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1.
Logan J Carruthers NI Letavic MA Sands S Jiang X Shea C Muench L Xu Y Carter P King P Fowler JS 《Psychopharmacology》2012,223(4):447-455
Rationale
The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone) as a high-affinity histamine H3 receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors.Objective
This study measured brain histamine H3 receptor blockade by JNJ-39220675 (1?mg/kg) in the female baboon.Methods
Positron emission tomography imaging and [11C]GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H3 receptor, was used to measure histamine H3 receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1?mg/kg) in the anesthetized baboon. Histamine H3 receptor availability was estimated as the total distribution volume (V T) in brain regions. The sensitivity of [11C]GSK189254 binding to injected mass and carryover effects was determined.Results
JNJ-39220675 produces robust (ca. 90?%) blockade of [11C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1?mg/kg), the fractional receptor occupancy was >0.9 at 90?min with a slight increase from 90 to 240?min. Similar to prior studies in humans, V T was highly sensitive to the mass of GSK189254 with ED50 estimated to be 0.16?μg/kg.Conclusions
The robust blockade of binding of [11C]GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood–brain barrier and occupies the histamine H3 receptor after oral administration at low plasma concentrations (~1?ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [11C]GSK189254 to injected mass at doses >0.1?μg/kg. 相似文献2.
Mark E. Schmidt Peter de Boer Randolph Andrews Martine Neyens Stefaan Rossenu Demiana William Falteos Erik Mannaert 《Psychopharmacology》2012,224(4):549-557
Rationale
JNJ-37822681 is a highly selective, fast dissociating dopamine D2-receptor antagonist being developed for the treatment of schizophrenia. A single dose [11C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment.Objectives
The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D2-receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681.Methods
An open-label single- and multiple-dose study with 10?mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [11C]raclopride PET scans (up to 60?h after the last dose) from 11 subjects were used to estimate D2-receptor occupancy. A direct effect O max model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D2-receptor occupancy.Results
Steady state was reached after 4?C5?days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0?ng/mL resulted in D2 occupancies of 0?% to 62?%. The concentration leading to 50?% occupancy was 18.5?ng/mL (coefficient of variation 3.9?%) after single dose and 26.0?ng/mL (8.2?%) at steady state. JNJ-37822681 was well tolerated.Conclusions
Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30?mg JNJ-37822681 twice daily could be suitable for these studies. 相似文献3.
Rationale
The orexin (Orx)/hypocretin system has been implicated in reward-seeking, especially for highly salient food and drug rewards. We recently demonstrated that signaling at the OxR1 receptor is involved in sucrose reinforcement and reinstatement of sucrose-seeking elicited by sucrose-paired cues in food-restricted rats. Because sucrose reinforcement has both a hedonic and caloric component, it remains unknown what aspect of this reward drives its reinforcing value.Objectives
The present study examined the involvement of the Orx system in operant responding for saccharin, a noncaloric, hedonic (sweet) reward, and in cue-induced reinstatement of extinguished saccharin-seeking in ad libitum-fed vs food-restricted male subjects.Methods
Male Sprague Dawley rats were fed ad libitum or food-restricted and trained to self-administer saccharin. We determined the effects of pretreatment with the OxR1 receptor antagonist SB-334867 (SB; 10–30 mg/kg) on fixed ratio (FR) saccharin self-administration and on cue-induced reinstatement of extinguished saccharin-seeking.Results
SB decreased responding and number of reinforcers earned during FR responding for saccharin and decreased cue-induced reinstatement of extinguished saccharin-seeking. All of these effects were obtained similarly in food-restricted and ad libitum-fed rats.Conclusions
These results indicate that signaling at the OxR1 receptor is involved in saccharin reinforcement and reinstatement of saccharin-seeking elicited by saccharin-paired cues regardless of food restriction. These findings lead us to conclude that the Orx system contributes to the motivational effects of hedonic food rewards, independently of caloric value and homeostatic needs. 相似文献4.
Rationale
Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking.Objectives
Here, we asked whether orexin and glutamate interact within ventral tegmental area (VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm.Methods/results
We first found that bilateral VTA microinjections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself.Conclusions
These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA. 相似文献5.
Vivian Taciany Bonassoli Ewandro Braz Contardi Humberto Milani Rúbia Maria Weffort de Oliveira 《Psychopharmacology》2013,228(3):487-498
Rationale
Nitric oxide (NO)-mediated transmission in the dorsolateral periaqueductal gray matter (dlPAG) has been involved in the expression of anxiety-like behaviors. Ethanol withdrawal sensitizes the dlPAG and results in increased anxiety-like responses.Objectives
The objective of the study was to test the hypothesis that NO in the dlPAG is involved in the expression of ethanol withdrawal-induced anxiety.Methods
Male Wistar rats were implanted with guide cannulae aimed at the dlPAG. The animals were forced to consume a liquid diet containing ethanol 6–8 % (v/v) for 15 days as their only source of diet. Six days after surgery and 24 h after ethanol discontinuation, the animals received microinjections of the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective nitric oxide synthase inhibitor N G-nitro-L-arginine methyl ester (L-NAME), selective neuronal nitric oxide synthase inhibitor 1-(2-[trifluoromethyl]phenyl) imidazole (TRIM), or selective inducible nitric oxide synthase (iNOS) inhibitor N-([3-(aminomethyl)phenyl]methyl) ethanimidamide dihydrochloride (1400W) into the dlPAG. Ten minutes later, the animals were tested in the light/dark box.Results
Carboxy-PTIO (1 nmol), L-NAME (200 nmol), TRIM (20 nmol), and 1400W (0.3 and 1 nmol) decreased the anxiogenic-like effects of ethanol withdrawal in rats in the light/dark box test. The NO precursor L-arginine reversed the effects of L-NAME.Conclusions
NO production in the dlPAG may play a role in the modulation of ethanol withdrawal-induced anxiety-like behavior in rats. Furthermore, iNOS-mediated NO synthesis in the dlPAG is predominantly involved in the behavioral expression of anxiety-like behavior during ethanol withdrawal. 相似文献6.
Galici R Rezvani AH Aluisio L Lord B Levin ED Fraser I Boggs J Welty N Shoblock JR Motley ST Letavic MA Carruthers NI Dugovic C Lovenberg TW Bonaventure P 《Psychopharmacology》2011,214(4):829-841
Rationale
A few recent studies suggest that brain histamine levels and signaling via H3 receptors play an important role in modulation of alcohol stimulation and reward in rodents.Objective
The present study characterized the effects of a novel, selective, and brain penetrant H3 receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats.Methods
The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats.Results
Subcutaneous administration of the selective H3 receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens.Conclusions
These results indicate that blockade of H3 receptor should be considered as a new attractive mechanism for the treatment of alcoholism. 相似文献7.
Rationale
Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.Objectives
The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.Methods
Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.Results
Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.Conclusions
These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse. 相似文献8.
Masahiro Shibasaki Kenjiro Watanabe Kotaro Takeda Toshimasa Itoh Tomohisa Tsuyuki Minoru Narita Tomohisa Mori Tsutomu Suzuki 《Psychopharmacology》2013,228(2):207-215
Rationale
Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-opioid receptor system is involved in the reinforcing/rewarding effects of ethanol.Objectives
The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-opioid receptor and the development of morphine-induced rewarding effects.Methods
Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w/v ethanol. The direct involvement of μ-opioid receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [35S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm.Results
The function of μ-opioid receptor was increased by treatment with ethanol in the lower midbrain using [35S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic receptor kinase 1 inhibitor.Conclusions
The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-opioid receptor, mediated by GRK2. 相似文献9.
James R. Shoblock Natalie Welty Diane Nepomuceno Brian Lord Leah Aluisio Ian Fraser S. Timothy Motley Steve W. Sutton Kirsten Morton Ruggero Galici John R. Atack Lisa Dvorak Devin M. Swanson Nicholas I. Carruthers Curt Dvorak Timothy W. Lovenberg Pascal Bonaventure 《Psychopharmacology》2010,208(2):265-277
Rationale
The lack of potent, selective, brain penetrant Y2 receptor antagonists has hampered in vivo functional studies of this receptor.Objective
Here, we report the in vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a novel Y2 receptor antagonist.Methods
The affinity of JNJ-31020028 was determined by inhibition of the PYY binding to human Y2 receptors in KAN-Ts cells and rat Y2 receptors in rat hippocampus. The functional activity was determined by inhibition of PYY-stimulated calcium responses in KAN-Ts cells expressing a chimeric G protein Gqi5 and in the rat vas deferens (a prototypical Y2 bioassay). Ex vivo receptor occupancy was revealed by receptor autoradiography. JNJ-31020028 was tested in vivo with microdialysis, in anxiety models, and on corticosterone release.Results
JNJ-31020028 bound with high affinity (pIC50?=?8.07?±?0.05, human, and pIC50?=?8.22?±?0.06, rat) and was >100-fold selective versus human Y1, Y4, and Y5 receptors. JNJ-31020028 was demonstrated to be an antagonist (pKB?=?8.04?±?0.13) in functional assays. JNJ-31020028 occupied Y2 receptor binding sites (~90% at 10 mg/kg) after subcutaneous administration in rats. JNJ-31020028 increased norepinephrine release in the hypothalamus, consistent with the colocalization of norepinephrine and neuropeptide Y. In a variety of anxiety models, JNJ-31020028 was found to be ineffective, although it did block stress-induced elevations in plasma corticosterone, without altering basal levels, and normalized food intake in stressed animals without affecting basal food intake.Conclusion
These results suggest that Y2 receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions. 相似文献10.
Rationale
The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca2+)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca2+-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol.Objectives
In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA.Methods
Swiss mice were pretreated with W7 (0–10 mg/kg) 30 min before ethanol (0–3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0–15 mg/kg), cocaine (0–4 mg/kg), and saccharine (0.1 %, w/v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration.Results
Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration.Conclusions
These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca2+-dependent pathways on the central effects of ethanol. 相似文献11.
Kiri L. Wills Kiran Vemuri Alana Kalmar Alan Lee Cheryl L. Limebeer Alexandros Makriyannis Linda A. Parker 《Psychopharmacology》2014,231(22):4291-4300
Rationale
Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone-precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm.Objective
CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB1 antagonist/inverse agonist, AM251, and the neutral CB1 antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated.Materials and methods
Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (sc)) 24 h after receiving a high dose of morphine (20 mg/kg, sc) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (ip)), PF-3845 (10 mg/kg, ip), AM251 (1 or 2.5 mg/kg, ip), AM4113 (1 or 2.5 mg/kg, ip), and AM6527 (5 mg/kg, oral) were administered prior to conditioning.Results
AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA.Conclusions
Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal. 相似文献12.
Rationale
Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference.Objectives
In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference.Methods
Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session.Results
Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine-primed reinstatement.Conclusions
Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general. 相似文献13.
BACKGROUND AND PURPOSE
The enduring propensity for alcoholics to relapse even following years of abstinence presents a major hurdle for treatment. Here we report a model of relapse following protracted abstinence and investigate the pattern of neuronal activation following cue-induced reinstatement and administration of the orexin1 receptor antagonist SB-334867 in inbred alcohol-preferring rats.EXPERIMENTAL APPROACH
Rats were trained to self-administer alcohol under operant conditions and divided into two groups: immediate (reinstated immediately following extinction) and delayed (extinguished and then housed for 5 months before reinstatement). Prior to reinstatement, animals were treated with vehicle (immediate n= 11, delayed n= 11) or SB-334867 (20 mg·kg−1 i.p.; immediate n= 6, delayed n= 11). Fos expression was compared between each group and to animals that underwent extinction only.KEY RESULTS
SB-334867 significantly attenuated cue-induced reinstatement in both groups. Immediate reinstatement increased Fos expression in the nucleus accumbens (NAc), infra-limbic (IL), pre-limbic (PrL), orbitofrontal (OFC) and piriform cortices, the lateral and dorsomedial hypothalamus, central amygdala and basolateral amygdala (BLA), and the bed nucleus of the stria terminalis. Following delayed reinstatement, Fos expression was further elevated in cortical structures. Concurrent with preventing reinstatement, SB-334867 decreased Fos in NAc core, PrL and OFC following immediate reinstatement. Following protracted abstinence, SB-334867 treatment decreased reinstatement-induced Fos in the PrL, OFC and piriform cortices.CONCLUSIONS AND IMPLICATIONS
Cue-induced alcohol seeking can be triggered following protracted abstinence in rats. The effects of SB-334867 on both behaviour and Fos expression suggest that the orexin system is implicated in cue-induced reinstatement, although some loci may shift following protracted abstinence. 相似文献14.
Rationale
The action of serotonin (5-HT) at the 5-HT2A receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT2A receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior.Objectives
This study examined the hypothesis that M100907, a 5-HT2A receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior.Methods
Rats trained to self-administer cocaine (0.75?mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10?mg/kg, i.p.) within 1?min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5???g/0.2???l/side) into the vmPFC.Results
Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5???g) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement.Conclusions
The results suggest that the blockade of 5-HT2A receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues. 相似文献15.
Casey E. O’Neill Benjamin D. Hobson Sophia C. Levis Ryan K. Bachtell 《Psychopharmacology》2014,231(16):3179-3188
Rationale
Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors.Objectives
These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking.Methods
Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A2A agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A2A receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D2 receptor agonist, quinpirole.Results
All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking.Conclusions
These findings demonstrate that adenosine A1 or A2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A1 receptor stimulation or presynaptic adenosine A2A receptor blockade during extinction produces lasting changes in relapse susceptibility. 相似文献16.
Rationale
We have shown previously, using an animal model of voluntary ethanol intake and ethanol-conditioned place preference (EtOH-CPP), that exposure to chronic psychosocial stress induces increased ethanol intake and EtOH-CPP acquisition in mice.Objective
Here, we examined the impact of chronic subordinate colony (CSC) exposure on EtOH-CPP extinction, as well as ethanol-induced reinstatement of CPP.Methods
Mice were conditioned with saline or 1.5 g/kg ethanol and were tested in the EtOH-CPP model. In the first experiment, the mice were subjected to 19 days of chronic stress, and EtOH-CPP extinction was assessed during seven daily trials without ethanol injection. In the second experiment and after the EtOH-CPP test, the mice were subjected to 7 days of extinction trials before the 19 days of chronic stress. Drug-induced EtOH-CPP reinstatement was induced by a priming injection of 0.5 g/kg ethanol.Results
Compared to the single-housed colony mice, CSC mice exhibited increased anxiety-like behavior in the elevated plus maze (EPM) and the open field tests. Interestingly, the CSC mice showed delayed EtOH-CPP extinction. More importantly, CSC mice showed increased alcohol-induced reinstatement of the EtOH-CPP behavior.Conclusion
Taken together, this study indicates that chronic psychosocial stress can have long-term effects on EtOH-CPP extinction as well as drug-induced reinstatement behavior and may provide a suitable model to study the latent effects of chronic psychosocial stress on extinction and relapse to drug abuse. 相似文献17.
Rationale
Addiction is a disease of learning and memory, as learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play central roles in addiction. Early developmental stress enhances risk for drug problems in adulthood. Environmental factors influencing learning and memory processes relevant to addiction remain incompletely characterized.Objectives
To determine effects of prenatal immune activation and developmental stress on conditioned place preference to amphetamine, and reversal learning.Methods
Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or vehicle on gestational day 14. Half of the male offspring received 2?h of restraint stress at post-natal day 35. Behavioral testing was performed in adulthood.Results
Restraint stress inhibited acquisition of place preference to low-dose amphetamine (0.5?mg/kg), while poly I:C treatment had no measurable effect on place preference acquisition. In contrast, drug-induced reinstatement of preference for drug-paired chamber was enhanced in offspring of poly I:C-treated dams [F(1,25)?=?5.31, p?=?0.03]. Performance on a Morris water maze reversal learning task was impaired in poly I:C offspring. Reversal learning performance was correlated with place preference reinstatement in non-stressed (r 2?=?0.42, p?=?0.0095), but not stressed rats (r 2 =0.04, p?=?0.49).Conclusions
Prenatal immune activation enhances drug-induced reinstatement of conditioned place preference. These data demonstrate longstanding impact on behaviors with potential influence on risk for drug relapse as a consequence of prenatal immune activation. Further study is needed to determine clinical and epidemiological consequences of similar exposures in human populations. 相似文献18.
Lucas R. Watterson Peter R. Kufahl Natali E. Nemirovsky Kaveish Sewalia Lauren E. Hood M. Foster Olive 《Psychopharmacology》2013,225(1):151-159
Rationale
Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction.Objectives
Metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) have shown promise in significantly attenuating drug self-administration and drug-seeking in reinstatement paradigms. However, studies assessing the potential efficacy of mGluR5 NAMs that have been tested in human subjects are lacking. The current study sought to assess the effect of the mGluR5 NAM fenobam on METH-seeking behavior.Methods
Rats were trained to self-administer METH (0.05 mg/kg i.v.), and following extinction, tested for effects of fenobam (5, 10, or 15 mg/kg intraperitoneal) on cue- and drug-induced reinstatement of METH-seeking. To determine if fenobam also alters reinstatement of seeking of natural reinforcers, separate groups of rats were trained to self-administer sucrose or food pellets and were tested for the effects of fenobam on cue-induced reinstatement of sucrose- and food-seeking.Results
Fenobam attenuated drug- and cue-induced reinstatement of METH-seeking behavior at doses of 10 and 15 mg/kg. Fenobam also attenuated cue-induced reinstatement of sucrose- and food-seeking at all doses tested.Conclusions
The mGluR5 NAM fenobam attenuates the reinstatement of METH-seeking behavior, but these effects may be due to nonspecific suppression of general appetitive behaviors. 相似文献19.
Rationale
Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect.Objectives
We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues.Methods
Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 μg/side), into the nucleus accumbens core or shell.Results
Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell.Conclusion
These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context. 相似文献20.