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1.
Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. 总被引:1,自引:0,他引:1
The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (kappa)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor-BNI is a selective kappa-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the mu-opioid receptor, and nalmefene is primarily selective for the mu- and kappa-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the mu-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that kappa-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/kappa-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats. 相似文献
2.
Previous research in our laboratory has shown that responding for ethanol increases after a period of imposed deprivation during which no ethanol is available (the alcohol deprivation effect). This selective increase in responding for ethanol was blocked by chronic administration of acamprosate. In the present study the effects of naltrexone and the combination of naltrexone+acamprosate on oral ethanol self-administration were examined following an imposed period of abstinence. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice condition. After training, separate groups of rats received chronic injections (2 x /day) of saline, naltrexone, or naltrexone+acamprosate during a 5-day period of abstinence. Ethanol self-administration was tested in all groups of rats on the last day of abstinence, 30 min after the last drug injection. Responding for ethanol increased significantly following the deprivation period in animals treated with saline. Chronic administration of naltrexone and the combination naltrexone+acamprosate blocked the increased ethanol consumption following the imposed abstinence period on post-deprivation Day 1. On post-deprivation Day 2, the combination of acamprosate with naltrexone blocked the rebound increase in ethanol consumption observed in animals treated with a low dose of naltrexone. These results support the hypothesis that naltrexone and acamprosate are effective in modulating aspects of alcohol-seeking behavior, and under certain situations may be more effective in combination. 相似文献
3.
Thomas J Hopkins Laura E Rupprecht Matthew R Hayes Julie A Blendy Heath D Schmidt 《Neuropsychopharmacology》2012,37(10):2310-2321
Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Galantamine is an acetylcholinesterase inhibitor that also acts as a positive allosteric modulator of nicotinic acetylcholine receptors. Galantamine has recently been shown to reverse nicotine withdrawal-induced cognitive impairments in mice, which suggests that galantamine may function to prevent relapse in human smokers. However, there are no studies examining whether galantamine administration modulates nicotine self-administration and/or reinstatement of nicotine seeking in rodents. The present experiments were designed to determine the effects of galantamine administration on nicotine taking and reinstatement of nicotine-seeking behavior, an animal model of relapse. Moreover, the effects of galantamine on sucrose-maintained responding and sucrose seeking were also examined to determine whether galantamine''s effects generalized to other reinforced behaviors. An inverted U-shaped dose-response curve was obtained when animals self-administered different unit doses of nicotine with the highest responding for 0.03 mg/kg per infusion of nicotine. Acute galantamine administration (5.0 mg/kg, i.p.) attenuated nicotine self-administration when animals were maintained on either a fixed-ratio 5 (FR5) or progressive ratio (PR) schedule of reinforcement. Galantamine administration also attenuated the reinstatement of nicotine-seeking behavior. No significant effects of galantamine on sucrose self-administration or sucrose reinstatement were noted. Acetylcholinesterase inhibitors have also been shown to produce nausea and vomiting in humans. However, at doses required to attenuate nicotine self-administration, no effects of galantamine on nausea/malaise as measured by pica were noted. These results indicate that increased extracellular acetylcholine levels and/or nicotinic acetylcholine receptor stimulation is sufficient to attenuate nicotine taking and seeking in rats and that these effects are reinforcer selective and not due to adverse malaise symptoms such as nausea. 相似文献
4.
Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable to those that target μ- and δ-opioid receptor mechanisms alone. 相似文献
5.
Burattini C Burbassi S Aicardi G Cervo L 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2008,11(1):103-109
The non-selective opioid receptor antagonist naltrexone reduces cocaine-induced reinstatement of drug-seeking behaviour in abstinent rats. The current study sought to determine whether the opioid system is also involved in cocaine-seeking behaviour induced by cocaine-associated stimuli in abstinent rats. Adult male rats were trained to press a lever either to self-administer cocaine or to obtain sucrose pellets in the presence of distinctive discriminative and conditioned stimuli. After a period of extinction, re-exposure to cocaine-associated cues selectively elicited robust and enduring responding at the active lever; sucrose pellet-associated cues revived seeking behaviour less pronouncedly. Pretreatment with naltrexone (0.25, 1, 2.5 mg/kg s.c., 20 min before reinstatement tests) dose dependently prevented cue-induced cocaine-seeking behaviour, whereas (2.5 mg/kg s.c.) did not affect the degree of cue-induced sucrose-seeking behaviour. These results provide the first evidence that naltrexone influences cocaine seeking induced by conditioned stimuli in abstinent rats; this effect appears selective for cocaine reinstatement as opposed to a non-drug reinforcer. 相似文献
6.
Sabino V Cottone P Koob GF Steardo L Lee MJ Rice KC Zorrilla EP 《Psychopharmacology》2006,189(2):175-186
Rationale The role of positive vs negative ethanol reinforcement in ethanol intake of Sardinian alcohol-preferring (sP) rats is unclear.Objectives To test the hypothesis that spontaneous ethanol self-administration of sP rats was sensitive to the opioid receptor antagonist naltrexone, whereas withdrawal-induced, but not spontaneous, ethanol self-administration would be sensitive to corticotropin-releasing factor1 (CRF1) antagonists, implicating differential roles for positive and negative reinforcement, respectively.Methods Male sP rats operantly (FR1, 30 min/day) self-administered ethanol (10% v/v) until responding stabilized. One group (n=11) was made ethanol dependent through intermittent ethanol vapor exposure. Both nondependent (n = 10) and dependent rats received the CRF1 antagonist LWH-63 (5, 10, and 20 mg/kg, s.c.). Separate nondependent sP rats (n = 10) received the opioid antagonist naltrexone (16, 50, 150, and 450 μg/kg, s.c.). Finally, CRF1 antagonists (MJL-1-109-2, LWH-63, and R121919) were studied for their actions on home-cage ethanol drinking in nondependent sP rats (n = 6–8/group) under continuous, limited-access, or stressed conditions.Results Naltrexone potently reduced ethanol self-administration in nondependent sP rats. LWH-63 reduced heightened ethanol self-administration of vapor-sensitive, dependent sP rats. CRF1 antagonists did not reduce ethanol intake in nondependent sP rats. R121919 (10 mg/kg, s.c.) retained antistress activity in sP rats, blunting novelty stress-induced suppression of ethanol intake.Conclusions Spontaneous ethanol self-administration of sP rats was opioid dependent with CRF1 receptors implicated in withdrawal-induced drinking. Opioid and CRF1 receptors play different roles in ethanol reinforcement and perhaps the ethanol addiction cycle. Such distinctions may apply to subtypes of alcoholic patients who differ in their motivation to drink and ultimately treatment response.V.S. and P.C. contributed equally to this work.Supported by NIAAA Alcohol Research Center Grant P60 AA0006420-21 (G.F.K., E.P.Z.), NIDDK 64871 (E.P.Z.), by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute on Drug Abuse (M.J.L. and K.C.R.), by the Pearson Center for Alcoholism and Addiction Research (G.F.K., E.P.Z.), by a merit fellowship award from the University of Palermo (V.S.), and by a merit fellowship award from the University of Rome La Sapienza (P.C.). 相似文献
7.
Current pharmacotherapies for alcohol dependence in humans (e.g., naltrexone, acamprosate) are meeting with only limited therapeutic success. The development of novel pharmacotherapies is urgently needed but is reliant upon the screening of large numbers of candidate "anticraving" drugs using appropriate animal models. The development of animal models is complex because (1) laboratory animals are often reluctant to consume large quantities of alcohol, (2) inducing a state of alcohol dependence, analogous to the human condition, may require many months of alcohol exposure, (3) concluding that a given drug selectively reduces alcohol craving requires very carefully controlled experiments, and (4) false positives and false negatives may result from the sometimes distinct physiology and psychology of the alcohol-addicted human and rat. To address some of these problems, our laboratory has recently developed the "beer model" of alcohol dependence and craving. Rats, like humans, have a prodigious appetite for beer and will drink much more beer than equivalent ethanol solutions in water. Beer consumption in rats leads to clear signs of intoxication, anxiety reduction, and signs of withdrawal when beer access is suddenly denied. We have found that beer craving in rats is selectively reduced by the cannabinoid receptor antagonist SR 141716 and the opioid receptor antagonist naltrexone. Combining these two drugs appears to have a synergistic anticraving effect. Other promising pharmacotherapies for the future are discussed. 相似文献
8.
María José Sánchez-Catalán Lucía Hipólito Teodoro Zornoza Ana Polache Luis Granero 《Psychopharmacology》2009,204(4):641-653
Rationale A recently published study has shown that microinjections of ethanol, or its metabolite, acetaldehyde into the substantia
nigra pars reticulata, are able to produce behavioral activation in rats. Another brain site that could participate in such effects is the ventral
tegmental area (VTA).
Objectives We have investigated the locomotor-activating effects of local microinjections of ethanol and acetaldehyde into the posterior
VTA of rats and the role of opioid receptors in such effects.
Materials Cannulae were placed into the posterior VTA to perform microinjections of ethanol (75 or 150 nmol) or acetaldehyde (25 or
250 nmol) in animals not previously microinjected or microinjected with either the nonselective opioid antagonist naltrexone
(13.2 nmol) or the irreversible antagonist of the μ-opioid receptors β-funaltrexamine (β-FNA; 2.5 nmol). After injections,
spontaneous activity was monitored for 60 min.
Results Injections of ethanol or acetaldehyde into the VTA increased the locomotor activity of rats with maximal effects at doses
of 150 nmol for ethanol and 250 nmol for acetaldehyde. These locomotor-activating effects were reduced by previously administering
naltrexone (13.2 nmol) or β-FNA (2.5 nmol) into the VTA.
Conclusions The posterior VTA is another brain region involved in the locomotor activation after the intracerebroventricular administration
of ethanol or acetaldehyde. Our data indicate that opioid receptors, particularly the μ-opioid receptors, could be the target
of the actions of these compounds in the VTA. These results are consistent with the hypothesis that acetaldehyde could be
a mediator of some ethanol effects. 相似文献
9.
R. Spanagel Inge Sillaber Walter Zieglgänsberger William A. Corrigall Jane Stewart Yavin Shaham 《Psychopharmacology》1998,139(4):391-401
Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative
link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects
of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization
to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous
(IV) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily
with either morphine (10 mg/kg, SC) or saline for 14 days. Three days later in a test for the expression of sensitization,
an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously
exposed to morphine. Acamprosate (two injections of 200 mg/kg; 12 h apart; IP) suppressed the expression of the sensitized
responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate
(two injections of 50–200 mg/ kg; IP) had no consistent effects on IV heroin self-administration (50–100 μg/kg per infusion)
and, in experiment 3, that acamprosate (100–200 mg/ kg, IP) did not alter reinstatement of drug seeking induced by priming
injections of heroin (0.25 mg/kg, SC) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus,
although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have
any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free
state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models
for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior
in heroin users.
Received: 4 November 1997/Final version: 25 January 1998 相似文献
10.
Rationale Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed
“drinking in the dark” (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine
receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in
binge-like ethanol consumption is unknown.
Objectives To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice.
Materials and methods Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-β-erythroidine,
and methyllycaconitine. Immediately following injection, mice were presented with 20% ethanol for 2 h in the DID assay to
measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine
and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry.
Results Mecamylamine dose dependently reduced ethanol consumption; whereas, the peripheral antagonist hexamethonium had no significant
effect. Nicotinic agonists, cytisine and nicotine, reduced ethanol consumption. None of the effective nicotinic receptor drugs
reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them
without additional activation by ethanol.
Conclusions Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine
on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption
by blocking activation of dopaminergic neurons; whereas, nicotinic agonists may activate the same reward pathway as alcohol. 相似文献
11.
Perkins KA Lerman C Coddington SB Jetton C Karelitz JL Scott JA Wilson AS 《Psychopharmacology》2008,200(4):529-544
Rationale Impulsivity is related to greater risk of nicotine dependence, perhaps by enhancing sensitivity to nicotine’s reinforcing
and rewarding effects during initial smoking experiences.
Objective We examined the influence of impulsivity characteristics on acute sensitivity to nicotine reward, reinforcement, and other
effects in 131 young adult nonsmokers.
Materials and methods Participants engaged in four sessions: the first three to assess dose–response effects of nasal spray nicotine (0, 5, 10 μg/kg)
on reward, as well as mood, physiological, and performance effects, and the fourth to assess nicotine reinforcement using
a choice procedure. Five impulsivity factors, derived from factor analysis of self-report (e.g., Barratt Impulsivity Scale,
Sensation-Seeking Scale, Novelty seeking) and computer (stop–go, delay discounting, probability discounting) measures of impulsivity,
were labeled “novelty seeking”, “response disinhibition”, “extraversion”, “inhibition”, and “probability/delay discounting”.
Results The associations of novelty seeking with nicotine reinforcement and reward tended to move in opposite directions by sex, generally
being directly related in men but inversely or unrelated in women. Similarly, response disinhibition was associated with reward
and some mood responses to nicotine that differed by sex. Extraversion was inversely associated with nicotine reinforcement.
Characteristics loading on to the other impulsivity factors had little association with nicotine sensitivity.
Conclusions These results are preliminary, but they suggest that characteristics broadly related to impulsivity, especially novelty seeking
and response disinhibition, are associated with initial sensitivity to some effects of acute nicotine, including reinforcement
and reward, and may do so differentially between men and women. 相似文献
12.
Rationale Evidence suggests a role for the opioid system in the control of ethanol reinforcement and drinking. Previous findings have
shown that naltrexone, an opioid antagonist that decreases ethanol consumption in humans and experimental animals, reduces
the acquisition of acute ethanol tolerance in rats. However, there are few data regarding the role of the opioid system in
the acquisition of ethanol tolerance, particularly in brain areas involved in the rewarding actions of ethanol.
Objectives This study investigates the effects of systemic and of intra-accumbens injections of naltrexone on the development of rapid
tolerance to ethanol.
Methods Wistar rats received intraperitoneal injections of naltrexone (0.1–3.0 mg/kg) or microinjections into the core or shell portions
of the nucleus accumbens (5–20 μg) before ethanol (2.7 g/kg i.p.). The animals were tested for motor coordination on the tilting
plane apparatus. Tolerance was assessed 24 h later by administering the same dose of ethanol to all animals and retesting
them on the tilting plane.
Results The second injection of ethanol resulted in less motor incoordination on Day 2, suggesting the development of rapid tolerance.
Pretreatment with naltrexone, either i.p. (0.3 and 0.6 mg/kg) or intra-accumbens (5–20 μg), on Day 1, blocked the development
of rapid tolerance to the motor-incoordinating effects of ethanol on Day 2 without affecting the motor performance of the
animals on Day 1.
Conclusions The results suggest that the opioid system may be involved in the development of ethanol tolerance, and that the nucleus accumbens
may play a role in this phenomenon. 相似文献
13.
Finn DA Mark GP Fretwell AM Gililland-Kaufman KR Strong MN Ford MM 《Psychopharmacology》2008,201(3):423-433
Rationale Recent work in our laboratory documented that the “sipper” method of operant ethanol self-administration produced high ethanol
intake and blood ethanol concentrations as well as the typical extinction “burst” in responding under nonreinforced conditions
in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined
in mice with this model.
Objectives Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of
ethanol self-administration, the present study determined the effect of ALLO on the reinstatement of extinguished ethanol-seeking
behavior and compared this effect to the reinstatement of responding for sucrose reward.
Materials and methods Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution.
A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or
5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions
where responding had no scheduled consequence. Once responding stabilized below the preextinction baseline, mice received
an intraperitoneal injection of ALLO (0, 3.2, 5.6, 10, or 17 mg/kg) 15 min prior to the extinction session in a within-subjects
design.
Results ALLO produced a dose-dependent increase in responding under nonreinforced conditions in both the 10E and 5S groups. Additional
work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate nonreinforced
responding on the previously active lever.
Conclusions These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol-
and sucrose-seeking behavior in C57BL/6 mice. 相似文献
14.
Analgesic effects of pellet implantation of the opiate antagonists naloxone and naltrexone and of chronic administration of
naloxone by subcutaneous injection were examined. Rats were implanted with a slow-release pellet containing 10 mg naloxone
or 10 mg naltrexone and tested for paw-lick latency on a hotplate apparatus. Controls were implanted with placebo pellets
or given saline injections as appropriate. There were five test trials at intervals up to 72 h after implantation of naloxone
and up to 120 h after the implantation of naltrexone. In a separate experiment, 5 mg/kg naloxone was injected; there were
single trials on 5 consecutive days. All drug-treated animals displayed clear and substantial analgesia by their second test
trial. This “paradoxical” analgesia was gradually reversed in the pellet-implant groups as tissue levels of the antagonists
declined, but increased progressively with each trial involving injections. It was hypothesized that blockade of endogenous
opiates by antagonists resulted in a form of “super-pain” on the hotplate, which in turn activated a normally redundant “backup”
analgesic system. The results with naloxone injections show that unlike opiate-mediated analgesia, this hypothetical system
is resistant to tolerance. 相似文献
15.
Nestby P Schoffelmeer AN Homberg JR Wardeh G De Vries TJ Mulder AH Vanderschuren LJ 《Psychopharmacology》1999,142(3):309-317
It has been postulated that opioid systems in the brain may play a role in ethanol reinforcement. In this respect, μ- and
δ-opioid receptors may mediate the rewarding effects whereas κ receptors are thought to mediate the aversive effects of opioids.
Accordingly, long-acting benzomorphans such as bremazocine, that simultaneously act as μ and δ receptor antagonists and κ receptor agonists may be particularly effective in reducing ethanol self-administration. Therefore, we studied the effect
of bremazocine on oral ethanol self-administration in rats using a paradigm [unrestricted free-choice drinking of 10% (v/v)
ethanol], previously shown to cause long-term neuroadaptations in the nucleus accumbens and caudate putamen. Bremazocine (0.1 mg/kg,
once daily for five consecutive days) reduced ethanol drinking by about 50% during the active period of the animals, whereas
the intake of sucrose (3–10% w/v) was affected neither in naive nor in ethanol-experienced rats. This effect of bremazocine
appeared not to be secondary to its acute sedative effect or the slight increase in total fluid consumption. Unlike bremazocine,
the selective κ-opioid receptor agonist U50,488H (10 mg/kg, once daily) inhibited ethanol drinking only during the first of 5 treatment days
and the opioid receptor antagonist naltrexone (0.3–10 mg/kg, once daily) only caused a modest (about 20%) suppression of ethanol
drinking during the first hours after drug injection. Thus, bremazocine appears to be far more potent than the clinically
applied drug naltrexone in this respect. Our data further support the role of opioid receptors in ethanol reinforcement and
indicate that long-acting mixed-action opioids such as bremazocine may be useful as adjuvants for the clinical management
of ethanol addiction.
Received: 1 July 1998/Final version: 3 September 1998 相似文献
16.
Daniel M. Hartung Dennis McCarty Rongwei Fu Katharina Wiest Mady Chalk David R. Gastfriend 《Journal of substance abuse treatment》2014
Through improved adherence, once-monthly injectable extended-release naltrexone (XR-NTX) may provide an advantage over other oral agents approved for alcohol and opioid dependence treatment. The objective of this study was to evaluate cost and utilization outcomes between XR-NTX and other pharmacotherapies for treatment of alcohol and opioid dependence. Published studies were identified through comprehensive search of two electronic databases. Studies were included if they compared XR-NTX to other approved medicines and reported economic and healthcare utilization outcomes in patients with opioid or alcohol dependence. We identified five observational studies comparing 1,565 patients using XR-NTX to other therapies over 6 months. Alcohol dependent XR-NTX patients had longer medication refill persistence versus acamprosate and oral naltrexone. Healthcare utilization and costs was generally lower or as low for XR-NTX-treated patients relative to other alcohol dependence agents. Opioid dependent XR-NTX patients had lower inpatient substance abuse-related utilization versus other agents and $8170 lower total cost versus methadone. 相似文献
17.
Rationale: Clinical studies have shown that the opioid antagonist naltrexone is effective in the treatment of alcoholism. However,
the mechanism by which it produces this effect is not understood. Objective: This study was designed to investigate the effect of acute naltrexone on consumption of ethanol in healthy, non-problem
social drinkers. Methods: Subjects (n=24) participated in an eight-session, within-subject, placebo-controlled choice procedure which measured ethanol preference
and consumption. The procedure consisted of two blocks of four sessions in which subjects received either naltrexone (50 mg
oral) or placebo 1 h before consuming an ethanol or placebo beverage. On the first two sessions of each block, subjects received
a color-coded beverage containing ethanol (0.75 g/kg) or placebo, in five equal portions at 15-min intervals. On the next
two sessions of each block, subjects chose which beverage they preferred (i.e., placebo or ethanol) and how much they wished
to take, in unit doses (placebo or ethanol 0.15 g/kg/dose). The primary behavioral measures were (1) the number of times subjects
chose ethanol over placebo, and (2) the number of doses they consumed. Subjects rated their mood states and subjective drug
effects at regular intervals during each session. Results: Naltrexone did not alter the frequency of ethanol (versus placebo) choice. Although naltrexone did decrease the total number
of ethanol doses subjects took (mean 2.7 doses after naltrexone; 3.4 doses after placebo), it also decreased the number of
placebo ”doses” subjects took on sessions when they chose the placebo beverage (mean 1.6 placebo doses after naltrexone; 2.8
doses after placebo). Ethanol produced its prototypic subjective effects (e.g., increased ratings of ”feel drug”, ”like drug”
and ”high”), and these effects were not altered by naltrexone. Naltrexone produced mild sedative-like effects, and several
subjects reported adverse effects such as nausea. Conclusions: These findings show that naltrexone reduces ethanol consumption in healthy volunteers, as it does in alcoholics. However,
this reduction was not specific to alcohol; subjects also consumed less of a non-alcoholic, placebo beverage. These findings
suggest that naltrexone may reduce alcohol consumption by a non-specific mechanism.
Received: 17 September 1998 / Final version: 14 April 1999 相似文献
18.
Mickaël Naassila Elisabeth Legrand Françoise d’Alche-Birée M. Daoust 《Psychopharmacology》1998,140(4):421-428
The effect of cyamemazine a dopamine D2 receptor antagonist on voluntary ethanol consumption in rats and on ethanol withdrawal in mice was examined. Male Sprague-Dawley
rats were tested in a free choice (water and 10% ethanol) experiment and consumed 5 g/kg ethanol daily. Rats were treated
daily IP with cyamemazine ( 0.5, 1, or 2 mg/kg) or acamprosate (100 mg/kg) during 2 weeks. Both acamprosate and 1 mg/kg cyamemazine
significantly decreased ethanol intake by 45% without affecting either fluid or food intake. The lowest dose of cyamemazine
had no effect on alcohol intake but increased food intake. The highest dose had no effect on any variables. During the post-treatment
period, only 1 mg/kg cyamemazine decreased both ethanol and fluid intakes. Mice were made dependent on alcohol using a chocolate
fluid diet containing increasing concentrations of alcohol and withdrawn after 9 days. Mice were treated with cyamemazine
(1 or 0.5 mg/kg, respectively) or with the same doses of lorazepam acutely on the day of withdrawal or chronically (during
alcohol treatment). Both chronic and acute cyamemazine and lorazepam treatments decreased convulsions during ethanol withdrawal.
Both acute treatments decreased locomotor activity in control and alcohol dependent mice. Chronic treatment had no effect
on locomotor activity. We suggest that cyamemazine could reduce alcohol consumption by antagonizing the activation of the
dopaminergic pathways during the induction of alcohol dependence. The action of cyamemazine on 5-HT3 receptors could also explain its effect on alcohol convulsions during withdrawal convulsions.
Received: 19 October 1997/Final version: 6 April 1998 相似文献
19.
Rationale Abstinence from drug occurs in human addicts for several reasons, including the avoidance of adverse consequences.
Objectives To explore a model of drug use in the face of adverse consequences in rats through intermittent punishment of drug seeking
and to investigate whether the ability to withhold seeking responses depends upon the duration of drug history.
Materials and methods Rats were trained under a seeking–taking chained schedule with sucrose or cocaine as reinforcer. Pressing the seeking lever
gave access to the taking lever, and a single press on this lever delivered the reinforcer after which the seeking–taking
chain recycled. During punishment, half of the seeking links terminated with a mild foot shock without access to the taking
link.
Results After a moderate history of reinforcement, punishment of the terminal response in the seeking link suppressed both sucrose-
and cocaine-seeking responses. By contrast, rats with an extended cocaine history were more resistant to punishment than those
with a moderate cocaine history. This enhanced resistance to punishment was due to a sub-group of rats that showed minimal
or no suppression of drug seeking. No differences in suppression of sucrose seeking were observed in animals with moderate
versus extended sucrose histories.
Conclusions These results suggest that an extended drug self-administration history decreases the ability of vulnerable rats to suppress
their drug seeking.
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20.
Vulnerability to the effects of drugs of abuse during adolescence may be related to altered incentive motivation, a process believed to be important in addiction. Incentive motivation can be seen when a neutral stimulus acquires motivational properties through repeated association with a primary reinforcer. We compared adolescent (postnatal day (PND) 24–50) and adult (>PND 70) rats on a measure of incentive motivation: responding for a conditioned reinforcer (CR). Rats learned to associate the delivery of 0.1 ml of 10% sucrose with a conditioned stimulus (CS; light and tone); 30 pairings per day were given over 14 days. Then, we measured responding on a lever delivering the CS (now a CR) after injections of amphetamine (0, 0.25 or 0.5 mg/kg). We also examined responding for CR when the CS and sucrose were paired or unpaired during conditioning, and responding for the primary reinforcer (10% sucrose) in control experiments. Finally, we examined the effects of D1 and D2 dopamine receptor antagonists (SCH 39166 and eticlopride, respectively) and an opioid receptor antagonist (naltrexone) on responding for a CR in adolescent rats. Adolescents but not adults acquired responding for a CR, but adolescents responded less than adults for the primary reinforcer. Responding for a CR depended upon the pairing of the CS and sucrose during conditioning. Both dopamine and opioid receptor antagonists reduced responding for the CR. Therefore, incentive motivation may be enhanced in adolescents compared with adults, and incentive motivation may be mediated in part by both dopamine and opioid systems. 相似文献