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Effects of cocaine on EEG in rats after single or repeated administrations
MOLECULAR CORRELATES OF NICOTINE SELFADMINISTRATION IN RATS C. Chiamulera, M. Tessari, S. Pagliusi, E. Valerio, U. Boschert, D. Talabot, D.G. Trist, E. Medo-Pich and G. Gaviraghi. Glaxo Research Laboratories, via Fleming, 2, 1-37100 Verona, Italy. Glaxo Institute for Molecular Biology, CH1228 Geneva, Switzerland.
DOPAMINE LEVELS IN P L A T E L E T S AND PLASMA OF H E R O I N PLUS C O C A I N E A D D I C T S ARE I N C R E A S E D C, A, Fontes Ribeirg, T. R. A. Macedo, P. Tavares, M. T. Morgadinho, M. A. V. Abreu, P. P. Cunha, M. T. Nunes Vicente*, L. Rodrigues*, M.L.Keating*, Inst. of Pharmacol. and Exp.Ther., Fac. of Medicine; *Centre for the Study and Prevention of Drug Abuse, Coimbra, Portugal.
Recent reports have shown that nicotine (NIC) plays a major role in tobacco addiction. However, few studies have investigated the reinforcing properties of NIC and its underlying substrates. In this study, we describe the pattern of neural activation, as obtained by staining immediate early gene expression at different anatomical CNS levels, during NIC intravenous (iv) self-administration in rats, a behavioural model of NIC addiction. Rats were trained to press a lever for iv NIC infusion (0.03 mg/kg/infusion on a fixed-ratio 3 schedule of reinforcement). After 8 consecutive daily sessions of self-administration, 90 min after the end of the last session, animals were anesthetized, perfused transcardiacally with paraformaldheyde 4% and brains were prepared for immunohistochemistry. Specific antibodies for cFos and cJun gene products were used for immunostaining. Both acute and chronic exposure to iv NIC produced strong increases of Fos immunoreactivity in the superior colliculus and in the medial terminal nucleus of the accessory optic tract. Significant levels of los immunoreactivity were also found in forebrain structures like the piriform cortex, septal nuclei and paraventricular thalamic nuclei. Jun expression did not significantly change. Fos activation by nicotine persisted even after chronic exposure to NIC suggesting that desensitization of NIC-dependent Fos expression does not occur during self-administration.
Several studies have shown that the central dopaminergic pathway is implicated in the reinforcing properties of drugs of abuse. However, data describing changes of blood catecholamines and 5-HT are limited. Therefore, this work aimed to study sympathetic and 5-hydroxytryptaminergic alterations induced by heroin plus cocaine addiction in man. Free and sulfoconjugated (after acid hydro[isis) catecholamines and 5-HT were measured by HPLC-ECD, and erythrocyte COMT and plasma dopamine-~-hydroxylase activities by a HPLC technique. Platelet catecholamines and 5-HT were extracted with HC104 and then also measured by HPLC-ECD. When compared with control (healthy) subjects (N=26), the results in drug addicts (N=24) revealed: a) Significant increases in plasma dopamine (DA) (free and sulfoconjugated), noradrenaline (NA) sulfate and MHPG; b) Significant elevation of platelet adrenaline (Ad) and DA; c) No appreciable difference in the concentrations of: free NA, free or sulfate-conjugated Ad, serum and platelet 5-HT, COMT and DA-[~-hydroxylase. The differences found may be interpreted as a reflection of the activation of adrenergic neurotransmission. Furthermore, platelets and sulfoconjugation may protect catecholamines from metabolization during circulation. Thus, platelet amine levels may be a marker of this kind of drug abuse.
EFFECTS OF COCAINE ON EEG IN RATS AFTER SINGLE OR REPEATED ADMINISTRATIONS K.Kuschinsky and B. Ferger Institute of Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Ketzerbach 63, D-35032 Marburg, Germany
PERIADOLESCENTRATSAND COCAINE SENSITIZATION G. Laviola,*,C.KuhnA and L.P. Spear# *Sect. Behav. Pathophysiology, Lab. F.O.S., Istituto Superiore di Sanit&, Rome, Italy; #Centr. Develop. Psychobiology, State University of New York at Binghamton, USA; ^Dept. Pharmacology, Duke University, Durham, USA
(Supported by G. P. C. C. D., Ministry of Justice, Portugal)
Periadolescent rats have been reported to be differentially affected by catecholaminergic agents when compared with younger or adult animals. The present study evaluated the behavioral responsivity of periadolescent (34-39-day-old) and adult (60-70-day-old) Sprague-Dawley male and female rats to chronic IP administration of cocaine (0, 10, or 20 mg/kg once daily for four days). To assess the role of context in the develooment of behavioral sensitization, all animals received injections of both 'saline and cocaine every day paired with a different context, with half of the animals receiving the drug in the home cage (Coc-Home) and the other half in the testing chamber (Coc-Test). Forty-eight hr after the last drug injection alt animals were challenged with 10 mg/kg IP cocaine, and were placed in the test chamber where their behavior was scored. As expected, acute cocaine induced a prominent increase in a number of behaviours and this response profile was less marked in periadolescent relative to adult subjects. In contrast, Coc-Test animals of both ages previously exposed chronically to cocaine showed clear sensitization on a number of behaviours relative to those in the chronic saline group. No evidence of carry-over effects was found in Coc-Home subjects. A marked sex difference emerged, with females showing a more marked sensitivity than males to acute cocaine effects. Chronic cocaine reduced body weight and food consumption, particularly in adult males, whereas it did not affect periadolescent patterns. Plasma corticosterone and ACTH levels following cocaine challenge were higher in females than males and in adult than periadolescents. No evidence of sensitization,following chronic cocaine was found using these hormonal measures.
In a previous study (Ferger et al., Psychopharmacol. 114:297 (!994)), it was shown that a moderate dose of cocaine (10 mg/kg i.p.) produces a pattern in EEG power spectrum suggesting activation of dopamine D1 receptors, whereas a large dose (30 mg/kg) induces a qualitative change suggesting an additional activation olD2 receptors. The present experiments were performed in male Wistar rats of about 300 g in order to supplement the dose-responserelationship and to evaluate possible tolerance or sensitization phenomena. The EEG studies were performed telemetrically in awake, freely moving rats. Five mg/kg of cocaine produced a smaller effect than 10 mg/kg (general decrease of power in ill of the frequency bands), 20 mg/kg a more pronounced effect, with evidence of a slight additional activation of D2 receptors. After ten daily administrations of 10 mg/kg of cocaine and a drag-free intelval of 4 days the same dose of cocaine produced a siL-,nificantly enhanced effect, but no evidence for an additional activation of D2 dopamine receptors was found. Accordingly, there was a sensitization but no evidence of a shift to an additional activation of D~ receptors.
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DOPAMINE LEVELS IN P L A T E L E T S AND PLASMA OF H E R O I N PLUS C O C A I N E A D D I C T S ARE I N C R E A S E D C, A, Fontes Ribeirg, T. R. A. Macedo, P. Tavares, M. T. Morgadinho, M. A. V. Abreu, P. P. Cunha, M. T. Nunes Vicente*, L. Rodrigues*, M.L.Keating*, Inst. of Pharmacol. and Exp.Ther., Fac. of Medicine; *Centre for the Study and Prevention of Drug Abuse, Coimbra, Portugal.
Recent reports have shown that nicotine (NIC) plays a major role in tobacco addiction. However, few studies have investigated the reinforcing properties of NIC and its underlying substrates. In this study, we describe the pattern of neural activation, as obtained by staining immediate early gene expression at different anatomical CNS levels, during NIC intravenous (iv) self-administration in rats, a behavioural model of NIC addiction. Rats were trained to press a lever for iv NIC infusion (0.03 mg/kg/infusion on a fixed-ratio 3 schedule of reinforcement). After 8 consecutive daily sessions of self-administration, 90 min after the end of the last session, animals were anesthetized, perfused transcardiacally with paraformaldheyde 4% and brains were prepared for immunohistochemistry. Specific antibodies for cFos and cJun gene products were used for immunostaining. Both acute and chronic exposure to iv NIC produced strong increases of Fos immunoreactivity in the superior colliculus and in the medial terminal nucleus of the accessory optic tract. Significant levels of los immunoreactivity were also found in forebrain structures like the piriform cortex, septal nuclei and paraventricular thalamic nuclei. Jun expression did not significantly change. Fos activation by nicotine persisted even after chronic exposure to NIC suggesting that desensitization of NIC-dependent Fos expression does not occur during self-administration.
Several studies have shown that the central dopaminergic pathway is implicated in the reinforcing properties of drugs of abuse. However, data describing changes of blood catecholamines and 5-HT are limited. Therefore, this work aimed to study sympathetic and 5-hydroxytryptaminergic alterations induced by heroin plus cocaine addiction in man. Free and sulfoconjugated (after acid hydro[isis) catecholamines and 5-HT were measured by HPLC-ECD, and erythrocyte COMT and plasma dopamine-~-hydroxylase activities by a HPLC technique. Platelet catecholamines and 5-HT were extracted with HC104 and then also measured by HPLC-ECD. When compared with control (healthy) subjects (N=26), the results in drug addicts (N=24) revealed: a) Significant increases in plasma dopamine (DA) (free and sulfoconjugated), noradrenaline (NA) sulfate and MHPG; b) Significant elevation of platelet adrenaline (Ad) and DA; c) No appreciable difference in the concentrations of: free NA, free or sulfate-conjugated Ad, serum and platelet 5-HT, COMT and DA-[~-hydroxylase. The differences found may be interpreted as a reflection of the activation of adrenergic neurotransmission. Furthermore, platelets and sulfoconjugation may protect catecholamines from metabolization during circulation. Thus, platelet amine levels may be a marker of this kind of drug abuse.
EFFECTS OF COCAINE ON EEG IN RATS AFTER SINGLE OR REPEATED ADMINISTRATIONS K.Kuschinsky and B. Ferger Institute of Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Ketzerbach 63, D-35032 Marburg, Germany
PERIADOLESCENTRATSAND COCAINE SENSITIZATION G. Laviola,*,C.KuhnA and L.P. Spear# *Sect. Behav. Pathophysiology, Lab. F.O.S., Istituto Superiore di Sanit&, Rome, Italy; #Centr. Develop. Psychobiology, State University of New York at Binghamton, USA; ^Dept. Pharmacology, Duke University, Durham, USA
(Supported by G. P. C. C. D., Ministry of Justice, Portugal)
Periadolescent rats have been reported to be differentially affected by catecholaminergic agents when compared with younger or adult animals. The present study evaluated the behavioral responsivity of periadolescent (34-39-day-old) and adult (60-70-day-old) Sprague-Dawley male and female rats to chronic IP administration of cocaine (0, 10, or 20 mg/kg once daily for four days). To assess the role of context in the develooment of behavioral sensitization, all animals received injections of both 'saline and cocaine every day paired with a different context, with half of the animals receiving the drug in the home cage (Coc-Home) and the other half in the testing chamber (Coc-Test). Forty-eight hr after the last drug injection alt animals were challenged with 10 mg/kg IP cocaine, and were placed in the test chamber where their behavior was scored. As expected, acute cocaine induced a prominent increase in a number of behaviours and this response profile was less marked in periadolescent relative to adult subjects. In contrast, Coc-Test animals of both ages previously exposed chronically to cocaine showed clear sensitization on a number of behaviours relative to those in the chronic saline group. No evidence of carry-over effects was found in Coc-Home subjects. A marked sex difference emerged, with females showing a more marked sensitivity than males to acute cocaine effects. Chronic cocaine reduced body weight and food consumption, particularly in adult males, whereas it did not affect periadolescent patterns. Plasma corticosterone and ACTH levels following cocaine challenge were higher in females than males and in adult than periadolescents. No evidence of sensitization,following chronic cocaine was found using these hormonal measures.
In a previous study (Ferger et al., Psychopharmacol. 114:297 (!994)), it was shown that a moderate dose of cocaine (10 mg/kg i.p.) produces a pattern in EEG power spectrum suggesting activation of dopamine D1 receptors, whereas a large dose (30 mg/kg) induces a qualitative change suggesting an additional activation olD2 receptors. The present experiments were performed in male Wistar rats of about 300 g in order to supplement the dose-responserelationship and to evaluate possible tolerance or sensitization phenomena. The EEG studies were performed telemetrically in awake, freely moving rats. Five mg/kg of cocaine produced a smaller effect than 10 mg/kg (general decrease of power in ill of the frequency bands), 20 mg/kg a more pronounced effect, with evidence of a slight additional activation of D2 receptors. After ten daily administrations of 10 mg/kg of cocaine and a drag-free intelval of 4 days the same dose of cocaine produced a siL-,nificantly enhanced effect, but no evidence for an additional activation of D2 dopamine receptors was found. Accordingly, there was a sensitization but no evidence of a shift to an additional activation of D~ receptors.
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