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1.
The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative
stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; IG) from ethanol (2.0 g/kg; IG) from water (4.7 ml; IG) using food
reinforcement. Substitution tests were conducted following administration of the GABAA positive modulators allopregnanolone (5.6–30.0 mg/kg; IP), diazepam (0.3–10.0 mg/kg; IP) and pentobarbital (1.0–21.0 mg/kg;
IP), the non-competitive NMDA antagonist phencyclidine (0.3–10.0 mg/kg; IP), the 5-HT1 agonists TFMPP (0.3–5.6 mg/kg; IP) and RU 24969 (0.3–3.0 mg/kg; IP), and isopropanol (0.10–1.25 g/kg; IP). Allopregnanolone,
diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol.
Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training
drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates
that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding
that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABAA- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg
ethanol.
Received: 18 November 1997 / Final version: 10 February 1998 相似文献
2.
Rationale Interactions among compounds at GABAA receptors might have important implications for the therapeutic and other effects of positive GABAA modulators (e.g. benzodiazepines).Objectives This study examined whether a midazolam discriminative stimulus is modified by GABAA agonists that act at sites other than benzodiazepine sites.Methods Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABAA receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABAA receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam.Results When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1–3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32–1 mg/kg), gaboxadol (3.2–10 mg/kg) and progabide (10–32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive.Conclusions Direct-acting GABAA receptor agonists are qualitatively different from positive GABAA modulators in rhesus monkeys trained to discriminate midazolam. Although GABAA receptor agonists and modulators can enhance the actions of benzodiazepines at the GABAA receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl– flux at the GABAA receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine. 相似文献
3.
The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40–60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABAA agonist progabide and its metabolite 4-{[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino}] butyric acid (SL 75102) also partially substituted for PB, producing means of 39–73% PB-lever responding. The GABAB agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABAA agonists, PB and diazepam, although similar to one another, differ from those of direct GABAA receptor agonists, which produced only partial substitution for PB. The GABAB agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists. 相似文献
4.
Rationale: Some evidence suggests an involvement of nucleus accumbens in spatial learning. However, it is controversial whether the
mesoaccumbens dopaminergic pathways play a specific role in the acquisition of spatial information. Objective: The goal of these experiments was to investigate the effect of dopaminergic manipulations in the nucleus accumbens on a non-associative
task designed to estimate the ability to encode/transmit spatial and non-spatial information. Methods: The effects of focal administrations of the D1 and D2 dopamine receptor antagonists, SCH 23390 (6.25, 12.5, 50 ng/side) and
sulpiride (12.5, 50, 100 ng/side), respectively, and dopamine (DA; 1.25 and 2.5 μg/side) into the nucleus accumbens were studied
on reactivity to spatial and non-spatial changes in an open field with objects. Results: Both SCH 23390 and sulpiride impaired reactivity to spatial change. However, several differences were found in the effects
induced by the two DA antagonists. SCH 23390 did not affect locomotor activity and only slightly impaired exploration of the
novel object. On the contrary, the D2 antagonist, induced a general, dose-dependent, impairment on all variables measured.
Local administration of DA increased locomotor activity, but did not affect reactivity to spatial and non-spatial changes. Conclusions: These results demonstrate a facilitatory role of mesoaccumbens dopamine in the acquisition of spatial information. Moreover,
they suggest that nucleus accumbens D1 DA receptors, play a more selective role in the modulation of spatial learning than
accumbens D2 DA receptors.
Electronic Publication 相似文献
5.
Hodge CW Cox AA Bratt AM Camarini R Iller K Kelley SP Mehmert KK Nannini MA Olive MF 《Psychopharmacology》2001,154(1):13-22
RATIONALE: The neurobiological systems that mediate the discriminative stimulus effects of self-administered drugs are largely unknown. The present study examined the discriminative stimulus effects of self-administered ethanol. METHODS: Rats were trained to discriminate ethanol (1 g/kg, IP) from saline on a two-lever drug discrimination task with sucrose (10% w/v) reinforcement. Test sessions were conducted with ethanol (0 or 10% v/v) added to the sucrose reinforcement to determine if self-administered ethanol would interact with the discriminative stimulus effects of investigator-administered ethanol, or with the ethanol-like discriminative stimulus effects of the GABAA-positive modulator pentobarbital or the non-competitive NMDA antagonist MK-801. RESULTS: During a saline test session, ethanol (10% v/v) was added to the sucrose reinforcement. Responding by all animals began accurately on the saline-appropriate lever and then switched to the ethanol-appropriate lever after rats self-administered a mean dose of 1.2 +/- 0.14 g/kg ethanol. During cumulative self-administration trials, responding initially occurred on the saline lever and then switched to the ethanol-appropriate lever after ethanol (0.68 +/- 0.13 g/kg) was self-administered. Investigator-administered MK-801 (0.01-1.0 mg/kg, cumulative IP) and pentobarbital (0.3-10.0 mg/kg, cumulative IP) dose-dependently substituted for ethanol. When ethanol (10% v/v) was added to the sucrose reinforcer, MK-801 and pentobarbital dose-response curves were shifted significantly to the left. CONCLUSIONS: Self-administered ethanol substituted for and potentiated the stimulus effects of investigator-administered ethanol, suggesting that the discriminative stimulus effects of self-administered ethanol are similar to those produced by investigator-administered ethanol. Self-administered ethanol enhanced the ethanol-like discriminative stimulus effects of MK-801 and pentobarbital, which suggests that the discriminative stimulus effects of self-administered ethanol are mediated by NMDA and GABAA receptors. 相似文献
6.
If the pregnant and lactating female rats are exposed to environmental levels of bisphenol-A (BPA), their male offspring will display hyperactivity and attention-deficit. In patients with attention-deficit/hyperactivity disorder (ADHD), the size of the amygdala is reported to be reduced. This study examined functional alterations in the basolateral amygdala (BLA) of the postnatal 28-day-old male offspring exposed perinatally to BPA (BPA-rats). We specifically focused on the synaptic properties of GABAergic/dopaminergic systems in the BLA. A single electrical stimulation of the capsule fibers evoked multispike responses with an enhanced primary population spikes (1st-PS) in the BPA-rats. A single train of high-frequency stimulation of the fibers induced NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in BPA-rats, but not in control rats. Also, paired-pulse inhibition (PPI, GABA-dependent) in control rats was reversed to paired-pulse facilitation (PPF) in BPA-rats. Perfusion of slices obtained from BPA-rats with the GABAA receptor (GABAAR) agonist muscimol blocked the multispike responses and LTP, and recovered PPI. By contrast, the dopamine D1 receptor antagonist SCH23390 abolished LTP and attenuated the increased amplitude of 1st-PS in BPA-rats. Conversely, blockade of GABAAR by bicuculline could produce the multispike responses and PPF in BLA in control rats. Furthermore, in BLA the infusion of SCH23390, muscimol or the NMDAR blocker MK801 ameliorated the hyperactivity and improved the deficits in attention. These findings suggest that the perinatal exposure to BPA causes GABAergic disinhibition and dopaminergic enhancement, leading to an abnormal cortical-BLA synaptic transmission and plasticity, which may be responsible for the hyperactivity and attention-deficit in BPA-rats.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’. 相似文献
7.
Amanda Kiemes Felipe V. Gomes Diana Cash Daniela L. Uliana Camilla Simmons Nisha Singh Anthony C. Vernon Federico Turkheimer Cathy Davies James M. Stone Anthony A. Grace Gemma Modinos 《Neuropsychopharmacology》2022,47(3):687
Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.Subject terms: Psychosis, Schizophrenia, Experimental models of disease, Schizophrenia, Psychosis 相似文献
8.
《European neuropsychopharmacology》2009,19(4):256-265
N-methyl-d-aspartate (NMDA) receptor blockade in rodents induces behavioural and neurochemical changes reminiscent of schizophrenia symptoms and pathology. To examine how NMDA receptor blockade affects glutamatergic and GABAergic pathways when administered during early brain development, [3H]MK-801 and [3H]muscimol binding to NMDA and GABAA receptors was examined at four time-points following injections of phencyclidine (PCP) or saline on postnatal days (PN)7, 9 and 11. [3H]MK-801 binding was significantly increased in PCP-treated rats in the thalamus from PN18 to PN96, in the prefrontal and anterior cingulate cortices at PN32, and in the hippocampus at PN96. In a similar manner, [3H]muscimol binding was increased in PCP-treated rats in the thalamus and hippocampus from PN18 to PN96, and in the prefrontal and anterior cingulate cortices at PN32. Glutamatergic and GABAergic transmission is therefore chronically altered by this treatment, which has relevance to disease processes that may be involved in schizophrenia. 相似文献
9.
Rationale
The hypofunction of NMDA receptors in the prefrontal cortex (PFC) has been suggested to produce corticolimbic hyperactivity through the reduction of cortical GABA transmission.Objectives
The present study investigates the effects of injections of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) into the PFC on (1) the release of dopamine and/or acetylcholine in the amygdala and hippocampus, (2) the levels of corticosterone in the hippocampus and (3) spontaneous motor activity. Also, the stimulation of GABAA receptors, by prefrontal injections of muscimol, on the effects produced by NMDA antagonists on these same neurochemical, hormonal and behavioural parameters was evaluated.Methods
Male Wistar rats were implanted with guide cannulae to perform bilateral microinjections into the PFC and microdialysis experiments in the amygdala and/or ventral hippocampus, simultaneously. Spontaneous motor activity was monitored in the open field.Results
Injections of CPP (1???g/0.5???l) into the PFC increased dialysate concentrations of dopamine and acetylcholine in the amygdala, acetylcholine and free corticosterone in the hippocampus and also motor activity. Simultaneous injections of muscimol (0.5???g/0.5???l) into the PFC counteracted the increases of dopamine and acetylcholine in the amygdala and hippocampus and also significantly reduced the peak increase of corticosterone in the hippocampus. Injections of muscimol (0.05 and 0.5???g/0.5???l) reduced the increases of motor activity produced by prefrontal NMDA antagonists.Conclusions
These results suggest that the hypofunction of NMDA receptors in the PFC produces corticolimbic hyperactivity through the activation of prefrontal efferent projections to subcortical/limbic areas. 相似文献10.
The discriminative stimulus effects of the N-methyl-d-aspartate (NMDA) antagonists 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and phencyclidine were assessed in a drug discrimination based on the competitive NMDA antagonist 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626). Adult male Sprague-Dawley rats were trained to discriminate NPC 12626 from saline using a standard two-lever fixed ratio 32 schedule of food reinforcement. NPC 12626 dose-dependently substituted for the training dose (20 mg/kg IP) with an ED50 of 9.5 mg/kg. The competitive NMDA antagonist CPP completely substituted for NPC 12626 (ED50=1.4 mg/kg IP). The non-competitive NMDA antagonist phencyclidine, as well as pentobarbital and NMDA, failed to substitute completely for NPC 12626, even at doses of these drugs that reduced response rates. These data indicate that the discriminative stimulus properties of NPC 12626 are selective and shared by CPP but not by phencyclidine, pentobarbital or NMDA. The emerging evidence for differences in the discriminative stimulus effects of competitive NMDA antagonists and phencyclidine suggests that competitive antagonists such as NPC 12626 and CPP may not have phencyclidine-like abuse liability. 相似文献
11.
Animal models of schizophrenia symptoms include administration of noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonists, such as MK-801, and post-weaning social isolation (SI). We tested the hypothesis that a “double-hit” model, in which MK-801 administration during adulthood [post-natal day (P) 56-62] and SI are combined, produces greater behavioral and neurochemical effects than either insult alone. Rats obtained at weaning (P21) were either SI (n = 21) or group housed (n = 16) for the duration of the experiment. Subgroups received subchronic treatment with MK-801 (0.5 mg/kg i.p., 2 times daily for 7 days) or saline injections from P56-62. At P70, all groups were tested for locomotor activity and subsequently sacrificed to assess GAT-1 activity and GABAA receptor expression in the frontal cortex and hippocampus. SI resulted in increased locomotor activity, GAT-1 activity in frontal cortex and hippocampus and GABAA receptor expression in the frontal cortex; MK-801 increased GABAA receptor expression in the hippocampus. Activity changes were correlated with changes in hippocampal GAT-1 and frontocortical GABAA receptor number. There was no evidence that the double-hit produced a greater effect. Increased GAT-1 activity may be associated with suppression of GABA-mediated inhibitory synaptic transmission and increased GABAA receptor expression may be a compensatory response to decreased availability of GABA. Results suggest that SI and subchronic MK-801 may act through independent mechanisms. 相似文献
12.
Rationale
Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABAA receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABAA, N-methyl-d-aspartate (NMDA), σ1, or 5-HT3 receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.Objective
The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABAA receptors might contribute to its discriminative stimulus effects.Methods
Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.Results
Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABAA receptors, such as extrasynaptic GABAA, NMDA, σ1, and 5-HT3 receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA2 values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.Conclusion
While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABAA receptors, they indicate a primary and possibly exclusive role of synaptic GABAA receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABAA receptors. 相似文献13.
Stephanie C. Licata Donna M. Platt John R. Atack Gerard R. Dawson Michael L. Van Linn James K. Rowlett 《Neuropharmacology》2010,58(2):357-193
Previous reports suggest that γ-aminobutyric acid type A (GABAA) receptors containing α1 subunits may play a pivotal role in mediating the discriminative stimulus effects of benzodiazepines (BZs). L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine) is a GABAA receptor modulator with intrinsic efficacy in vitro at α2, α3, and α5 subunit-containing GABAA receptors, and little demonstrable intrinsic efficacy in vitro at α1 subunit-containing GABAA receptors. The present study evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the α2, α3, and α5 subunit-containing GABAA receptors contribute to the interoceptive effects of BZ-type drugs. Squirrel monkeys (Saimiri sciureus) were trained to discriminate L-838,417 (0.3 mg/kg, i.v.) from vehicle under a 5-response fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 administration resulted in dose-dependent increases in drug-lever responding that were antagonized by the BZ-site antagonist, flumazenil. Administration of non-selective BZs, compounds with 10-fold greater affinity for α1 subunit-containing GABAA receptors compared to α2, α3, and α5 subunit-containing GABAA receptors, barbiturates and ethanol (which modulate the GABAA receptor via a non-BZ site), all resulted in a majority of responses on the L-838,417-paired lever (65-100% drug-lever responding). βCCT, an antagonist that binds with 20-fold greater affinity for α1 subunit-containing GABAA receptors relative to α2, α3, and α5-containing GABAA receptors, had no significant effect on the discriminative stimulus effects of L-838,417 or the L-838,417-like effects of diazepam or zolpidem. These data suggest that efficacy at α2, α3, and/or α5 subunit-containing GABAA receptors likely are sufficient for engendering BZ-like discriminative stimulus effects. 相似文献
14.
Abstract
Rationale. The discriminative stimulus effects of zolpidem in squirrel monkeys trained at doses greater than or equal to 3.0 mg/kg differ
from those of conventional benzodiazepines (BZs), but the extent to which these effects reflect the selectivity of zolpidem
for GABAA/α1 receptors is not known.
Objectives. The present study investigated the ability of GABAA/α1-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.0 mg/kg and the ability of GABAA/α1-preferring antagonists to block zolpidem's discriminative stimulus effects.
Methods. Squirrel monkeys were trained to discriminate intravenous injections of zolpidem (3.0 or 5.6 mg/kg) from saline and tested
with BZ agonists differing in selectivity and efficacy at GABAA/α1 receptors. Antagonism of the effects of zolpidem was studied using the GABAA/α1-preferring antagonists β-carboline-3-carboxylate-t-butyl ester (β-CCT) and 3-propyloxy-β-carboline (3-PBC).
Results. Zolpidem and quazepam (GABAA/α1-preferring agonist) engendered full substitution for zolpidem, whereas CL 218,872 (GABAA/α1-preferring partial agonist) and the non-selective BZ agonists alprazolam and flunitrazepam engendered low and variable levels
of zolpidem-lever responding (35–58%). Both β-CCT and 3-PBC antagonized the discriminative stimulus effects of zolpidem in
a surmountable fashion.
Conclusions. Our findings provide evidence for a key role of GABAA/α1 receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity
and relatively high efficacy at GABAA/α1 receptors is required for BZ agonists to reproduce these discriminative stimulus effects.
Electronic Publication 相似文献
15.
Several non-competitive NMDA receptor ion channel blockers, competitive NMDA antagonists and compounds acting at other sites
on the NMDA receptor complex were examined for their ability to substitute for the discriminative stimulus effects of dizocilpine.
Swiss-Webster mice were trained with food to discriminate the non-competitive NMDA receptor antagonist, dizocilpine (0.17
mg/kg), from saline in a T-maze. Mice rapidly acquired the discrimination with minimal amounts of drugs required for training
and testing. Several non-competitive antagonists dose-dependently substituted for dizocilpine with a rank order of potency
of dizocilpine>TCP>(–)-MK-801>SKF 10,047>dextrorphan>PCP. There was a positive correlation between the potencies of the compounds
that substituted for dizocilpine and their previously reported affinities for the [3H]dizocilpine binding site of the NMDA receptor ion channel. Compounds acting at other sites on the NMDA receptor complex,
including NMDA, the partial agonist at the strychnine-insensitive glycine site, ACPC, and the polyamine antagonist, ifenprodil,
failed to substitute fully. In addition, the AMPA antagonist, NBQX, the monoamine uptake inhibitor, cocaine, and the GABAA receptor agonists, diazepam and phenobarbital, failed to substitute fully for dizocilpine. However, like the ion channel blockers,
the competitive NMDA antagonists, CGS 19755, NPC 17742, (±)CPP and LY 233536 dose-dependently substituted for dizocilpine.
The competitive antagonist, LY 274614, and its active enantiomer, LY 235959, failed to substitute for dizocilpine, each producing
severe disruptions in locomotor activity. That most of the competitive antagonists substituted for dizocilpine is in accordance
with other behavioral data (e.g., ataxia, locomotor activity) documenting similarities in the effects of non-competitive and
competitive antagonists. These findings are also consistent with results of clinical investigations suggesting overlap in
the behavioral and subjective profiles of competitive and non-competitive NMDA blockers.
Received: 29 October 1996 / Final version: 9 April 1997 相似文献
16.
The discriminative stimulus effects of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were investigated in animals trained to discriminate 1.5g/kg (pigeons) or 1.25g/kg (mice) ethanol from vehicle. Key-pecking of pigeons and lever responding of mice were maintained under fixed ratio schedules of mixed grain or milk reinforcement, respectively. Phencyclidine (PCP) and ketamine dose-dependently substituted for the ethanol stimulus in both species, with PCP being about 10-fold more potent than ketamine. In pigeons, PCP and ketamine fully substituted for ethanol at doses that did not significantly alter rates of responding; with mice, complete substitution was accompanied by response rate-decreasing effects. In pigeons, the highly selective NMDA receptor/ionophore antagonist MK-801 also substituted for ethanol at a dose that was accompanied by reduced response rates. Compounds that did not substitute for the ethanol stimulus were cocaine (both species), the 5-HT(1B) receptor agonist TFMPP (pigeon), the H(1) receptor antagonist hydroxyzine (mice), and the anticonconvulsants phenytoin and ethosuximide (mice). The present data show that PCP-like drugs that are antagonists of NMDA receptor-mediated neurotransmission share common discriminative stimulus effects with ethanol. 相似文献
17.
The discriminative stimulus properties of compounds that interact with the NMDA receptor complex were investigated in rats
trained to discriminate ethanol from saline. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm
to make differential responses [fixed ratio 10 (FR10)] for food after ethanol (1 g/kg IP; 12% v/v ethanol solution) and saline
vehicle injections. Drug effects were assessed by means of generalization and antagonism tests. In the generalization tests,
the noncompetitive NMDA antagonists acting at the ion channel dizocilpine, memantine, phencyclidine (PCP) and the sigma1 receptor agonists (+)-pentazocine and (+)-N-allyl-normetazocine (NANM) dose-dependently generalized for ethanol, whereas the α-amino-3-hydroxy- 5-methyl-4-isoxazole-propionate
(AMPA) antagonist GYKI 52466, the glycine antagonists L-701,324 and MRZ 2/502, the polyamine site antagonist arcaine and the
polyamine site ligand spermidine, did not. Our results show that the noncompetitive NMDA antagonists fully substitute dose-dependently
for ethanol in a drug-discrimination task. The ethanol-like discriminative stimulus effects of PCP, pentazocine and NANM,
which are also sigma receptor ligands, are likely to be attributed to their activity at NMDA receptors. We therefore assume
that some of the acute effects of ethanol are mediated via NMDA receptor antagonism at the PCP binding site.
Received: 28 January 1997/Final version: 10 June 1997 相似文献
18.
Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats 总被引:3,自引:0,他引:3
Disruption of prepulse inhibition (PPI) induced by NMDA receptor antagonists, such as MK801, has been used as an animal model of positive and negative symptoms of schizophrenia. Previous studies suggested that atypical, but not typical, neuroleptics can selectively restore MK801-induced PPI disruption and that such selectivity may depend on strain differences. The present study re-examined PPI disruption by systemic MK801 in Wistar (WS) and Sprague-Dawley (SD) strains, and addressed the issue whether clozapine (atypical), compared to haloperidol (typical), effectively antagonizes MK801-induced PPI disruption. In addition, we tested the effects of bilateral microinfusion of MK801 into the ventral hippocampus in WS. Systemic MK801 disrupted PPI in both strains. Neither clozapine nor haloperidol antagonized MK801-induced PPI in either strain. Our clozapine data do not agree with previous reports of clozapine's ability to antagonize MK801-induced PPI disruption. Similar to previous results with SD, MK801 infusion into the ventral hippocampus failed to affect PPI in WS. In our view, the selective ability of atypical neuroleptics to restore PPI disruption by NMDA antagonists, and to serve as a tool for identifying possible atypical neuroleptics, requires further examination. PPI disruption with systemic MK801 may be due to the blockade of NMDA receptors in multiple brain sites. 相似文献
19.
Rationale: Administration of voltage-gated calcium-channel (VGCC) modulators with ethanol can result in enhancement or attenuation
of some behavioral effects of ethanol, including its discriminative stimulus effects. Objectives: The present study used a drug- discrimination paradigm to characterize modulation of the ethanol-like discriminative stimulus
effects of a γ-amino-butyric acid (GABA)A and N-methyl-d-aspartate (NMDA) ligand by administration of VGCC ligands. Methods: Two groups of adult male Long-Evans rats were trained to discriminate either 1.0 g/kg ethanol (n=8) or 2.0 g/kg ethanol (n=9) from water under a fixed-ratio (FR) 20 schedule of food presentation. Following training, ethanol substitution tests were
conducted with cumulative doses of the GABAA-positive modulator diazepam (0.3–10 mg/kg, i.p.) (DZP) and the uncompetitive NMDA antagonist phencyclidine (0.3–5.6 mg/kg,
i.p.) (PCP). Next, a single dose of the VGCC antagonist nimodipine, nifedipine, isradipine, or the VGCC agonist (–)-BAY k
8644 (0.3 mg/kg, i.p.) was administered prior to a cumulative DZP or PCP dose–response determination. Results: None of the VGCC modulators produced robust or consistent alterations in the ethanol-like discriminative stimulus effects
of DZP in animals trained with either 1.0 g/kg or 2.0 g/kg ethanol. However, the ethanol-like discriminative stimulus effects
of PCP were significantly enhanced in the presence of the VGCC antagonists and attenuated in the presence of the agonist in
animals trained with 2.0 g/kg ethanol. Conclusions: Overall, these data show that VGCC modulation is not a robust component of ethanol-like discriminative stimulus effects
of DZP in animals trained with 1.0 g/kg or 2.0 g/kg ethanol. However, the ethanol-like effects of PCP, particularly at higher
training doses, appear to be modulated by dihydropyridine-sensitive VGCCs.
Received: 26 August 1999 / Final version: 22 October 1999 相似文献
20.
Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats 总被引:1,自引:0,他引:1