共查询到20条相似文献,搜索用时 31 毫秒
1.
Rationale
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a widely abused drug, particularly in adolescent and young adult populations. Although it was shown that MDMA-associated cues reinstate extinguished MDMA seeking in an animal relapse model, there is little information regarding the neural mechanisms underlying this behavior.Objectives
Because the medial prefrontal cortex (mPFC) plays an important role in relapse to cocaine and methamphetamine seeking, we tested the effects of lidocaine inactivation of prelimbic (PL) and infralimbic (IL) subregions of mPFC on cue-induced relapse to MDMA seeking.Methods
Rats were trained to respond for MDMA infusions (0.50?mg/kg/infusion, i.v.) paired with a discrete cue in daily 2-h sessions. Responding was reinforced contingent on a modified fixed ratio 5 schedule of reinforcement. Cue-induced reinstatement tests were conducted after responding was extinguished in the absence of MDMA and the conditioned cues. Prior to reinstatement tests, rats received bilateral microinjections of either lidocaine (100???g/0.5???l/side) or physiological saline (0.5???l/side) delivered to either PL or IL mPFC.Results
Microinjections of lidocaine into PL completely blocked reinstatement of MDMA-seeking behavior compared with saline microinjections into the same region. Lidocaine microinjections did not, however, have an effect on food-maintained responding, ruling out a nonspecific disruption of motor performance. Conversely, lidocaine inactivation of IL had no effect on reinstatement of MDMA seeking or food-maintained responding.Conclusions
Our results provide direct support for PL activation in reinstatement of MDMA-seeking behavior. Moreover, akin to cocaine seeking, there appears to be differential involvement of PL and IL subregions in this behavior. 相似文献2.
Rationale
Ro 64-6198, the prototypical non-peptide nociceptin/orphanin FQ peptide (NOP) receptor agonist, has potent anxiolytic-like effects in several preclinical models and species. However the effects of Ro 64-6198 on distinctive anxiety-provoking conditions related to unconditioned conflict behavior as well as its role in despair-like behavior remain to be addressed.Objective
Here we examined the effects of Ro 64-6198 on unconditioned conflict anxiety using stimuli with different salience and on regulation of autonomic reactivity and compared these to the effects of benzodiazepine receptor agonists. We also addressed the potential effects of Ro 64-6198 on despair-like behavior.Materials and methods
Ro 64-6198 (0.1 to 10?mg/kg?i.p.) and either diazepam or chlordiazepoxide were tested in the Vogel conflict punished drinking test (VCT) in Sprague Dawley rats, in the social approach?Cavoidance (SAA) test in Lewis rats, in the novelty-induced hypophagia (NIH) in C57BL/6J mice, and in stress-induced hyperthermia in NMRI mice, as well as in the forced swim test (FST) in Sprague Dawley rats and the tail suspension test (TST) in C57BL/6J mice.Results
Ro 64-6198 (0.3 to 3?mg/kg) dose-dependently produced anxiolytic-like effects in the VCT, SAA, NIH, and SIH, similar to benzodiazepine receptor agonists. Ro 64-6198 did not alter immobility time in the FST and TST.Conclusions
Ro 64-6198 produced marked anxiolytic-like effects in response to a variety of mild to strong anxiogenic stimuli, whereas it did not facilitate depression-related behaviors. This data extend previous literature suggesting that NOP receptors are a viable target for the treatment of anxiety disorders. 相似文献3.
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4.
Rationale
Indirect-acting serotonin (5-HT) receptor agonists (e.g., selective 5-HT reuptake inhibitors [SSRI]) stimulate multiple 5-HT receptors, although the role of particular receptors as well as interaction(s) among different receptors in the therapeutic effects of SSRIs is not fully understood.Objectives
Relatively few studies have systematically examined direct-acting agonists in combination. This study examined the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT; 0.01?C10.0?mg/kg) and 3-chloro-4-fluorophenyl-4-fluoro-4-([(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl)-piperidin-1-yl-methanone (F13714; 0.01?C1.0?mg/kg) and the 5-HT2A receptor agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.32?C10.0?mg/kg) and dipropyltryptamine (DPT; 1.0?C32.0?mg/kg), alone and in combination, in rats responding under a fixed ratio schedule of food presentation.Results
When administered alone, each drug decreased the rate of responding in a dose-related manner with the potency order being F13714?>?8-OH-DPAT?>?DOM?>?DPT. WAY100635 (5-HT1A receptor antagonist; 0.01?C0.1?mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT2A receptor antagonist; 0.01?C0.1?mg/kg) attenuated the rate-decreasing effects of DOM and DPT. Dose addition analysis showed that the interaction between 8-OH-DPAT and F13714, as well as the interaction between DOM and DPT, was additive. In contrast, the interaction between 8-OH-DPAT and DOM, as well as the interaction between F13714 and DOM, was infra-additive.Conclusions
This study shows that for some dose combinations, agonist actions at one 5-HT receptor subtype attenuate agonist actions at another 5-HT receptor subtype; thus, the combined neuropharmacological actions and therapeutic effects of indirect-acting agonists are not likely to be adequately characterized by examining in isolation activity at particular 5-HT receptor subtypes. 相似文献5.
Nancy S. Woehrle Stephanie J. Klenotich Naseem Jamnia Emily V. Ho Stephanie C. Dulawa 《Psychopharmacology》2013,227(3):545-551
Rationale
Obsessive-compulsive disorder (OCD) patients show overactivation of the orbitofrontal cortex and deficits in cognitive tasks that require proper orbitofrontal functioning including delayed alternation tests of spatial working memory. We recently showed that OCD-like behavior is induced in mice by activating orbitofrontal serotonin 1B receptors (5-HT1Bs). However, the role of 5-HT1Bs in delayed alternation remains unclear.Objectives
We examined the effects of 5-HT1B receptor activation on delayed alternation task (DAT) performance. We also assessed the ability of an effective OCD treatment, fluoxetine, to prevent 5-HT1B-induced deficits in DAT performance.Methods
Mice were tested on the DAT after acute treatment with saline, 3 or 6 mg/kg RU24969 (5-HT1B/1A agonist), 0.3 or 3 mg/kg 8-OH-DPAT (5-HT1A agonist), or co-injection with 3 mg/kg RU24969 and 5 mg/kg GR127935 (5-HT1B/1D antagonist). Separate mice were pretreated chronically (28 days) with 10 mg/kg fluoxetine and then tested on the DAT after acute treatment with 3 mg/kg RU24969, 0.3 mg/kg 8-OH-DPAT, or saline.Results
Both doses of RU24969 decreased accuracy and increased latency on the DAT, and GR127935 blocked RU24969-induced effects on accuracy. The 0.3 mg/kg 8-OH-DPAT did not affect the DAT performance, whereas 3 mg/kg increased omissions on the DAT. Finally, RU24969-induced DAT deficits were absent in fluoxetine-pretreated mice.Conclusions
We show that 5-HT1B receptor activation disrupts DAT performance in mice, and chronic fluoxetine pretreatment blocks these 5-HT1B-induced deficits. Our findings suggest that 5-HT1B receptors play an important role in modulating orbitofrontal-dependent delayed alternation. Moreover, 5-HT1B-induced DAT deficits may provide a mouse model for DAT deficits in OCD. 相似文献6.
Rationale
Two pharmacological stressors commonly used in the study of stress-induced reinstatement of drug seeking are central injections of the stress peptide, corticotropin-releasing factor (CRF), and systemic administration of the ??2-adrenoceptor antagonist, yohimbine. Despite the widespread use of these stressors, the neurochemical systems mediating their ability to reinstate cocaine-seeking behaviour have not been fully characterized.Objective
The present study was designed to characterize the role, specifically, of dopamine transmission in the reinstating effects of CRF and yohimbine on cocaine seeking.Methods
Male Long-Evans rats were trained to self-administer cocaine (0.23?mg/kg/infusion) for 8?C10?days. Subsequently, responding for drug was extinguished, and tests for CRF- (0.5???g; i.c.v.) and yohimbine-induced (1.25?mg/kg; i.p.) reinstatement were conducted following pretreatment with the dopamine D1/5 receptor antagonists, SCH23390 (0.05, 0.1?mg/kg; i.p.) and/or SCH31966 (0.2?mg/kg; i.p.), and the D2/3 receptor antagonist, raclopride (0.25, 0.5?mg/kg; i.p.).Results
Pretreatment with SCH23390, but not raclopride, blocked CRF-induced reinstatement of cocaine seeking. Pretreatment with SCH23390 and SCH31966, but not raclopride, blocked yohimbine-induced reinstatement of cocaine seeking.Conclusions
These findings demonstrate that transmission at D1/5, but not D2/3, receptors mediates the reinstatement of cocaine seeking induced by CRF and yohimbine. 相似文献7.
Rationale
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects in rodents and humans after systemic administration. Previous results from our group showed that CBD injection into the bed nucleus of the stria terminalis (BNST) attenuates conditioned aversive responses. The aim of this study was to further investigate the role of this region on the anxiolytic effects of the CBD. Moreover, considering that CBD can activate 5-HT1A receptors, we also verified a possible involvement of these receptors in those effects.Methods
Male Wistar rats received injections of CBD (15, 30, or 60?nmol) into the BNST and were exposed to the elevated plus-maze (EPM) or to the Vogel conflict test (VCT), two widely used animal models of anxiety.Results
CBD increased open arms exploration in the EPM as well as the number of punished licks in the VCT, suggesting an anxiolytic-like effect. The drug did not change the number of entries into the enclosed arms of the EPM nor interfered with water consumption or nociceptive threshold, discarding potential confounding factors in the two tests. Moreover, pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.37?nmol) blocked the effects of CBD in both models.Conclusions
These results give further support to the proposal that BNST is involved in the anxiolytic-like effects of CBD observed after systemic administration, probably by facilitating local 5-HT1A receptor-mediated neurotransmission. 相似文献8.
Valentina Gigliucci Grainne O’Dowd Sheena Casey Danielle Egan Sinead Gibney Andrew Harkin 《Psychopharmacology》2013,228(1):157-166
Rationale
Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown.Objectives
As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed.Methods
The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3?×?150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days).Results
In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion.Conclusions
These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response. 相似文献9.
Rationale
Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits.Objective
We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test.Results
MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25–1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit.Conclusion
The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs. 相似文献10.
Ratchanee Rodsiri Clare Spicer A. Richard Green Charles A. Marsden Kevin C. F. Fone 《Psychopharmacology》2011,213(2-3):365-376
Rationale
3,4-methylenedioxymethamphetamine (MDMA, ecstasy) produces an acute release of 5-HT in the brain, together with increased locomotion and hyperthermia.Objective
This study examined whether the acute functional changes of locomotor activity and body temperature are related to enhanced 5-HT release induced by MDMA.Methods
We concomitantly measured changes in extraneuronal 5-HT by in vivo brain microdialysis and used radiotelemetry to measure locomotion and body temperature to establish whether any positive correlations occur between these three parameters. ??Binge-type?? repeated administration of low doses of MDMA (3 and 6?mg/kg given at 2-h intervals three times) were given to provide drug exposure similar to that experienced by recreational drug users.Results
MDMA induced acute hyperactivity, changes in core body temperature (both hypothermia and hyperthermia) and elevation of hippocampal 5-HT overflow, all of which were dependent on the dose of MDMA administered. The change in locomotor activity and the magnitude of the hyperthermia appeared to be unrelated both to each other and to the magnitude of MDMA-induced 5-HT release. The study also found evidence of long-term disruption of novel object discrimination 2?weeks following ??binge-type?? repeated MDMA administration.Conclusions
MDMA-induced 5-HT release in the brain was not responsible for either the hyperthermia or increased locomotor activity that occurred. Since neither dose schedule of MDMA induced a neurotoxic loss of brain 5-HT 2?weeks after its administration, the impairment of recognition memory found in novel object discrimination probably results from other long-term changes yet to be established. 相似文献11.
Dupre KB Eskow KL Steiniger A Klioueva A Negron GE Lormand L Park JY Bishop C 《Psychopharmacology》2008,199(1):99-108
Rationale
Serotonin 1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson’s disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.Objective
To further delineate the relationship between 5-HT1A receptors and glutamate, the current study examined the effects of the 5-HT1AR agonist, ±8-OH-DPAT and the N-methyl-d-aspartic acid receptor (NMDAR) antagonist, MK-801, on l-DOPA-induced motor behavior.Materials and methods
Unilateral 6-hydroxydopamine lesioned male Sprague–Dawley rats were rendered dyskinetic with 1 week of daily l-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: ±8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined ±8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by l-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of ±8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.Results
Individually, both ±8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of ±8-OH-DPAT+MK-801 reduced l-DOPA-induced AIMs and potently enhanced contralateral rotations without altering l-DOPA-induced motor improvements.Conclusions
The current results indicate a functional interaction between 5-HT1AR and NMDAR that may improve pharmacological treatment of PD patients. 相似文献12.
13.
Rationale
Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse.Objective
To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking.Methods
One hundred thirty-two male Sprague?CDawley rats underwent place conditioning with oxycodone (2?mg/kg, SC; ×6?days), extinction (vehicle?×?6?days), and reconditioning with 0, 0.25, 2, or 5?mg/kg oxycodone (2?days). Yohimbine (0, 2.5, or 5?mg/kg, IP) was administered 30?min prior to reconditioning.Results
Pretreatment with 2.5?mg/kg yohimbine increased, while 5?mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n?=?30) further indicated that the effect of yohimbine was specific to reacquisition.Conclusion
The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse. 相似文献14.
Mei Huang Anna R Felix Sunoh Kwon David Lowe Tanya Wallace Luca Santarelli Herbert Y Meltzer 《Psychopharmacology》2014,231(10):2199-2210
Rationale
Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission.Objectives
In the current study, the effects of partial nAChR agonist and 5-HT3 receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats.Results
R3487/MEM3454, at doses of 0.1–10 mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose–response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0 mg/kg), completely blocked RG3487-induced (0.45 mg/kg) DA but not ACh efflux, while the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (1.0 mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45 mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1 mg/kg), but not typical APD haloperidol (0.1 mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3 mg/kg), olanzapine (1.0 mg/kg), and quetiapine (30 mg/kg), also produced additive effects on DA efflux.Conclusions
These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia. 相似文献15.
Rationale
Trilostane is a competitive inhibitor of 3??-hydroxysteroid dehydrogenase (3??-HSD), which notably converts pregnenolone into progesterone or dehydroepiandrosterone into androstenedione. Trilostane shows antidepressant-like properties in the forced swimming test (FST). The compound, however, induced only moderate effects on neuroactive steroid levels that could be related to its behavioral efficacy.Methods
We compared the behavioral effect of trilostane with the other 3??-HSD inhibitor, cyanoketone, and analyzed the putative involvement of the ??-type estrogen receptor (ER??) in its antidepressant effect.Results
Trilostane reduced immobility in the FST significantly at 12.5 and 25?mg/kg subcutaneously (s.c.), whereas cyanoketone (0?C100?mg/kg s.c.) was ineffective. The negative ER modulator fulvestrant (ICI 182780) dose-dependently blocked the effect of trilostane (25?mg/kg). Trilostane increased circulating estradiol levels in the 12.5?C50?mg/kg dose-range, and this effect was unaffected by stress and not shared by cyanoketone (25?mg/kg). The trilostane (25?mg/kg) treatment increased the ER?? mRNA expression in adrenals (+100%) and centrally, in the hippocampus (+330%). Stress and cyanoketone failed to affect ER?? mRNA levels in periphery or in the brain.Conclusions
These data demonstrate that the antidepressant-like potential of trilostane is not due to its 3??-HSD inhibiting activity, since it is not shared by cyanoketone, but rather to its estrogenic activity. The compound, which releases estradiol and up-regulates ER?? receptors, could be used as a therapeutic tool to allow an estrogenic facilitation of antidepressant efficacy. 相似文献16.
Rationale
Glutamatergic projection neurons in the medial prefrontal cortex (mPFC) are hyperexcitable in cocaine-sensitized animals, resulting in increased excitatory output to addiction-associated regions such as the ventral tegmental area (VTA) and nucleus accumbens. Evidence suggests that Group I metabotropic glutamate receptor 5 (mGluR5) is necessary for cocaine sensitization, and stimulation of this receptor in the mPFC potentially alters cell excitability directly through glutamate release or indirectly through downstream signaling cascades.Objectives and methods
Experiments in this report examined the role of mPFC mGluR5 in behavioral sensitization to cocaine. Group I mGluR agonist dihydroxyphenylglycine (DHPG) (15 nmol/side), mGluR5 antagonist 3((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) (15 nmol/side), mGluR1 antagonist YM298198 (15 nmol/side), AMPA receptor antagonist CNQX (1 nmol/side), and/or saline were administered through cannulae implanted 1 mm above the mPFC and/or VTA in male rats. Cocaine (15 mg/kg, i.p.) was systemically administered for four consecutive days to induce sensitization and/or once on test day immediately preceding locomotor monitoring.Results
Intra-mPFC DHPG induced an mGluR5-mediated cross-sensitization to cocaine preventable through the prior administration of an AMPA receptor antagonist in the VTA. Furthermore, mGluR5 blockade in the mPFC failed to prevent the initiation of sensitization. However, intra-mPFC injections of the mGluR5 antagonist MTEP prevented the expression of cocaine sensitization at 21, but not 7, days following daily cocaine injections suggesting a possible role for mPFC mGluR5 in the persistence of the cocaine-sensitized state.Conclusions
These data suggest that stimulation of mGluR5s in the mPFC is sufficient to induce cocaine sensitization and is necessary for the expression of this sensitized response. 相似文献17.
Florence R. M. Theberge Charles L. Pickens Evan Goldart Sanya Fanous Bruce T. Hope Qing-Rong Liu Yavin Shaham 《Psychopharmacology》2012,224(4):559-571
Rationale and objectives
Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence.Methods
We trained rats to self-administer heroin or saline for 9?C10?days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone??s (0?C1.0?mg/kg) effect on extinction responding after 1 and 15?days.Results
Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day?11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day?1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1?day.Conclusions
Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving. 相似文献18.
Petra J. J. Baarendse Catharine A. Winstanley Louk J. M. J. Vanderschuren 《Psychopharmacology》2013,225(3):719-731
Rationale
The inability to make profitable long-term decisions has been implicated in several psychiatric disorders. There is emerging evidence to support a role for dopamine (DA) in decision making, but our understanding of the role of noradrenaline (NA) and serotonin (5-HT) in decision making, and of possible interactions between the three monoamines, is limited. Moreover, impulsivity has been associated with aberrant decision making, but the underlying mechanisms are incompletely understood.Objective
The purpose of this study is to improve our understanding of the neuropharmacological mechanisms of decision making and impulse control.Methods
We investigated the effects of amphetamine (0.25–1.0 mg/kg) and selective reuptake inhibitors of DA (GBR12909; 2.5–10 mg/kg), NA (atomoxetine; 0.3–3.0 mg/kg), and 5-HT (citalopram; 0.3–3.0 mg/kg) in a rat gambling task (rGT). Since the rGT allows for detection of impulsive action, i.e., premature responding, we also assessed the relationship between decision making and impulsivity.Results
In the rGT, rats developed an optimal choice strategy from the first session onwards. Elevation of endogenous DA or NA levels increased and decreased impulsivity, respectively, but did not alter decision making. However, simultaneous blockade of DA and NA disrupted decision making, reflected by a relative decrease in choice for the advantageous choice options. Increasing 5-HT neurotransmission did not affect decision making or impulsivity.Conclusions
These data suggest important but complementary or redundant roles of DA and NA neurotransmission in decision-making processes based on reward probability and punishment. Moreover, impulse control and decision making in the rGT rely on dissociable mechanisms. 相似文献19.
Ohmura Y Tsutsui-Kimura I Kumamoto H Minami M Izumi T Yamaguchi T Yoshida T Yoshioka M 《Psychopharmacology》2012,219(2):421-432
Rationale
Higher impulsivity is a pathological symptom in several psychiatric disorders, including bipolar disorder, and is a risk factor for suicide.Objectives
Our goal was to determine whether major mood-stabilizing drugs used for the treatment of bipolar disorder could suppress impulsive-like action in the three-choice serial reaction time task (3-CSRTT).Methods
Following training for the 3-CSRTT, rats were acutely administered lithium chloride (LiCl; 0, 3.2, 10, and 32?mg/kg, i.p.), valproic acid (0, 10, 32, and 100?mg/kg, i.p.), or carbamazepine (0, 10, 20, and 30?mg/kg, i.p.). To assess the anorexic effects of lithium, a simple food consumption test was conducted.Results
LiCl dose-dependently decreased the number of premature responses, an index of impulsive-like action. A high dose of LiCl (32?mg/kg) decreased food consumption, but its anorexic effects were not correlated with the effects of LiCl on premature responses. A moderate dose of LiCl (20?mg/kg) significantly reduced the number of premature responses without affecting motivation-related measures in the 3-CSRTT or the amount of food consumption. Although carbamazepine prolonged reward latency, an index of motivation for food, neither valproic acid nor carbamazepine significantly affected premature responses.Conclusion
It is likely that lithium has a suppressive effect on impulsive action independent of the anorexic effect. Lithium may suppress impulsive behavior and thereby decrease the risk of suicide. The present results could provide an explanation for the antisuicidal effects of lithium and suggest that lithium could be a beneficial treatment for impulsivity-related disorders. 相似文献20.