed by levomepromazine (9). Oral neuroleptics were given 2.2 (s.d.=0.96; range: 1-4) times per day. Nine patients were on depot preparations, and in 6 cases concurrent oral administration was given. Twelve patients were on 2 or more neuroleptics, 37 received other psychotropic drugs, viz. anxiolytics (29), hypnotics (13), lithium (5), antidepressants (5), antiepileptics (4). Concurrent anti-Parkinson medication was given to 10 patients. Potential medication improvements (e.g., discontinuation trials of anti-Parkinson drugs, once-a-day drug administration) have been discussed with the team of consultants. Hospital-based monitoring programs, also in the presence of good prescribing skills, may be useful self-audits for hospital staff and may help to promote care upgrading and continuing education enhancement.
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Brain microdialysis was used to investigate the effects of typical and atypical neuroleptic drugs on the extracellular levels of DA, DOPAC and HVA in striatum of awake rats. We have found significant correlation between the abilities of typical (haloperidol, spiperone, thioproperazine) and atypical (clozapine, thioridazine, (+)UH-232, (+)-AJ-76) neuroleptics administered i.p. to affect preferentially DA metabolism or release in the rat striatum in vivo and their relative potencies at D2 and D3 receptor. It has been hypothesized that DA D3 terminal autoreceptor preferentialy involved in regulation of DA release while D2 one regulates DA synthesis in rat basal ganglia in vivo. Local application of haloperidoll spiperone, elozapine, (+)-UH232, (+)-AJ-76 by addition into the perfusing medium also resulted in concentration-dependent increase of DA level in. striatum up to maximal values observed following systemic drug-administration. Importantly that subsequent i.p. administration of all the drugs studied did not induced further elevation of striatal DA release. The difference in local effects of typical and atypical neuroleptics was only the degree of elevation of DA release (the maximal responses were: for haloperidol and spiperone about 160%, for clozapine and (+)-UH-232 190%, for (+)-AJ-76 - 480% to basal). DOPAC and HVA extraeellular levels were elevated only following systemic but not local administration of all the drugs studied.The present results give further support to the leading role o f nerve terminal DA autorecepters, presumably D3 type, in neur01eptic - induced augmentation of dopamine release in the striatum.
2 8 4
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STUDY OF THE ANTIDEPRESSANT-LIKE EFFECT O F RB 101, AN ENKEPHALIN CATABOLISM INHIBITOR, ON LEARNED HELPLESSNESS MODEL OF DEPRESSION P. Teiedor-ReaP, J.A. Mic6,t C.S. Smadja, M.C.Foumi4-Zaluski, B.P. Roques, J. Gibert-Rahola.t 1Dpt. Neurosciences, School Medicine, Cadiz, Spain. 2 Dpt. Organic Chemistry, Fac. Pharmaceutical Ski. Biol., Paris, France.
Antidepressant properties of 5-HTIA receptor ligands (the full agonist 8-OH-DPAT, the partial agonists buspirone and ipsapirone, and the selective and silent antagonist WAY 100135) were studied in a chronic mild stress model of depression. In that model, rats subjected to a variety of mild stressors for a prolonged period of time showed a substantial decrease in the consumption of a palatable sucrose solution (anhedonia), an effect sensitive to repeated treatment with antidepressant drugs. In the present study we found that the stress-induced deficit in sucrose intake %~s gradually reversed by chronic (3-5 weeks) treatment with buspirone (2.5 - 5 mg/kg i.p., b.i.d.) or WAY 100135 (10 mg/kg s.c., b.i.d.), but not with 8-OH-DPAT (0.5 mg/kg s.c., b.i.d.) or ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude of the effects of buspirone and ~i~Y 100135 and their time course were cc¢~oarable to those observed following similar administration of the antidepressants imipramine (10 mg/kg i.p.) or citalopram (10 mg/kg i.p.). The increase in sucrose intake following chronic trea~t with buspirone, WAY 100135, imipramJ_ne or citalopram was specific to stressed animals; the behaviour of non-stressed controls was unchanged by any of the drugs tested. The above results indicate that buspirone and WAY 100135 may have antidepressant properties. However, further experiments are necessary to evaluate possible links between the anti-anhedonic effect of these drugs and their interaction with 5-HTIA receptors.
The presence of opio[d peptides in the human brain and the observed euphorogenic, properties of opiates suggest the involvement of the endogenous opioidergic system in the pathogenesis of several mental disorders. In previous studies we have found that administration of enkephalins or enkephalin metabolism inhibitors (RB 38A, inhibitor of both aminopeptidase N and neutral endopeptidase, and RB 38B, inhibitor of neutral endopeptidase) to rats, previously subjected to inescapable shocks, exhibited an escape failure number decrease in the learned helplessness paradigm. The aim of this study was to investigate whether administration of RB 101, a new mixed enkephalin metabolism inhibitor able to cross the blood brain barrier, could reverse helplessness effects induced by inescapable shocks. Other purpose was to determine whether naltfindole could antagonize the effect of RB 101 in the same paradigm. Learned helplessness was chosen for this study because it has been shown to be of good validity for the screening of antidepressant therapies. Results showed that administration of RB 101 to rats previously exposed to inescapable shocks reduced dose-dependent the number of escape failure in the shuttle-box test. Interestingly, combined administration of both RB 101 and naltrindole showed that naltrindole was able to antagonize the effect of RB 101, suggesting the preferentially role of delta receptors in this effect. Enkephalin degrading enzyme inhibitors could be in the future a new strategy in the treatment of depressive states. This research has been supported by a BIOMED grant n ° PL 931721 and a DGICYT n° CE 94-0003.
PRESCRIBING PATTERNS OF NEUROLEPTIC DRUGS IN LONGSTAY HOSPITAL RESIDENT CHRONIC PSYCHIATRIC PATIENTS M. Cosentino, O. Leoni, L. Rispoli*, C. Pellegrini*, L. Finavera*, S. Lecchini and G.M. Frigo Department of Internal Medicine and Therapeutics, II Faculty of Medicine, University of Pavia, and *Psychiatric Unit, USSL n.1, Via O. Rossi n.9, 1-21100 Varese, Italy.
EFFECTS OF TYPICAL AND ATYPICAL NEUROLEPTICS ON DOPAMINE RELEASE AND METABOLISM IN RAT STRIATUM IN VIVO: SYSTEMIC AND LOCAL ADMINISTRATION RR.Gainetdinov. T.D.Sotnikova, T.V.Grekhova and K.S. Rayevsky Institute of Pharmacology Russian Academy of Medical Sciences, Baltiyskaya str., 8, Moscow , 125315, Russia
Surveys of drug utilization in psychiatric hospital practice have pointed out some concerns about psychotropic drug prescribing habits with particular regard to neuroleptics, namely polypharmacy, inappropriate prescribing, inadequate review of precdptions. As a part of a study devised to introduce pharmacoepidemiologic data collection into hospital routine, a drug prescription monitoring program was implemented in the psychiatric hospital of Varese (Italy), in collaboration with the hospital staff, Fifty female patients aged (mean+s.d.) 65+12,7 years permanently reside in the ward included in the program. Psychiatric diagnoses are (ICD 10): schizophrenia (n-25), mental retardation (13), affective disorders (10), personality disorders (4), vascular dementia (1). Details about neureleptic use have been retrieved from a computerized data base periodically updated with informations concerning all drug prescriptions. At the onset of the monitoring program, 42 patients were on neuroleptics. Haloperidol accounted for the majority of prescriptions (19), followed by levomepromazine (9). Oral neuroleptics were given 2.2 (s.d.=0.96; range: 1-4) times per day. Nine patients were on depot preparations, and in 6 cases concurrent oral administration was given. Twelve patients were on 2 or more neuroleptics, 37 received other psychotropic drugs, viz. anxiolytics (29), hypnotics (13), lithium (5), antidepressants (5), antiepileptics (4). Concurrent anti-Parkinson medication was given to 10 patients. Potential medication improvements (e.g., discontinuation trials of anti-Parkinson drugs, once-a-day drug administration) have been discussed with the team of consultants. Hospital-based monitoring programs, also in the presence of good prescribing skills, may be useful self-audits for hospital staff and may help to promote care upgrading and continuing education enhancement.
- -
Brain microdialysis was used to investigate the effects of typical and atypical neuroleptic drugs on the extracellular levels of DA, DOPAC and HVA in striatum of awake rats. We have found significant correlation between the abilities of typical (haloperidol, spiperone, thioproperazine) and atypical (clozapine, thioridazine, (+)UH-232, (+)-AJ-76) neuroleptics administered i.p. to affect preferentially DA metabolism or release in the rat striatum in vivo and their relative potencies at D2 and D3 receptor. It has been hypothesized that DA D3 terminal autoreceptor preferentialy involved in regulation of DA release while D2 one regulates DA synthesis in rat basal ganglia in vivo. Local application of haloperidoll spiperone, elozapine, (+)-UH232, (+)-AJ-76 by addition into the perfusing medium also resulted in concentration-dependent increase of DA level in. striatum up to maximal values observed following systemic drug-administration. Importantly that subsequent i.p. administration of all the drugs studied did not induced further elevation of striatal DA release. The difference in local effects of typical and atypical neuroleptics was only the degree of elevation of DA release (the maximal responses were: for haloperidol and spiperone about 160%, for clozapine and (+)-UH-232 190%, for (+)-AJ-76 - 480% to basal). DOPAC and HVA extraeellular levels were elevated only following systemic but not local administration of all the drugs studied.The present results give further support to the leading role o f nerve terminal DA autorecepters, presumably D3 type, in neur01eptic - induced augmentation of dopamine release in the striatum.
2 8 4
- -