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1.
This study was designed to compare the reinforcing efficacy of PCP (phencyclidine:phenylcyclohexyl-piperidine) and the PCP-derivatives BTCP (N-[1-(2-benzo(b)thiophenyl) cyclohexyl]piperidine) and TCP (N-[1-(2-thienyl)cyclohexyl]-piperidine) to that of cocaine, using a progressive ratio schedule of reinforcement (PR). On the PR schedule the number of responses required to obtain an i.v. infusion of drug was escalated with each injection until a breaking point was reached when the animal stopped responding. Since BTCP has an affinity for the DA uptake site comparable to that of cocaine, it was hypothesized that BTCP and cocaine would show similar patterns of self-administration and comparable breaking points. In contrast, the high affinity of TCP and PCP for the NMDA-ion channel complex suggested that these two compounds would also support comparable self-administration behaviors. Rats were trained to self-administer i.v. cocaine during daily 5h sessions under a fixed-ratio-1 (FR1) schedule. Once consistent lever-pressing behavior was established, BTCP, PCP or TCP was substituted for cocaine. Under the FRI schedule, BTCP elicited a regular pattern of lever pressing, unlike PCP and TCP. However, under the PR schedule BTCP elicited breaking points comparable to those produced by equivalent doses of cocaine, whereas TCP and PCP produced considerably lower breaking points. These results suggest that BTCP has comparable rewarding properties to that of cocaine, and that like those of cocaine they are most probably mediated through a site of action at the DA transporter. In contrast, the relatively weak reinforcing efficacy of PCP and TCP would correlate better with their primary site of action on the PCP binding site within the NMDA-ion channel complex. 相似文献
2.
Because the dopamine reuptake inhibitors cocaine and BTCP produce different behavioral effects after repeated administration,
we studied whether they could alter each other’s effects by examining the effects of crossing over repeated treatment with
cocaine and BTCP on cocaine-induced locomotion. Male C57BL/6 mice were treated repeatedly with cocaine or BTCP during a first
phase (days 1–3) and 3 days later, treated repeatedly with the same or the other compound during a second phase (days 7–9),
after which they were administered one of several doses of cocaine on the next day. Locomotor activity was assessed after
every daily treatment. The results show that 1) cocaine induced sensitization to its locomotor effects, 2) cocaine-induced
sensitization was not altered by subsequent repeated treatment with BTCP, 3) initial repeated treatment with BTCP induced
apparent cross-tolerance to cocaine, and 4) the initial effects of repeated BTCP were not markedly altered by subsequent repeated
treatment with cocaine. The results indicate that the initial effects produced by repeated cocaine or BTCP are enduring and
relatively difficult to alter by crossing over repeated treatment with the other compound. Thus, sensitization to the locomotor
effects of cocaine in mice appeared to be attenuated by prior repeated treatment with BTCP but not reversed when followed
by repeated treatment with BTCP.
Received: 11 January 1998/Final version: 17 September 1998 相似文献
3.
Although they likely involve activation of N-methyl-D-aspartate (NMDA) receptors, the mechanisms giving rise to perinatal hypoxic-ischemic-induced damages remained unclear. The purpose of the present study was to investigate in vivo the mechanisms regulating the glutamate-induced release of toxic hydroxyl radicals (.OH) in neonatal rat. Anesthetized 7-day-old Wistar rat pups bearing a microdialysis cannula implanted in the striatum were perfused with a solution containing salicylate as an.OH trap. Hydroxyl radicals formation was evaluated, after a 3 hr postoperative delay, by measuring the 2,3-DHBA levels by HPLC/EC before, during and over 3 hr after the administration of glutamatergic agonists or antagonists. Administration of NMDA and of ibotenate dramatically increased the efflux of.OH, 17-fold and sixfold, respectively. Glutamate, used at the same concentration did not produce any significant increase in the.OH release and may even decrease this efflux when given at larger concentrations. The NMDA-induced.OH response was partially but progressively reduced by glutamate coinjection and completely blunted by DHPG [(RS)-3, 5-dihydroxyphenylglycine], a group I metabotropic glutamate receptor agonist. Conversely, AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid], an antagonist of the same receptors, unmasked an.OH response to glutamate. These results are evidence that the glutamate-induced activation of a group I metabotropic glutamate receptor normally protected the neonatal brain from any glutamate activation of NMDA receptor, which otherwise would produce the release of toxic hydroxyl radicals. Targeting group I metabotropic glutamate receptors and/or.OH might contribute to protecting the neonatal brain against perinatal hypoxic-ischemic induced lesions. 相似文献
4.
Gacyclidine, a channel blocker of N-methyl-D-aspartate receptors (NMDAR), exhibits potent neuroprotective properties and a low self-neurotoxicity. Preventing its interaction with NMDARs we demonstrate, through the use of its enantiomers, that gacyclidine also interacts with other ('non-NMDA') binding sites. The autoradiographic study showed that these sites displayed a uniform specific binding in the forebrain and a more discrete distribution in the molecular layer of the cerebellum. The 'non-NMDA' binding sites could exert a modulatory control on glutamatergic neurotransmission. 相似文献
5.
Cambonie G Hirbec H Michaud M Kamenka JM Barbanel G 《Journal of neuroscience research》2004,75(1):125-132
Prenatal infection constitutes an important risk factor for brain injury, in both premature and full-term infants. Unfortunately, as the mechanisms involved are far from understood, no therapeutic strategy emerges to prevent the damage. We tested the hypothesis that administration of lipopolysaccharide (LPS) to gravid female rats enhanced glutamate-induced oxidative stress in brain of pups. A microdialysis probe was implanted into the striatum of 14-day-old animals and the release of hydroxyl radicals (.OH) in the perfusion medium was evaluated. Glutamate promoted a delayed.OH release in the offspring of dams given LPS, contrasting with the.OH decreases observed in control animals. A similar response occurred after infusion of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a Group I metabotropic glutamate receptor (mGluR) agonist. This response was not consecutive to a remote activation of N-methyl-D-aspartate (NMDA) receptors, as it was unaffected by an NMDA receptor antagonist. Furthermore, the response to NMDA itself decreased in the offspring of dams given LPS. Massive amounts of DHPG, however, likely internalizing the mGlu receptor, still blunted the response to NMDA, as in controls. No quantitative variation occurred in mGluR1, mGluR5, or the NR1 subunit of the NMDA receptor between controls and neonates born from LPS-treated dams. Direct LPS injection into age-matched pups, by contrast, affected the response to neither glutamate nor DHPG. These results confirm that normally during perinatal development, the brain is protected from any oxidative stress resulting from excess glutamate, and the results support the hypothesis that maternal infection before delivery may lead to critical brain damage via the release of toxic free radicals. 相似文献
6.
Disruption of glutamate homeostasis frequently leads to oxidative stress and to the release of hydroxyl radicals (radical OH). Here, we investigated, via a microdialysis approach, the possible involvement of metabotropic glutamate receptors in the glutamate-induced release of hydroxyl radicals in adult rat striatum. Glutamate was applied at low amount, resulting in a moderate release that was not inhibited by dizocilpine (MK-801), a specific NMDA receptor antagonist. (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), a broad spectrum metabotropic antagonist, that does not exert any effect on the basal release of radical OH suppressed their response to glutamate. (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), a non-selective metabotropic glutamate receptors agonist, promoted an radical OH release almost similar to that observed after glutamate, which was similarly impaired by co-infusion with MCPG. By contrast, infusion of (RS)-3,5-dihydroxyphenylglycine (DHPG), a more specific group I metabotropic glutamate receptors agonist, did not result in any appreciable radical OH response. Thus, beside NMDA receptors, some metabotropic glutamate receptors may also be involved in the glutamate-induced release of hydroxyl radicals. 相似文献
7.
8.
Primary cultures of embryonic cortical cells were used to test the neuroprotective effect of two novel non-competitive N-methyl-D-aspartate antagonists against the neurotoxicity of glutamate. These two compounds, GK 11 and GK 222, are phencyclidine derivatives that contain asymetric carbon atoms. We have tested the neuroprotective effects of the racemates as well as those of the corresponding plus and minus enantiomers and have compared them with the reference drug dizocilpine (MK-801). We show here that the (-) enantiomers have a significantly better protective effect than the (+) enantiomers, but that the former are as efficient as the corresponding racemates. Qualitative analysis with different neuronal and glial markers does not reveal any difference in the population of protected cells among the different molecules tested. 相似文献
9.
Hlne Hirbec Jean-Ren Teilhac Jean-Marc Kamenka Alain Privat Jacques Vignon 《Brain research》2000,859(2)
Gacyclidine (cis(pip/me)-1-[1-(2-thienyl)-2-methylcyclohexyl]piperidine) is a TCP derivative, which exhibits potent neuroprotective properties against glutamate-induced neurotoxicity in vitro and in vivo. In order to better understand gacyclidine pharmacological properties, the binding parameters of its enantiomers ((−) and (+)[3H]GK11) were determined in the rat central nervous system (CNS). An autoradiographic study has shown that their binding distributions are correlated with those of N-methyl-
-aspartate (NMDA) receptors throughout the CNS. Globally, the labeling was the highest with (−)[3H]GK11. In the cerebellum, both radioligands similarly labeled the molecular layer. For both radioligands, on telencephalic, cerebellum and spinal cord homogenates, the association and dissociation kinetics were accounted for by multiphasic process. In all regions, (−)[3H]GK11 exhibited the highest affinity in the nanomolar range. The pharmacological study revealed that both enantiomers labeled both high and low affinity sites in all regions. The pharmacological profile of high affinity sites was correlated with those of NMDA receptors. Those of low affinity sites were different in telencephalic and cerebellar homogenates. Overall, this study showed that low affinity sites might constitute a heterogeneous population, which could include σ receptors in the cerebellum. The autoradiographic study has shown that these sites may be located in the molecular layer. The contribution of low affinity sites to the neuroprotective properties of gacyclidine remains to be investigated. 相似文献
10.
J M Kamenka B Chiche R Goudal P Geneste J Vignon J P Vincent M Lazdunski 《Journal of medicinal chemistry》1982,25(4):431-435
The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomeric pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1-piperidinyl)cyclohexanol. Inhibition of specific binding of tritiated PCP, morphine, or quinuclidinyl benzylate (QNB) in rat brain homogenates was measured for these compounds. Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity. The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting [3H]PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor. An important exception to these general observations was the metaphenolic derivative of PCP. This PCP derivative has an affinity for the [3H]PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself. 相似文献