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1.
We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study
with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice
between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate
drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg
per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day).
Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions
remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the
rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external
conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls:
0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during
withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day).
Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol
and opiates.
Received: 3 April 1998/Final version: 26 August 1998 相似文献
2.
Jo A. Talledo Ashley N. Sutherland Owens Tijmen Schortinghuis Neal R. Swerdlow 《Psychopharmacology》2009,204(1):165-175
Background Dopamine agonists disrupt prepulse inhibition (PPI) of startle in male rodents. In humans, this is observed only in some studies.
We reported that PPI was disrupted by d-amphetamine in men, but only among those with high basal PPI levels. Here, amphetamine effects on PPI were tested in normal
women and female rats.
Materials and methods Acoustic startle and PPI were tested in normal women after placebo or 20 mg amphetamine, in a double-blind, crossover design,
and in female rats after vehicle or 4.5 mg/kg amphetamine. Rats were from Sprague–Dawley (SD) and Long Evans (LE) strains
that differ significantly in gene expression in PPI-regulatory circuitry, including levels of nucleus accumbens (NAC) catechol-O-methyl transferase (COMT) mRNA.
Results Amphetamine was bioactive in humans based on quantitative autonomic and self-rating measures, but did not significantly change
startle magnitude or PPI across all subjects. Amphetamine’s effects on PPI in women correlated significantly (p < 0.0008) with placebo PPI levels (reducing PPI only in women whose basal PPI levels exceeded the sample median) and with
measures of novelty and sensation seeking. Amphetamine decreased PPI in SD rats that have relatively low NAC COMT gene expression
and increased PPI in LE rats that have relatively high NAC COMT gene expression.
Conclusion The dopaminergic regulation of PPI in humans is related to basal levels of sensorimotor gating and to specific personality
traits in normal men and women. In rats, the effects of amphetamine on PPI differ significantly in strains with low vs. high
NAC COMT expression. 相似文献
3.
John H. Krystal Elizabeth Webb Christian Grillon N. Cooney Lisa Casal C. A. Morgan III. Steven M. Southwick Michael Davis Dennis S. Charney 《Psychopharmacology》1997,131(3):207-215
Preclinical studies suggest that acoustic startle amplitude is increased during ethanol withdrawal. The current study evaluated
the effects of intravenous infusion of the α2-adrenergic antagonist, yohimbine (0.4 mg/kg), the serotonin partial agonist m-chlorophenylpiperazine (mCPP, 0.1 mg/kg), and placebo administered to 22 male patients meeting DSM-III-R criteria for alcohol
dependence and 13 male healthy subjects. Patients and healthy subjects completed 3 test days under double-blind conditions
in a randomized order. Patients were sober for 12–26 days prior to testing. On each test day, participants completed startle
testing 80 min following drug infusion. Stimuli with varying intensities (90, 96, 102, 108, 114 dB) were presented in a randomized
order balanced across four blocks. Stimuli consisted of 40-ms bursts of white noise administered every 45–60 s for 15–20 min
through headphones. Analyses indicated that patients exhibited elevated acoustic startle magnitudes on the placebo day relative
to healthy subjects. In patients, the magnitude of startle amplitudes elicited at 90 dB, but not 114 dB, correlated significantly
with the number of previous alcohol detoxifications. Yohimbine increased startle magnitudes and reduced startle latencies
relative to placebo and mCPP in both patients and healthy subjects. mCPP did not alter startle magnitude in either group.
Yohimbine also increased the probability that a 90-dB stimulus produced a startle response in healthy subjects, but not in
patients. Blunting of yohimbine effects on startle probability may reflect the baseline elevations in startle probability
levels in patients, but may also be consistent with other evidence of reduced postsynaptic, but not presynaptic, noradrenergic
function in these same patients. These data replicate and extend previous reports indicating that yohimbine facilitates the
acoustic startle response in humans. They also further implicate the number of episodes of ethanol withdrawal as a factor
influencing subsequent neurobiological responsivity in chronic alcoholic patients. Based on the current data, future research
should explore whether measurement of the acoustic startle response provides an objective quantitative severity measure of
ethanol withdrawal.
Received: 31 August 1995 /Final version: 4 October 1996 相似文献
4.
The present study investigated the effects of cigarette smoking on prepulse inhibition (PPI) of the acoustic startle reflex
in healthy men. Cigarette smoking in a group of overnight smoking-deprived smokers increased PPI as compared to the smoking-deprived
condition. This finding is consistent with previous animal studies showing that nicotine increases PPI of the acoustic startle
reflex. In addition, cigarette smoking also reduced startle amplitude during the first 6–7 min of the post-smoking session.
Received: 4 March 1996 / Final version: 17 June 1996 相似文献
5.
Post-weaning housing conditions influence the behavioural effects of cocaine and d-amphetamine 总被引:4,自引:0,他引:4
Post-weaning social isolation can induce profound and long lasting effects on an animal’s behaviour. The present study investigated
the influence of post-weaning housing conditions on the sensitivity of rats to the behavioural effects of d-amphetamine and cocaine. The locomotor stimulant effects of both drugs were compared following acute and chronic administration.
The influence of post-weaning housing conditions on the effects of d-amphetamine and cocaine on responding for food and for a conditioned reinforcer were also examined. Isolated rats showed
enhanced locomotor activity on exposure to a novel environment. This difference was further exaggerated following administration
of d-amphetamine (0.5 mg/kg) and cocaine (5 mg/kg). Isolated, but not enriched, rats exhibited sensitisation to the locomotor
activating effects of repeated administration of a dose of 0.5 mg/kg d-amphetamine, whilst both groups sensitised equally to a dose of 1.0 mg/kg d-amphetamine. Rearing conditions did not affect sensitisation to cocaine (5, 10 mg/kg). Isolated rats exhibited a higher rate
of responding for a conditioned stimulus and for food on a progressive ratio schedule of reinforcement, both of which were
enhanced to a greater extent in isolates following administration of cocaine (5 mg/kg) and d-amphetamine (0.5 mg/kg). These results suggest that isolation rearing induces an enhancement in sensitivity to both the locomotor
stimulant and reinforcing properties of amphetamine and cocaine.
Received: 12 June 1996 / Final version: 17 October 1996 相似文献
6.
Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats
This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor
gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, IP) on prepulse inhibition of acoustic startle (PPI) and locomotor activity.
The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not
reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant
effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0,
0.1, 0.2, 0.4 and 0.8 mg/kg, SC) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These
findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants
do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications
of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed.
Received: 15 May 1997/Final version: 7 July 1997 相似文献
7.
Sandra D. Comer Margaret Haney Richard W. Foltin Marian W. Fischman 《Psychopharmacology》1996,127(1-2):39-46
The effect of task performance feedback and associated monetary earnings on drug self-administration were evaluated using
eight subjects in a residential laboratory setting. The hypothesis was that if subjects believed thatd-amphetamine impaired performance and reduced monetary earnings,d-amphetamine self-administration would decrease. Subjects performed computer tasks every day: on certain days that they received
capsules, subjects were given bogus feedback regarding their performance (“better” or “worse” than average). On sample days,
subjects were required to taked-amphetamine (10 mg BID) or placebo (0 mg BID) capsules. On choice days, subjects could choose between eitherd-amphetamine or placebo. Subjects received feedback on their task performance on 2 sample days and 2 of 4 choice days. Subjects
received no feedback on the remaining two choice days. When subjects received no feedback, they chosed-amphetamine over placebo 78% of the time, and when they were given better feedback messages, they chosed-amphetamine 87.5% of the time. In contrast,d-amphetamine self-administration decreased significantly to 25% when subjects were told that it impaired their performance
on work tasks and resulted in reduced earnings. In reality,d-amphetamine had little effect on work task performance. However, compared to placebo,d-amphetamine significantly increased subjective ratings of “Stimulated” and “Good Drug Effect” and significantly decreased
ratings of “Tired” and “Sleepy”. These results demonstrate thatd-amphetamine served as a reinforcer under conditions in which drug self-administration did not influence monetary earnings,
but thatd-amphetamine self-administration could be modified by feedback/monetary earnings. Thus, contingencies associated with performance
have important implications for drug use in the workplace. 相似文献
8.
Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule 总被引:10,自引:8,他引:2
Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement.
In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following
a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy
in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted
with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then
imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest
that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug.
Received: 16 July 1997 / Final version: 22 October 1997 相似文献
9.
Neal R. Swerdlow Sophia A. Lelham Ashley N. Sutherland Owens Wei-Li Chang Sebastiaan D. T. Sassen Jo A. Talledo 《Psychopharmacology》2009,205(4):689-698
Background Dopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle
after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist,
pramipexole, on PPI in normal men and Sprague–Dawley rats.
Materials and Methods Acoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n = 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague–Dawley rats using
a parallel design [vehicle vs. 0.1 mg/kg (n = 8), vehicle vs. 0.3 mg/kg (n = 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in
humans.
Results Pramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not
moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval
(120 ms) PPI, while low doses actually increased short-interval (10–20 ms) PPI. Effects of pramipexole on PPI in rats were
independent of baseline PPI and changes in startle magnitude.
Conclusion The preferential D3 agonist pramipexole modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists,
pramipexole increases long-interval PPI in humans, in a manner that is independent of baseline PPI and personality measures.
These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor
gating. 相似文献
10.
Drugs of abuse produce amnestic effects in humans and laboratory animals in a variety of tasks. Generally, only a few compounds
have been examined in any particular procedure. It was the goal of the present studies to examine drugs of abuse of different
pharmacological classes in rats responding under two behavioral schedules historically employed as experimental models of
memory: spatial alternation and matching to position. One group of rats responded under a single-response spatial-alternation
baseline with a 10-s delay and another group responded under a matching-to-position baseline with delay values of 3, 10 and
30 s. Performance under the spatial-alternation baseline was characterized by low variability and >90% accuracy. Under the
matching-to-position baseline, saline control percent accuracy was >95% at 3 s, >85% at 10 s and >70% at 30 s. Under spatial
alternation cocaine, d-amphetamine, pentobarbital, diazepam, phencyclidine, scopolamine and methscopolamine produced significant (P<0.05) effects on accuracy, whereas only cocaine, d-amphetamine, pentobarbital and phencyclidine disrupted accuracy under the matching-to-position baseline. These results suggest
that spatial alternation may be a more sensitive baseline for determining drug effects on working memory in the rat.
Received: 16 April 1997 / Final version: 25 November 1997 相似文献
11.
W. S. Pritchard Michael E. Houlihan Thomas D. Guy John H. Robinson 《Psychopharmacology》1999,143(3):273-279
Rationale: A substantial portion of cigarette smokers prefer menthol-flavored cigarettes. To date, however, no studies have examined
whether menthol in cigarettes has central pharmacological effects. Objective: We investigated psychophysiological and subjective effects of smoking menthol versus non-menthol cigarettes in both menthol
and non-menthol smokers. To assess these effects independently of the immediate effects of nicotine, all cigarettes employed
were “denicotinized” (FTC nicotine yield = 0.06 mg). Methods: The psychophysiological measures were EEG and heart rate (HR). The subjective measures assessed mental alertness, muscular
relaxation, anxiety/nervousness, and how much a participant wanted to smoke one of his usual brand of cigarettes. Menthol
and non-menthol smokers participated in a single session in which each participant smoked both a menthol and a non-menthol
denicotinized cigarette (order balanced across participants). The psychophysiological and subjective measures were recorded
before and after smoking each cigarette. Results: Out of 48 F-ratios spanning 22 analyses of variance involving the critical interaction between pre-/post-smoking and menthol/non-menthol
cigarette, only one unambiguously fit a “pharmacological” pattern, a result indistinguishable from a type-I statistical error.
We report evidence that menthol smokers may be chronically less aroused and more sensitive to the effects of nicotine than
non-menthol smokers. Conclusions: We found little evidence that menthol in cigarettes has central pharmacological effects.
Received: 27 July 1998/Final version: 26 October 1998 相似文献
12.
The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the effects of haloperidol on the ASR and PPI
were examined in C57BL/6J (B6) and DBA/2 (D2) inbred mouse strains and their F1 and F2 progeny. The startle stimulus was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms white noise bursts at 56,
68 and 80 dB against a 50-dB background presented 100-ms before the startle pulse. The B6 strain showed modest PPI (25–40%);
in contrast, the D2 strain showed on average no PPI and numerous individuals showed prepulse augmentation (PPA). The F2 progeny showed an intermediate PPI; however, the extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol
in dose-dependent fashion, increased PPI in both the B6 and D2 strains; the threshold dose was in the range of 0.1–0.2 mg/kg.
Raclopride (0.3 mg/kg), clozapine (2 mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The effects of
haloperidol (0.4 mg/kg) on PPI in 140 F2 progeny were examined. For all prepulse intensities, there were highly significant (r > 0.80) and negative correlations between baseline PPI and the haloperidol-induced change in PPI. Thus, those animals that
showed the greatest PPA showed the greatest haloperidol-induced increase in PPI. There was, however, significant variance
in the haloperidol response; plots of the regression residuals showed the most and least responsive animals differed by almost
100% in effect on PPI. The F2 progeny were subsequently phenotyped for haloperidol-induced catalepsy. There was no association between the variation in
effects on catalepsy and PPI. However, it was observed that those individuals with the poorest baseline PPI were catalepsy
non-responsive.
Received: 11 February 1997 /Final version: 20 May 1997 相似文献
13.
Objectives: Since grapefruit juice (Gra) inhibits hepatic P450 (CYP3A4), we studied its potential to enhance the effects of midazolam
(Mid) and triazolam (Trz), which are metabolized by the CYP3A4 isoenzyme.
Methods:
In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice (GraMid), two placebo
groups receiving water or Gra. The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue
scales before and 30 and 90 min after intake. Study II was similar, but the post-treatment tests were at 45 and 90 min, and
the active drugs used were 0.250 mg Trz, GraTrz, and Mid 10 mg. In the crossover Study III, 6 subjects took Mid 10 mg alone
and with Gra (GraMid) and 750 mg erythromycin (EryMid). Performance tests were made and blood was sampled before and 30, 60
and 90 min after intake. Midazolam and its active metabolite α-OH-midazolam were assayed by gas chromatography (GC) and radioreceptor
assay (RRA).
Results:
In Study I, both Mid and GraMid impaired digit symbol substitution (DSS), letter cancellation (LC) and flicker fusion (CFF)
at 90 min. GraMid had more effect (P < 0.05) than Mid on the DSS performance. Mid caused drowsiness at 30 and 90 min. Both Mid and GraMid caused clumsiness and
a feeling of impaired performance at 90 min. In Study II, the active drugs impaired objective test performances (DSS, LC,
CFF) at 90 min, without having a clear subjective effect. In Study III, Mid, EryMid and GraMid impaired performance in the
DSS, LC and CFF tests. EryMid proved stronger than Mid and GraMid on DSS and LC tests at 30 min. Mean values of plasma midazolam
(and α-OH-midazolam) at 30, 60, 90 and 120 min after Mid 10 mg were 68 (19), 61 (19), 43 (14) and 42 (12) μg⋅l−1. The corresponding values after EryMid were 164 (14), 137 (13), 104(10) and 89(10) μg ⋅l−1, and after GraMid 60 (12), 69 (16), 61 (15) and 57 (14) μg⋅l−1.
Conclusions:
The grapefruit juice used did have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in
healthy young subjects.
Received: 4 September 1995/Accepted in revised form: 5 January 1996 相似文献
14.
Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats 总被引:2,自引:2,他引:0
Rationale Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity.Objective The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague–Dawley rats.Materials and methods The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus).Results Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects.Conclusion These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating. 相似文献
15.
The present study investigated the effect of sensitization, induced by repeated injections of d-amphetamine, on sexual behavior in the naive male rat tested in a drug-free state. Injections of either d-amphetamine (1.5 mg/kg, IP) or saline were given every other day for a total of ten injections, and this regimen induced
behavioral sensitization of locomotor activity in drug-treated rats. After a 3-week post-drug period, d-amphetamine-treated rats exhibited facilitated sexual behavior, as indicated by shorter latencies to mount and intromit,
and a greater percentage of rats copulating. These rats also exhibited a general increase in the amount of copulation. Furthermore,
sensitized rats displayed a facilitated acquisition of sexual behavior (i.e. mount and intromission latency <300 s for 3 consecutive
days). After repeated sexual experience, rats pre-treated with d-amphetamine also showed an augmented increase in level changes made in anticipation of the presentation of a receptive female.
Finally, enhanced sexual behavior was independent of the environment in which repeated administration of d-amphetamine occurred, indicating that facilitation was not a consequence of conditioned associations between drug and test
environment. These results demonstrate that behavioral sensitization due to repeated psychostimulant administration can “cross-sensitize”
to a natural motivated behavior, such as sex. Furthermore, the subsequent facilitation of anticipatory sexual behavior (i.e.
level changes) after repeated experience in rats previously treated with d-amphetamine suggests that behavioral sensitization can influence incentive learning.
Received: 10 June 1998/Final version: 7 August 1998 相似文献
16.
This study examined the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Bilateral post-session
intra-amygdala microinjections of d-amphetamine were carried out in rats during training in a discriminative approach task known to be sensitive to experimental
manipulations of the amygdala. The experiment consisted of two phases: discriminative approach training, and a subsequent
assessment of instrumental conditioned reward efficacy. During discriminative approach training, subjects were trained to
associate a neutral stimulus with 10% w/v sucrose reward. Each trial consisted of a 1-s light stimulus followed by a 5-s presentation
of the sucrose reward. Approach behaviour into the recess housing sucrose reward was measured during each trial. Inappropriate
approach behaviour (approach outside of the trial periods) was punished by delaying the next trial. Intra-amygdala d-amphetamine (10 μg/side) enhanced the rate of acquisition of discriminative approach behaviour. This effect was most evident
early during training (sessions 2–4) and by the tenth session both groups had reached similar asymptotic performance. Horizontal
and vertical activity increased slightly across sessions, but there was no indication of a differential effect of d-amphetamine. Thus, intra-amygdala microinjections of d-amphetamine enhanced selectively the acquisition of the stimulus-reward association. During a subsequent test of instrumental
conditioned reward, presentation of the conditioned light stimulus was made contingent upon performance of a novel lever-pressing
response (probability 0.5). Responding on a second, control lever was without programmed consequences. Sucrose reward was
not available at any point, and subjects were tested drug-free. In both groups the conditioned stimulus was found to possess
significant conditioned rewarding efficacy. Extraneous behaviour was increased in the d-amphetamine group but the rewarding properties of the conditioned stimulus were unaltered. These findings demonstrate that
the mesoamygdaloid dopamine projection modulates the acquisition of a stimulus-reward association, but is apparently without
subsequent effect on the rewarding efficacy of a conditioned stimulus.
Received: 24 October 1996/Final version: 28 February 1997 相似文献
17.
Effects of central and peripheral nicotinic blockade on human nicotine discrimination 总被引:2,自引:1,他引:1
Perkins KA Sanders M Fonte C Wilson AS White W Stiller R McNamara D 《Psychopharmacology》1999,142(2):158-164
Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not
yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared
effects of mecamylamine (10 mg PO), a central and peripheral nicotine antagonist, on nicotine discrimination with those of
trimethaphan (10–40 μg/kg per min IV), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 μg/kg nicotine by nasal spray and then tested on generalization
of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 μg/kg) following antagonist/placebo pretreatment.
Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between
nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose
of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some
subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous
animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in
part by its central effects.
Received: 15 April 1998/Final version: 23 July 1998 相似文献
18.
B. A. Johnson John D. Roache Patrick S. Bordnick Nassima Ait-Daoud 《Psychopharmacology》1999,144(3):295-300
Rationale: Dopamine (DA) pathways in the midbrain mediate d-methamphetamine’s rewarding effects associated with its abuse liability. Isradipine, a dihydropyridine-class calcium channel
antagonist, reduces the rewarding effects of psychostimulants such as cocaine and d-amphetamine, presumably by antagonizing these central DA pathways. This is the first experiment to test the hypothesis that
the rewarding effects of d-methamphetamine, like other psychostimulants, can be reduced by isradipine. Objective: We studied the effects of high dose isradipine (0.21 mg/kg orally), on the positive subjective effects associated with the
abuse liability of low and high dose d-methamphetamine (0.21 mg/kg and 0.42 mg/kg orally, respectively). Methods: Using a double-blind, double-dummy, placebo-controlled, Latin-Square, cross-over design, 18 healthy male and female volunteers
received each of the following six treatments separated by a rest period of 2–7 days: a) placebo+placebo; b) low-dose d-methamphetamine+placebo); c) high-dose d-methamphetamine+placebo; d) high dose isradipine+placebo); e) low-dose d-methamphetamine+high dose isradipine, and f) high-dose d-methamphetamine+high dose isradipine. Results: d-Methamphetamine produced orderly increases in positive subjective measures of both stimulation and mood. Pre-treatment with
isradipine significantly reduced some of these positive subjective effects and craving for d-methamphetamine. Conclusion: Isradipine as an anti-reward or craving reducing medication is a promising therapeutic agent for the treatment of d-methamphetamine dependence.
Received: 17 November 1998 / Final version: 4 February 1999 相似文献
19.
R. D. Hurt K. P. Offord I. T. Croghan G. A. Croghan L. C. Gomez-Dahl T. D. Wolter L. C. Dale T. P. Moyer 《Psychopharmacology》1998,140(1):98-104
Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this
randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal
spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal
symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence
was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no
withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline,
then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years,
48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose
of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine
gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while
the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to
serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal
symptoms, possibly in combination with other medications with longer acting effects.
Received: 18 February 1998/Final version: 1 May 1998 相似文献
20.
Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward 总被引:2,自引:2,他引:0
Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating
effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect
by investigating the effects of 5-HT agonists with differing affinities for 5-HT1 and 5-HT2 receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently
the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR)
lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned
as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 μg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT
(0.5 and 1 μg), RU24969 (10 μg), CP93,129 (1.25 and 2.5 μg) but not by DOI (10 μg) or 8-OH-DPAT (5 μg). The lower doses of
5-CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating
that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of
5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the5-HT1B/1D antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these
receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission.
Received: 22 April 1998/Final version: 28 July 1998 相似文献