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1.
This article discusses the theory and statistical aspects in the design and analysis of experiments to detect synergism between
two drugs that produce overtly similar effects. The current analysis extends and simplifies previously published work in this
area. Application is made to a study by Kimmel et al. in this issue that examined the combined action of buprenorphine and
cocaine in producing turning in rats having unilateral nigrostriatal lesions produced by 6-hydroxydopamine. The use of turning
as an endpoint is unusual in quantitative studies of synergism in that no clear maximum effect (turning), could be elicited.
Data from the turning study are analyzed statistically and reveal that the combination of buprenorphine and cocaine in each
of two fixed ratio mixtures tested is synergistic for this effect.
Received: 28 January 1997 / Final version: 7 June 1997 相似文献
2.
In rats with a unilateral 6-OHDA lesion of the substantia nigra a single exposure to cocaine significantly enhanced the ipsiversive rotational behavior produced by a second injection given one week later. It is concluded that it is not necessary to repeatedly administer psychomotor stimulant drugs to produce long-lasting changes in brain and behavior. 相似文献
3.
Stephen G. Holtzman 《Psychopharmacology》1997,130(3):292-299
Buprenorphine, a potent ”low efficacy” or ”partial” morphine-like opioid agonist, has morphine-like discriminative effects
in animals and humans discriminating morphine or a related drug. The purpose of the present study was to characterize further
the discriminative effects of buprenorphine in subjects trained to discriminate buprenorphine itself. Rats trained to discriminate
between SC injections of saline and either 0.03 or 0.1 mg/kg buprenorphine generalized completely to morphine and to other
morphine-like agonists. These drugs were approximately 3 times more potent in the rats trained with 0.03 mg/kg buprenorphine
than in those trained with 0.1 mg/kg; however, the potency of buprenorphine itself did not differ significantly between groups.
Indicative of efficacy differences among mixed-action opioids, rats discriminating 0.03 mg/kg buprenorphine generalized completely
to butorphanol and pentazocine and partially to nalbuphine, whereas those discriminating 0.1 mg/kg generalized completely
to butorphanol, partially to pentazocine, and little to nalbuphine. Stimulus control of behavior by 0.1 mg/kg buprenorphine
was blocked surmountably by low doses of antagonists, stereoselective, and pharmacologically selective. These results are
consistent with those of other studies showing that the discriminative effects of buprenorphine are morphine-like and mediated
by the mu-opioid receptor, and extend the conditions under which this has been demonstrated to stimulus control maintained by buprenorphine
itself.
Received: 18 September 1996 / Final version: 6 November 1996 相似文献
4.
Nine groups of rats self-administered intravenously-delivered cocaine (0.1, 0.2, or 0.4 mg/kg) during 24-h sessions contingent upon lever-press responses under a fixed-ratio (FR) 4 schedule. Three other groups of rats responded on tongue-operated drinking devices for deliveries (0.01 ml) of a solution of glucose and saccharin (G+S). There were an additional three groups that initially self-administered cocaine (0.2 mg/kg), and later saline replaced cocaine and extinction behavior was allowed to stabilize. All 15 groups of rats were injected twice daily for 5 days with one of three doses of buprenorphine (0.1, 0.2 or 0.4 mg/kg). Buprenorphine decreased cocaine self-administration, but the effect of the highest dose was only slightly greater than that of the lowest dose tested. Cocaine infusions were reduced on the first day of treatment, but they increased over the next 4 days of buprenorphine injections. Buprenorphine decreased G+S intake during the last 2 or 3 days of injections. When buprenorphine treatment was terminated, G+S intake decreased even further. These lower rates of intake persisted for at least 5 days, and they returned to baseline by 2 weeks. Saline self-administration was decreased by buprenorphine in all saline extinction groups. Food intake was not altered by buprenorphine in the groups self-administering IV cocaine or saline; however, food intake was reduced in the G+S groups. Water intake increased during buprenorphine treatment in some of the cocaine groups but not in the G+S groups. Responding on the inactive lever was not altered by buprenorphine during cocaine or G+S self-administration, but it decreased in the saline extinction group. These data indicate that buprenorphine is effective in reducing cocaine reinforced behavior, but it also produced decrements in behavior rewarded by nondrug substances. 相似文献
5.
Phencyclidine (PCP) and phencyclidine-like drugs (TCP, dexoxadrol, MK-801, and SKF 10,047) were evaluated for their ability
to induce rotational behavior in rats with unilateral 6-OHDA lesions of the medial forebrain bundle and for their ability
to alter striatal dopamine (DA) overflow with microdialysis procedures. All of the compounds tested produced rotational behavior
ipsilateral to the lesion, suggesting that they were enhancing extracellular dopamine in the intact striatum. The microdialysis
studies, however, did not support this contention. There appeared to be a complete dissociation between the ability of the
five compounds to produce ipsilateral rotations and their ability to enhance extracellular dopamine levels in the striatum.
PCP was the only compound able to elicit significant increases in striatal dopamine overflow following IP injections and also
produce dramatic rotational behavior. MK-801 was the most potent compound in enhancing rotational output while it had no effect
at all on striatal dopamine overflow. Dexoxadrol also produced significant rotational output without having any effect on
extracellular levels of dopamine following IP injections. TCP and SKF 10,047, at doses which produced significant rotational
behavior, only elevated dopamine 16% and 12%, respectively, at peak effect. It is most parsimonious to conclude that the effects
of PCP-like drugs on nigro-striatal function are mediated through their ability to act as indirect NMDA receptor antagonists
and not through their ability to alter striatal dopamine activity.
Received: 16 October 1996 / Final version: 2 August 1997 相似文献
6.
Pharmacological reversal of behavioral and cellular indices of cocaine sensitization in the rat 总被引:5,自引:0,他引:5
Rationale and objectives: Behavioral sensitization has been proposed as an animal model for the intensification of drug craving in cocaine addiction.
Interactions between dopamine and glutamate systems are important for the induction and maintenance of sensitization. The
goal of this study was to determine if established cocaine sensitization could be reversed by pharmacological manipulation
of these transmitter systems. Methods: Rats received 15 mg/kg cocaine (IP) on days 1–10 and were challenged with cocaine (10 mg/kg) on day 13 to verify that sensitization
had occurred. On days 14–20, separate groups of sensitized rats received daily injections of dopamine D1- or D2-class agonists, an NMDA receptor antagonist, or a dopamine agonist with an NMDA antagonist. Three days or 2 weeks later,
all rats were again tested for their response to cocaine to determine if sensitization had been reversed. Results: Reversal of sensitization was produced by repeated administration of either a D1-class agonist (SKF 81297) or the combination of an NMDA receptor antagonist and a D2-class agonist. Effective combinations were cocaine+MK-801, quinpirole+MK-801, quinpirole+CGS 19755, and pergolide+memantine.
The latter drugs are approved for human use. Reversal of sensitization persisted for at least 2 weeks after cessation of drug
treatment. Electrophysiological studies revealed that these drug treatments also reversed dopamine D1 receptor supersensitivity in the nucleus accumbens, a cellular correlate of sensitization. Conclusions: These results demonstrate that pharmacotherapy can reverse behavioral and cellular adaptations associated with repeated cocaine
administration, and may do so without the need for continued medication.
Received: 1 October 1999 / Accepted: 19 March 2000 相似文献
7.
C. J. Heyser Jeffrey S. McDonald Vanessa Beauchamp George F. Koob Lisa H. Gold 《Psychopharmacology》1997,132(2):202-208
The availability of numerous genetically homogenous mouse strains permits the analysis of genetic influences on behavior
and also behavioral sensitivity (responsivity) to drugs of abuse. The current study was conducted to characterize discriminated
operant responding for food in four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, SJL/J), an F1 Hybrid (C57BL/6×SJL), and one
outbred strain (CD1) of mouse. The effect of cocaine on this operant behavior was also examined. Initially, all animals were
trained to nosepoke for food on a continuous reinforcement schedule. The minimum response requirement for reinforcement was
increased every 5 days until the animals were responding on an FR-15 schedule of reinforcement. All strains increased operant
responding as the schedule of reinforcement was raised. However, significant differences in response rate and discrimination
learning were observed among the various strains of mice. Cocaine administration reduced operant responding for food in Balb/cByJ,
C57BL/6J, C57BL/6×SJL/J and CD1 mice at a dose of 15.0 mg/kg, whereas higher doses were required in DBA/2J mice (30.0 mg/kg)
and SJL/J mice (56.0 mg/kg). These results suggest that operant performance and the effect of cocaine on this behavior is
differentially influenced by genetic make-up.
Received: 20 December 1996 / Final version: 4 April 1997 相似文献
8.
Rationale: Ketoconazole (Keto) is an antifungal agent that also inhibits the synthesis of adrenocorticosteroids and has been reported
to act as a glucocorticoid receptor antagonist. Objective: The present experiments investigated the effects of Keto on the stressor-induced reinstatement of extinguished cocaine-seeking
behavior and on the generalization of a stressor-induced discriminative stimulus to cocaine in rats. Methods: In the first experiment, male Wistar rats were trained to self-administer cocaine (0.5 mg/kg per infusion, IV) under a fixed-ratio
4 schedule of reinforcement with a 90-s limited hold. Following ten consecutive extinction sessions, the effects of Keto (25
or 50 mg/kg, IP) or vehicle on the ability of EFS (electric footshock; 15 min) to reinstate extinguished cocaine-lever responding
were investigated. In the second experiment, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a
two-lever, food-reinforced drug discrimination design. The effects of Keto (50 mg/kg, IP) or vehicle on the EFS-induced generalization
to cocaine were determined. Results: EFS reinstated extinguished cocaine- but not food-reinforced responding. Keto (25 and 50 mg/kg, IP) blocked the EFS-induced
reinstatement of cocaine-seeking behavior and significantly attenuated the plasma corticosterone response to EFS. These same
doses of Keto failed to affect responding in rats trained to self-administer food pellets under an FR4 schedule of reinforcement.
EFS also produced significant cocaine-appropriate responding in rats trained to discriminate the drug from saline. However,
Keto (50 mg/kg) failed to block the EFS-induced generalization to cocaine. Conclusions: Overall, these data suggest that corticosterone contributes to the stressor-induced reinstatement of extinguished cocaine-seeking
behavior.
Received: 5 June 1998 / Final version: 7 October 1998 相似文献
9.
Badiani A Oates MM Fraioli S Browman KE Ostrander MM Xue CJ Wolf ME Robinson TE 《Psychopharmacology》2000,151(2-3):166-174
Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced
expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty
on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow
in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow
in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine
(0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the
other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate
concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced
DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability
of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate
or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context
independent of its primary neuropharmacological actions in the striatal complex.
Received: 27 July 1999 / Accepted: 30 November 1999 相似文献
10.
Alexander V. Kuzmin Mirjam A.F.M. Gerrits Edwin E. Zvartau Jan M. van Ree 《European neuropsychopharmacology》2000,10(6):12318-454
The influence of different mixed μ–κ-opioid receptor agonists–antagonists on cocaine reinforcement was studied using the method of initiation of intravenous cocaine self-administration in naive mice. Self-administration of cocaine was readily initiated according to an inverted U-shaped unit dose–response curve. Buprenorphine, butorphanol and nalbuphine tested against the optimal unit dose of cocaine (0.8 μg per infusion), inhibited initiation of cocaine self-administration in a dose-dependent manner. When tested against a scale of cocaine unit doses (0.2 –1.6 μg per infusion) buprenorphine (0.1 mg/kg, s.c.) and nalbuphine (2 mg/kg, s.c.) produced a shift of the optimal cocaine dose from 0.8 to 0.4 μg/inf, while butorphanol (1 mg/kg, s.c.) shifted the optimal unit dose of cocaine to the right along the cocaine unit doses axis. Co-administration of naloxone (0.1 mg/kg, s.c.) significantly reduced the effect of buprenorphine but failed to influence the effect of nalbuphine and butorphanol on cocaine intake. Taken together, these results suggest that nalbuphine is capable of affecting cocaine’s reinforcing properties in the same manner as buprenorphine during the initiation phase of cocaine self-administration behavior, while butorphanol causes the opposite effect. Although the exact opioid profile of action of the mixed opioid receptor agonists–antagonists is as yet not precisely known, the present findings suggest that multiple opioid receptor systems (i.e. μ and κ) play a role in reinforcing properties of cocaine and that a co-operative interaction between μ- and κ-opioid systems may be of importance during initiation of cocaine self-administration. 相似文献
11.
Recent investigations of the function of the strionigral pathway have utilized the intranigral injection of γ-aminobutyric acid (GABA) agonist and antagonist drugs. While the unilateral application of these substances typically produces rotational behavior, the direction of this turning (ipsilateral or contralateral to the injected hemisphere) differs in several reports. The present study determines whether the direction of this drug-induced turning depends upon the locus of nigral stimulation. Picrotoxin and bicuculline methiodide were injected into either the pars compacta or the pars reticulata of the substantia nigra at several anterior-posterior levels. Injection of these drugs into the pars compacta resulted in ipsilateral turning while injection into the pars reticulata produced contralateral rotation. Both of these effects were dose-dependent and were elicited by similar threshold doses of picrotoxin. Prior 6-hydroxydopamine treatment abolished the ipsilateral but not the contralateral rotation. In contrast, muscimol injections produced contralateral turning in dependent of whether they were made into the pars compacta or pars reticulata. However, 6-hydroxydopamine treatment only attenuated the contralateral turning produced by pars compacta injections. These findings provide a histological basis for understanding the different types of turning behavior elicited by the intranigral injection of GABA agonists and antagonists. In addition, they suggest that GABA receptors mediate at least two independent actions in substantia nigra. 相似文献
12.
L. V. Panlilio Steven R. Goldberg Joanne P. Gilman Rebecca Jufer Edward J. Cone Charles W. Schindler 《Psychopharmacology》1998,137(3):253-258
The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration
in an animal model of drug abuse. Seven male rhesus monkeys self-administered IV cocaine on a fixed-ratio 30 schedule (5-min
time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion
volume (0.5 ml) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions
lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate.
Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine
(starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of
the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine
(at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven
monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels
of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with
the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the 5-min time-out)
in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results
suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it.
Received: 1 July 1997 / Final version: 4 January 1998 相似文献
13.
Previous investigations have demonstrated the ability of atropine and chlorpromazine pretreatment to increase intravenous cocaine self-administration in rhesus monkeys. These results were interpreted as resulting from either an antagonism of cocaine's reinforcing effect or an effect of cocaine which may interfere with its self-administration. The generality of the postulated drug antagonism was tested in monkeys exhibiting stable FR10 food-reinforced behavior. Intramuscular pretreatment with 0.25–4.0 mg/kg of chlorpromazine significantly depressed this behavior as did pretreatment with 0.25–2.0 mg/kg of atropine. These same dosages had been shown to increase cocaine self-administration. Fifteen-minute infussions of cocaine (1.0–10 mg/kg), which began 15 min after session onset, also resulted in a depression of food reinforced behavior. When chlorpromazine pretreatment and cocaine infusion were combined, the decrement in food reinforced responding was lessened. However, when cocaine infusion and atropine pretreatment occurred concurrently, the depression in responding was increased. These data indicate that chlorpromazine may nonspecifically antagonize the behavioral effects of cocaine; whereas, atropine may enhance these effects. 相似文献
14.
Maria Jaszyna Maciej Gasior Mohammed Shoaib Sevil Yasar S. R. Goldberg 《Psychopharmacology》1998,140(3):257-271
Epidemiological surveys demonstrate that caffeine, the main psychoactive ingredient of coffee, is a positive correlate in
drug abuse. To characterize the behavioral nature of caffeine interactions with other psychomotor stimulants, we examined
the effects of chronic caffeine exposure on the behavioral responses to nicotine, amphetamine, cocaine, the selective D1 agonist SKF-82958 and the selective D2 receptor agonist NPA, in rats responding under a fixed interval (FI) schedule of food reinforcement. Following stabilization
of rates and temporal patterns of responding (mathematically expressed as quarter-life values, QL), twenty-one Sprague-Dawley
rats responding under a 5-min FI schedule of food reinforcement were divided into two groups; one (twelve rats) maintained
on tap water (control) and the other (nine rats) on caffeine (3 mg/ml added to the drinking water). Following the substitution
of caffeine solution for tap water, behavior was temporarily disrupted as evidenced by decreases in responding and QL values
which reached a maximum after 72 h (rate 60% and QL 30% below baseline levels). Rats developed complete tolerance to these
effects of caffeine over 5 days of caffeine exposure. After response rate and QL values stabilized, effects of drugs were
evaluated. Nicotine (0.01–1.0 mg/kg; SC), amphetamine (0.1–5.6; IP), and cocaine (1.0–17; IP) each produced biphasic dose-dependent
changes in response rate with maximum increases in response rate following intermediate doses and decreases in response rates
following higher doses. The increase in rates of responding produced by amphetamine or cocaine (but not nicotine) were greater
(P<0.05) in caffeine-drinking than in water-drinking rats. Both SKF-82958 (0.001–0.3 mg/kg; IP) and NPA (0.0001–0.1; IP) produced
only dose-dependent decreases in rates of responding. Caffeine-drinking rats were less sensitive to the rate-depressant effects
of SKF-82958 (P<0.05) than water-drinking rats. However, similar changes (P>0.05) were produced by NPA in both groups. Except for amphetamine, the remaining drugs produced similar (P>0.05) dose-dependent decreases in QL values in water- and caffeine-drinking rats. Amphetamine produced smaller decreases
in QL values in caffeine-drinking rats than in water-drinking rats (P<0.05). Chronic exposure to caffeine produced complete insurmountable tolerance to the response-rate increasing (stimulant)
effects of acute caffeine (3.0–17 mg/kg; IP) in caffeine-drinking rats. In conclusion, our study revealed that chronic caffeine
exposure potentiates the behavioral response to amphetamine and cocaine but not to that of nicotine in rats responding under
a FI schedule of food reinforcement. Thus, it is likely that these effects are mediated through different pharmacological
mechanisms.
Received: 3 September 1997 / Final version: 9 May 1998 相似文献
15.
The acute psychomotor response and development of sensitization to amphetamine is attenuated if IP injections are given in
the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore,
when the environmental cues predicting IP injections are completely eliminated by using remotely activated IV injections in
the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce
sensitization if IV injections are signaled by placement of the rat in a novel test cage. The present experiment was designed
to determine if there is a similar effect of environmental condition on the response to IV cocaine, and to what extent the
effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior)
of repeated IV administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in
the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute
psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization.
A higher dose of cocaine was required to induce sensitization when IV administrations were given in the home cage than when
they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization
regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift
the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs
to induce sensitization can be modulated by the circumstances surrounding drug administration.
Received: 19 August 1997 / Final version: 13 November 1997 相似文献
16.
The ability of the interoceptive cues produced following exposure to restraint stress to generalize to the discriminative
stimulus effects of cocaine was investigated. Rats were trained to discriminate cocaine (10 mg/kg, IP, n=10; or 20 mg/kg, IP, n=6) from saline using a two-choice, food-reinforced, drug discrimination design. Substitution for the 10 mg/kg training dose
of cocaine was observed subsequent to exposure to 15 min of restraint when administered immediately following an injection
of saline. Restraint-induced generalization in the 20 mg/kg training group was substantial, but not statistically significant.
These data suggest that a component of the subjective effects of cocaine may be associated with ”anxiety”.
Received: 19 July 1997 / Final version: 1 October 1997 相似文献
17.
S. J. Gatley Nora D. Volkow Andrew N. Gifford Joanna S. Fowler Stephen L. Dewey Yu-Shin Ding Jean Logan 《Psychopharmacology》1999,146(1):93-100
Objectives: Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of
cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than
50% occupancy for perception of the ”high”. The present experiments were conducted to examine dose–occupancy and dose–effect
relationships in mice for cocaine and also for methylphenidate, a dopamine uptake blocker used in pediatric psychiatry. Methods: Percentage occupancies of the dopamine transporter by cocaine and methylphenidate were estimated after intravenous injection
in mice from the displacement of in vivo binding of [3H]cocaine from the striatum. Locomotor activity was measured in a photocell apparatus. Results: The relationship between drug doses (milligrams of hydrochloride salt per kilogram body weight) and percentage occupancy
of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy
at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dose and transporter occupancy,
previously measured in human and baboons using [11C]cocaine or [11C]d-threo-methylphenidate and PET. Methylphenidate increased locomotor activity in the mice substantially more than cocaine at
the same dose and the same degree of dopamine-transporter receptor occupancy. Conclusions: The range of dopamine-transporter occupancy required for behavioral activation in the mice was thus similar to that previously
reported for experience of a cocaine- or methylphenidate-induced ”high” in human subjects. Our results are consistent with
other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were found to have
very similar psychopharmacological properties.
Received: 17 February 1999 / Final version: 17 April 1999 相似文献
18.
The behavioral response to separate and combined administration of dopamine D1 and D2 receptor agonists was assessed acutely and after chronic cocaine exposure (30 mg/kg SC b.i.d. for 5 days) in infant (PND11) and weanling (PND20) rats. In infants, quinpirole (quin) and SKF-38393 (SKF) elevated locomotion, mouthing and sniffing acutely. Rearing was
increased and mouthing decreased by combined administration. In weanlings, quin increased locomotion, mouthing and sniffing
in weanlings, while SKF increased only mouthing. SKF inhibited quin-induced rearing and locomotion. Infants treated chronically
with cocaine showed sensitized quin- and quin/SKF-induced locomotion and quin/SKF stimulated rearing and sniffing. In weanlings,
locomotion was sensitized with all drug combinations, and rearing with SKF alone. These results indicate a developmental progression
in the psychopharmacological response to dopamine receptor stimulation. While both D1 and D2 receptors are active in infants, the full complement of acute responses and complete capacity for sensitization develop later.
Received: 13 January 1996 / Final version: 4 September 1996 相似文献
19.
A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product,
cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse
of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine’s reinforcing potency,
ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or
alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine’s, was evaluated in the presence
and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given
10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant
effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration
of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased
by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this
paradigm, cocaethylene did not selectively modify cocaine’s reinforcing potency, but there appear to be individual differences
with respect to ethanol’s ability to stimulate rates of drug-maintained responding.
Received: 24 April 1996 / Final version: 7 November 1996 相似文献
20.
We assessed differences in food reinforced behavior between obese and lean Zucker rats with a progressive ratio schedule
3 (PR3) in which a subject emitted three additional lever-presses each time a reinforcer was delivered. The number of responses
required for a reinforcer eventually exceeded its value, termed the ”break point”, a sensitive measure of food motivated behavior.
Break points were higher in obese rats than lean controls for grain pellets (27.5 versus 9.5, P=0.01) but not for sweet pellets (51.6 versus 38.5, P=0.31). We determined if naloxone (0.01–3.0 mg/kg, SC), which reduces free food intake in obese Zucker rats, affects food
motivated behavior in obese Zuckers and lean controls. Naloxone reduced break points in both obese and lean rats to a similar
extent when working for either grain pellets or sweet pellets. Under free-access feeding conditions, naloxone again decreased
pellet intake similarly in the obese and lean Zucker rats. Naloxone appeared to decrease free-access pellet consumption to
a greater extent than break point in both groups. These results show that (1) obese rats exhibit higher levels of performance
for food than lean rats only when working for the less valued grain pellet, (2) naloxone reduces both break points and free-access
pellet consumption independent of genotype, and (3) naloxone appears to decrease food more effectively in rats given free
access to food than in rats working for food.
Received: 4 April 1998 / Final version: 19 August 1998 相似文献