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  • 1
    ISSN: 1432-2072
    Keywords: Diazepam ; Flunitrazepam ; Ethanol ; Psychomotor performance ; Drug plasma concentration ; Interindividual differences ; Drug sensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In a placebo controlled, crossover study psychomotor effects of single doses of diazepam, 10 and 20 mg, flunitrazepam, 1 and 2 mg, as well as 0.9 g ethanol/kg body weight were investigated over a time period of 6 h in 12 healthy men. Blood samples were collected simultaneously with the test sessions to determine drug concentrations in plasma or blood. The ethanol dose caused the least performance impairment, followed by 10 mg diazepam. The most pronounced impairment was caused by 2 mg flunitrazepam, whereas 20 mg diazepam and 1 mg flunitrazepam caused intermediate impairment and were approximately equipotent on group level. Considerable interindividual differences with respect to maximal impairment following a particular drug treatment were observed, with poor correlation between individual maximal impairments and individual peak plasma concentrations of the drug. The maximal impairment in simple reaction time following the flunitrazepam treatments occurred earlier relative to the peak plasma concentration of the drug as compared to the diazepam treatments. This may indicate that acute tolerance develops differently for the two drugs.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2072
    Keywords: Dopamine receptors ; Positron emission tomography ; Akathisia ; SCH 23390 ; Raclopride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D1-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310–810 µg. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [11C]SCH 23390 binding in the basal ganglia was at a high level with a central D1-dopamine receptor occupancy of 45–59%. The D2-dopamine receptor antagonist [11C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [11C]raclopride binding in the basal ganglia. The findings for [11C]raclopride and [11C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.
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  • 3
    ISSN: 1432-2072
    Keywords: Deoxyglucose ; Serotonin ; Meta-chlorophenylpiperazine ; Quipazine ; 8-Hydroxy-2(di-N-propylamino)tetralin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the serotonin (5-HT) agonists meta-chlorophenylpiperazine (m-CPP), quipazine and 8-hydroxy-2(di-n-propylamino)tetralin (DPAT) on behavior and on regional cerebral metabolic rates for glucose (rCMRglc) were measured in control rats or in rats pretreated for 2 weeks with continuous infusion of saline or m-CPP (2.5 mg/kg/day, subcutaneously). rCMRglc was measured in 71 brain regions, using the quantitative autoradiographic [14C]2-deoxy-D-glucose technique, at 15 min after acute administration of m-CPP 2.5 mg/kg, 60 min after quipazine 20 mg/kg, or 10 min after DPAT 1 mg/kg. Behavioral effects were assessed for m-CPP with an activity monitor, for quipazine by counting head shakes and for DPAT by scoring the serotonin syndrome. Chronic m-CPP pretreatment produced tolerance to hypolocomotion induced by acute m-CPP and to head shakes caused by acute quipazine, but did not alter the serotonin syndrome produced by DPAT. m-CPP 2.5 mg/kg IP produced widespread rCMRglc reductions in control rats but failed to modify rCMRglc in any region after chronic m-CPP pretreatment. Quipazine increased rCMRglc in 4 regions in control rats, but reduced rCMRglc in 14 brain areas of chronically m-CPP-pretreated animals. DPAT altered rCMRglc to the same degree in control (25 regions affected) and in chronically m-CPP-pretreated rats (28 regions affected). Reduced behavioral and metabolic effects of acute m-CPP in chronically m-CPP-pretreated rats were not due to pharmacokinetic alterations. These results demonstrate that chronic administration of m-CPP produces behavioral and metabolic tolerance to acute administration of m-CPP, but not of DPAT. They suggest that hypolocomotion and the serotonin syndrome are mediated by different 5-HT receptor subtypes, and that chronic m-CPP administration produces functional down-regulation of 5-HT1B/1C but not of 5-HT1A-coupled mechanisms.
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  • 4
    ISSN: 1432-2072
    Keywords: Cocaine ; Dopamine autoreceptor ; (+)-AJ 76 ; (+)-UH 232 ; Drug discrimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N=8) or 10 mg/kg (N=8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5–20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5–40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25–5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2–16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue.
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  • 5
    ISSN: 1432-2072
    Keywords: Neuroleptics ; Rat ; Field potentials ; Telemetry ; Frequency analysis ; Electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Under the assumption that field potentials recorded from particular brain areas reflect the net balance of neurotransmitter activities, the dose- and time-dependent responses induced by intraperitoneal application of different neuroleptic drugs are quantified by spectral analysis of the electroencephalogram recorded from frontal cortex, hippocampus, striatum and reticular formation. The actions of haloperidol, chlorpromazine, clozapine, prothipendyl and thioridazine in general were characterized by increases of the spectral power in the alpha1 and beta range, at higher dosages also in the theta range. This observed pattern of changes is in line with the neuroleptic induced spectral changes reported in the literature for other animals and man. In the light of the already known effects of other psychoactive drugs on the frequency content of field potentials in the rat, it should now be possible to classify different drugs in terms of their clinical indication. With respect to the type of neurotransmitter control underlying the changes produced by various neuroleptics, it is quite obvious from the comparisons with the respective drug effects that dopamine-D1-receptor controlled transmission is not responsible for this action. On the basis of earlier findings a possible interaction between dopamin-D2 receptor or glutamatergic transmitter control is discussed.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 107 (1992), S. 203-210 
    ISSN: 1432-2072
    Keywords: l-dopa ; Dopamine ; Pavlovian conditioning ; Parkinson's disease ; 6-Hydroxydopamine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drugl-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence ofl-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as thel-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior andl-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlikel-dopa-induced contralateral rotation, is not affected by D1/D2 receptor blockade. Thus, the conditoned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D1/D2 antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects ofl-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.
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  • 7
    ISSN: 1432-2072
    Keywords: Behavioral economics ; Drug self-administration ; Reinforcer interactions ; Concurrent reinforcers ; Cigarette smoking ; Coffee drinking ; Humans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In behavioral economics, consumption of a reinforcer is determined by its price and by the price of other available reinforcers. This study examined the effects of price manipulations on the consumption of concurrently available coffee and cigarettes. During fifteen 4-h sessions, coffee and cigarettes were concurrently available according to fixed-ratio (FR) schedules of reinforcement. After consumption stabilized under a fixed ratio 100 for both reinforcers, the response requirement for each reinforcer was varied separately (i.e., FR 100, 1000 and 2500), while the response requirement for the other reinforcer was kept at 100. Increasing the FR value decreased coffee and cigarette consumption to a similar degree. Also, as the price for cigarettes increased (and consumption decreased), coffee consumption decreased; however, as the price of coffee increased, cigarette consumption did not change. These results indicate that for this setting the reinforcing effects of cigarettes and coffee were comparable but interacted asymmetrically. These findings when analyzed and quantified via economic concepts of own-price and cross-price elasticity illustrate the viability of using behavioral economics to examine drug self-administration in a choice paradigm.
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  • 8
    ISSN: 1432-2072
    Keywords: Behavioural development ; Ontogeny of locomotor activity ; Conditioned place preference ; Cocaine ; Mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Conditioned place preference (CPP) procedures using jointly visual and tactile cues (white compartment with a wide-mesh metal floor versus black compartment with a narrow-mesh floor) were employed to assess the ontogenetic pattern of cocaine reinforcing properties in outbred CD1 mice. A classical 11-day-long schedule, in which the drug experience occurred in the initially less-preferred compartment (“biased” procedure, Spyraki 1988), served to study cocaine (0, 1, 5, or 25 mg/kg IP repeated four times at 48 h intervals) during the early postweaning stage (21–32 days). The result was a fully-fledged CPP at all cocaine doses. A subsequent experiment used a shortened (4-day) “unbiased” CPP schedule (animals assigned at random to drug experience in one or the other compartment); this enabled an assessment of the ontogenetic pattern of the drug action (single treatment, same dose range) in pups of both sexes at three different developmental ages (14–17, 21–24, or 28–31 days). At the 25 mg/kg dose, CPP developed in animals of all ages, while the 5 mg/kg dose was effective only in 21–24 day pups and the 1 mg/kg dose was ineffective. No significant sex differences were found, but the use of the unbiased procedure enabled a demonstration of an interaction between treatment, age, and type of CS. At the preweaning stage, CPP was due mainly to an increased preference for the black/narrowmesh compartment, while at the early postweaning stage it consisted mainly of an increased preference for the white/wide-mesh compartment; at the late postweaning stage the cue and the treatment factor did not interact. At all ages tested cocaine induced a dose-dependent increase in locomotor activity which was much more marked at both post-weaning stages than before weaning.
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  • 9
    ISSN: 1432-2072
    Keywords: Human ; Marijuana ; THC ; Subjective effects ; Reinforcing effects ; Self-administration ; Route of administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N=10) was tested with smoked marijuana and the other (N=11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.
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  • 10
    ISSN: 1432-2072
    Keywords: Cocaine ; Amphetamine ; Nicotine ; Self-administration ; Sensitization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The acquisition of low-dose (0.25 mg/kg/infusion) intravenous cocaine self-administration was measured in rats that had received nine daily injections of amphetamine (1.0 mg/kg, IP), nicotine (0.6 mg/kg base weight, SC) or vehicle. For control rats, the acquisition of self-administration was gradual with the number of responses per 2 h daily test session increasing between days 3 and 9. By comparison, rats preexposed with amphetamine and nicotine demonstrated elevated response means during the early days of testing, suggesting more rapid acquisition. All groups eventually reached similar asymptotic levels of responding. The enhanced responding observed during the early days of testing in the rats preexposed with amphetamine and nicotine was due to an increased number of subjects that reliably self-administered cocaine. Thus, the rats preexposed with amphetamine and nicotine seemed predisposed to the reinforcing effects of cocaine. In contrast to the self-administration data, preexposure to nicotine failed to sensitize rats to the locomotor activating effects of cocaine. In fact, the same preexposure regimen appeared to produce tolerance to this effect of cocaine. These data give evidence that different mechanisms may mediate sensitization to the reinforcing and locomotor activating effects of cocaine.
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