Biomedical subjects

D Manahan-Vaughan

Publications and source records attributed to D Manahan-Vaughan.

31 records · Page 2Linked to original sources

PubMed1998

Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats.

In this study, the role of metabotropic glutamate receptors in N-methyl-D-aspartate receptor-dependent and voltage-gated calcium channel-dependent long-term potentiation in the dentate gyrus of freely moving rats was investigated. Antagonists for group 1 metabotropic glutamate receptors ((S)-4-carboxyphenylglycine), group 1/2 metabotropic glutamate receptors ((RS)-alpha-methyl-4-carboxyphenylglycine) and group 2 metabotropic glutamate receptors ((RS)-alpha-methylserine O-phosphate monophenylester) were used. The N-methyl-D-aspartate receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid, and the L-type voltage-gated calcium channel antagonist, methoxyverapamil were used to investigate the N-methyl-D-aspartate receptor and voltage-gated calcium channel contribution to the long-term potentiation recorded. Field excitatory postsynaptic potential slope and population spike amplitude were measured. Drugs were applied, prior to tetanus, via a cannula implanted into the lateral cerebral ventricle. 200 Hz tetanization produces a long-term potentiation which is inhibited by application of D(-)-2-amino-5-phosphonopentanoic acid and (RS)-alpha-methyl-4-carboxyphenylglycine. In this study, a dose-dependent inhibition of 200 Hz long-term potentiation expression was obtained with (S)-4-carboxyphenylglycine. Long-term potentiation induced by 400 Hz tetanization was not inhibited by D(-)-2-amino-5-phosphonopentanoic acid, although the amplitude of short-term potentiation was reduced. (RS)-alpha-methyl-4-carboxyphenylglycine and (S)-4-carboxyphenylglycine, both in the presence and absence of D(-)-2-amino-5-phosphonopentanoic acid, inhibited the development of 400 Hz long-term potentiation. (RS)-alpha-methylserine O-phosphate monophenylester had no significant effect on long-term potentiation induced by either 200 or 400 Hz tetanization. Application of methoxyverapamil significantly inhibited 400 Hz long-term potentiation, but had no effect on 200 Hz long-term potentiation. These data suggest that 400 Hz long-term potentiation, induced in the presence of D(-)-2-amino-5-phosphonopentanoic acid, requires activation of L-type calcium channels. Furthermore, these results strongly support a critical role for group 1 metabotropic glutamate receptors in both N-methyl-D-aspartate receptor- and voltage-gated calcium channel-dependent long-term potentiation.

2-Amino-5-phosphonovalerate↗

PubMed1997

Group 1 and 2 metabotropic glutamate receptors play differential roles in hippocampal long-term depression and long-term potentiation in freely moving rats.

This study examined the role of metabotropic glutamate receptors (mGluRs) in hippocampal long-term depression (LTD) in vivo. The group 1 mGluR antagonist (S)4-carboxyphenylglycine (4CPG), group 1/2 antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), and group 2 antagonists (RS)-alpha-methylserine-O-phos-phate monophenyl ester (MSOPPE) and (2S)-alpha-ethylglutamic acid (EGLU) were used. The NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5) was used to examine the NMDA receptor contribution to the observed LTD. Adult male Wistar rats underwent implantation of stimulating and recording electrodes into the Schaffer collaterals and CA1 stratum radiatum, respectively. After recovery of 5-7 d, the field EPSP was measured from freely moving animals. Drugs were applied either before or after 1 Hz low-frequency train (LFT) or 100 Hz stimulation via a cannula implanted in the lateral cerebral ventricle. Nine hundred pulses at 1 Hz produced an LTD that was marked and long-lasting. This LTD was completely inhibited by pre-LFT application of AP5. MCPG inhibited LTD from 2 hr post-LFT. 4CPG partially impaired LTD. MSOPPE and EGLU completely blocked induction of LTD, although short-term depression remained intact. MSOPPE did not block long-term potentiation (LTP) induced by 100 Hz stimulation, whereas 4CPG produced a significant inhibition. When MSOPPE was present, LTD could not be induced either before or after LTP induction, whereas LTD could be induced in an identical protocol in vehicle-injected animals. These results suggest a differential role for mGluRs in NMDA receptor-dependent hippocampal LTD in vivo. Group 1 mGluRs may play a role in both LTD and LTP, whereas group 2 mGluRs may be critically involved only in LTD induction.

2-Amino-5-phosphonovalerate↗

PubMed1996

Physiological and pharmacological profile of trans-azetidine-2,4-dicarboxylic acid: metabotropic glutamate receptor agonism and effects on long-term potentiation.

In this study, we biochemically analysed the effects of the novel metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid and examined its role in hippocampal long-term potentiation. In cell lines expressing metabotropic receptor 1 or 5 subtypes, the compound stimulated phosphoinositide hydrolysis with EC50 values of 189.4 +/- 6.4 and 32.2 +/- 8.3 microM, respectively. In hippocampal slices, trans-azetidine-2,4-dicarboxylic acid also increased phosphoinositide hydrolysis, yet failed to show any effect on forskolin-stimulated formation of cyclic AMP, even if 1 mM azetidine was applied. Since trans-azetidine-2,4-dicarboxylic acid (20 mM in 5 microliters) injected cerebroventricularly prolongs long-term potentiation induced by weak tetanization, a possible interaction with N-methyl-D-aspartate receptors was investigated using patch-clamp techniques. Neither facilitation of N-methyl-D-aspartate (500 microM) currents nor induction of non-specific currents was observed in the presence of 50 and 500 microM azetidine. Strong tetanus-induced long-term potentiation in the dentate gyrus of freely moving rats was not influenced by azetidine. In combination with the antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (200 mM in 5 microliters), however, the potentiation was attenuated and returned to baseline within 90 min. Blockade of N-methyl-D-aspartate receptors using 2-amino-5-phosphonopentanoate (20 mM in 5 microliters) prevented the potentiation in controls, but not in the azetidine group, where normal potentiation was observed for both the population spike amplitude and the excitatory postsynaptic potential. These data suggest that (i) trans-azetidine-2,4- dicarboxylic acid is an agonist at glutamate metabotropic receptors; (ii) a facilitation of induction and maintenance of long-term potentiation via N-methyl-D-aspartate receptors seems unlikely; and (iii) pharmacological activation of metabotropic receptors prior to tetanization appears to bypass the N-methyl-D-aspartate receptor dependence of the potentiation. In conclusion, a role for metabotropic glutamate receptors in both short-term and long-term potentiation is indicated by these data.

Animals↗

PubMed1996

Metabotropic glutamate receptor subtype agonists facilitate long-term potentiation within a distinct time window in the dentate gyrus in vivo.

Trans-azetidine-2,4-dicarboxylic acid (ADA) is a putative selective agonist of group 1 metabotropic glutamate receptors. It has been shown previously that application of ADA prior to a short-term potentiation-inducing high-frequency tetanus facilitates long-term potentiation in vivo. In order to examine the role of metabotropic glutamate receptors in this response, we studied the effect of ADA in the dentate gyrus of the rat when applied after high-frequency tetanus to the perforant path. A comparison was made with the effects of the metabotropic glutamate receptor group 1 agonist 3,5-dihydroxyphenylglycine. Drugs were applied via a cannula implanted in the lateral cerebral ventricle. Both population spike amplitude and field excitatory postsynaptic potential were measured. Weak tetanization produced a short-term potentiation of field excitatory postsynaptic potential and population spike which decayed to baseline values by 90 min, and was unaffected by vehicle injections. Application of ADA (20 mM/5 microliters) or 3,5-dihydroxyphenylglycine (4mM/5 microliters) 5 min after high-frequency tetanus facilitated short-term potentiation into a long-term potentiation which lasted over 24 h. (R,S)-alpha-Methyl-4-carboxyphenylglycine (200 mM/5 microliters), a metabotropic glutamate receptor antagonist, when applied prior to high-frequency tetanus and ADA or 3,5-dihydroxyphenylglycine, completely inhibited this effect. ADA applied 10,15,20 and 25 min after high-frequency tetanus also facilitated short-term potentiation into long-term potentiation, but the magnitude of long-term potentiation was smaller than than produced by ADA given 5 min after tetanus. Similar effects were seen with 3,5-dihydroxyphenylglycine applied 25 min after high-frequency tetanus. When (R,S)-alpha-methyl-4-carboxyphenylglycine was applied prior to high-frequency tetanus and ADA or 3,5-dihydroxyphenylglycine applied 30 min after high-frequency tetanus, or after short-term potentiation decay, elicited no facilitation of long-term potentiation. These results indicate that a distinct time window for the enhancement by ADA and 3,5-dihydroxyphenylglycine of short-term potentiation into long-term potentiation occurs in the dentate gyrus in vivo. This suggests that metabotropic glutamate receptor activation in long-term potentiation occurs within a finite period of time and may be mediated by group 1 metabotropic glutamate receptors. Furthermore, it suggests that metabotropic glutamate receptor modulation of N-methyl-D-aspartate receptors does not account for the role of metabotropic glutamate receptors in long-term potentiation.

Animals↗

PubMed1995

1S,3R-ACPD dose dependently induces a slow onset potentiation in the dentate gyrus in vivo.

It has been demonstrated by others in vitro that application of 1S,3R-aminocyclopentane-2,3-dicarboxylic acid (ACPD) facilitates long-term potentiation and triggers a slow-onset potentiation in the hippocampus. This study examined the effect of ACPD in the dentate gyrus when applied in vivo. Weak tetanisation produced a short-term potentiation of field excitatory post-synaptic potential (EPSP) and population spike. A similar response was seen upon application of ACPD (40 microM in 5 microl vehicle) via the lateral cerebral ventricle 30 min prior to tetanus, whereas ACPD (80 microM/5 microl) facilitated short-term potentiation into long-term potentiation. (R,S)-alpha-Methyl-4-carboxyphenyl-glycine (MCPG 200 mM/5 microl), completely inhibited this effect. ACPD had no effect on baseline recordings at 40 and 80 microM/5 miccrol, however 4 mM/5 microl ACPD induced a slow-onset potentiation of field EPSP and population spike which was maintained for over 4 h. MCPG or D-2-amino-5-phosphonopentanoate (AP5 20 mM/5 microl) applied prior to ACPD completely inhibited this effect. These results suggest that previously reported in vitro effects of ACPD in the CA1 region, also occur in the dentate gyrus in vivo. Furthermore, they confirm that activation of mGlu receptors by ACPD in vivo facilitates long-term potentiation, and indicate that in the dentate gyrus, ACPD-induced slow-onset potentiation is NMDA receptor-dependent.

Action Potentials↗

PubMed1995

The azapirone metabolite 1-(2-pyrimidinyl)piperazine depresses excitatory synaptic transmission in the hippocampus of the alert rat via 5-HT1A receptors.

The effects of acute and repeated treatment with 1-(2-pyrimidinyl)piperazine (1-PP), a metabolite of the 5-HT1A receptor ligand azapirones, were investigated on hippocampal excitatory synaptic transmission. Recordings of the electrically evoked field population excitatory post-synaptic potentials (e.p.s.p.s.) were carried out in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert rats. Acute i.p. administration of 1-PP transiently reduced the e.p.s.p. amplitude in a dose-dependent (0.25-1 mg/kg) manner. This effect was blocked by the 5-HT1A receptor antagonists spiroxatrine (1 mg/kg) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethyl]-8-azaspirol[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg). Intrahippocampal administration of 1-PP (5 microg) evoked a transient reduction of the e.p.s.p. amplitude which was similar to that obtained with 5-HT (10 microg). 1-PP (0.25 mg/kg per day) administered for 9 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a decrease in the acute response to the drug. The chronic baseline reduction was transiently reversed by spiroxatrine and full recovery to pretreatment levels was observed 4 days after the last 1-PP dose. These findings indicate that the previously reported reduction in the e.p.s.p. produced by the azapirone group of 5-HT1A receptor ligands may be mediated in part by their metabolite 1-PP through activation of 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1995

Regional and developmental profile of modulation of hippocampal synaptic transmission and LTP by AP4-sensitive mGluRs in vivo.

L-AP4 is an agonist at the presynaptic metabotropic receptor subtypes mGluR4, mGluR6 and mGluR7. In vitro, L-AP4 has been shown to reduce glutamate release and thereby suppress hippocampal excitatory transmission. Little data is available with regard to the actions of this compound in vivo. This study examined the effects of L-AP4 injected i.c.v. in the hippocampus of freely-moving rats on synaptic transmission and long-term potentiation (LTP). Two age groups were employed: 8-week-old and 12-week-old. Administration of L-AP4, 80 mM/5 microliters, reduced evoked baseline responses in the dentate gyrus (DG) and CA1 of 8-week-old rats when compared with controls. This effect was blocked by MCPG. L-AP4, 40 mM/5 microliters, also reduced baseline in DG but not CA1. L-AP4 (20, 40 or 80 mM/5 microliters) had no effect on baseline in either DG or CA1 of 12-week-old animals. However, injection of L-AP4 (80 mM/5 microliters) significantly reduced the amplitude of LTP induced by tetanization in CA1 and DG. This effect was blocked by MCPG (200 mM/5 microliters). LTP reduction, tested in 12-week-old animals, also occurred with an L-AP4 concentration of 40 mM/5 microliters in CA1 but not in DG. These data indicate that L-AP4 inhibits LTP in vivo with a variation in sensitivity to the drug occurring between regions. It is suggested that the response in CA1 is produced by mGluR7, and in DG by presynaptic mGluR4 present on perforant path neurons. These results offer in vivo physiological evidence for a variation in functional response and in developmental regulation of these subtypes, dependent on the region of the hippocampus where they are located.

Aminobutyrates↗

PubMed1995

1S,3R-ACPD dose-dependently induces a slow-onset potentiation in the rat hippocampal CA1 region in vivo.

It has been reported that application of 1S,3R-1-aminocyclopentane 1,3-dicarboxylic acid (ACPD) in vitro triggers a slow-onset potentiation in the hippocampal CA1 region. This study examined the effect of ACPD in the CA1 of freely moving rats. No effect on fEPSP baseline recordings occurred at 40 and 400 microM/5 microliters, however at 4 mM/5 microliters ACPD induced a slow-onset potentiation. MCPG (200 mM/5 microliters) completely inhibited this ACPD effect. These results indicate that slow-onset potentiation in the CA1 region, also occurs in vivo.

Animals↗

PubMed1995

Metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid facilitates maintenance of LTP in the dentate gyrus in vivo.

We examined the role of metabotropic glutamate receptors by studying the effect of intracerebroventricular infusion of the putative mGluR agonist trans-azetidine-2,4-dicarboxylic acid (tADA) on long-term potentiation (LTP) in the dentate gyrus of freely moving rats. Weak tetanization caused a decremental potentiation which returned to baseline levels within 2 hr. Injections of tADA (20 mM/5 microliters) 30 min prior to weak tetanization prolonged LTP of the field EPSP for at least 24 hr.

Animals↗

PubMed1994

5-HT1A receptor-mediated inhibition in the hippocampus of the alert rat--effects of repeated gepirone treatment.

The effects of acute and repeated treatment with the 5-HT1A receptor ligand gepirone on hippocampal excitatory synaptic transmission were investigated. Recordings of the electrically evoked field population excitatory postsynaptic potentials (e.p.s.p.s) were made in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert male Wistar rats. Acute injection of gepirone reduced the e.p.s.p. amplitude in a transient dose-dependent (0.5-10 mg/kg, i.p.) manner. This effect was blocked by the 5-HT1A receptor antagonist MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethys]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg, i.p.). Gepirone (1 mg/kg per day, i.p.) administered for 7 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a concomitant reduction of the acute response to the drug. The chronic baseline reduction was transiently reversed by the 5-HT1A receptor antagonist spiroxatrine and complete recovery to pretreatment levels was observed 48 h after the last gepirone dose. The data indicate that with repeated administration, a prolongation and enhancement of the 5-HT1A receptor-mediated reduction in the e.p.s.p. by gepirone occurs. This delayed effect may contribute to the slow onset of therapeutic action of gepirone.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Adaptive changes in 5-HT1A receptor-mediated hippocampal inhibition in the alert rat produced by repeated 8-OH-DPAT treatment.

1. The effect of acute and repeated treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor ligand, on excitatory amino acid-mediated synaptic transmission was examined in the stratum radiatum CA1 region of the dorsal hippocampus of alert, gently restrained, rats. 2. Acute administration of 8-OH-DPAT transiently reduced the amplitude of the field excitatory postsynaptic potential (e.p.s.p.) in a dose-dependent (25-75 micrograms kg-1, i.p.) manner. This effect was blocked by the postsynaptic 5-HT1A receptor antagonist, MDL 73005EF (2 and 4 mg kg-1, i.p.). 3. 8-OH-DPAT (25 micrograms kg-1, i.p.) administered daily for 7 days produced a gradual reduction in the 24 h pre-injection baseline field e.p.s.p. amplitude. The reduction reached its lowest level after 7-8 days and was transiently reversed by acute injection of MDL 73005EF (2 mg kg-1, i.p.) on day 8. The field e.p.s.p. baseline amplitude recovered fully 5-8 days after cessation of drug treatment. 4. 8-OH-DPAT (25 micrograms kg-1, i.p.) administered daily for 7 days produced a marked reduction in acute response to 8-OH-DPAT (25 and 50 micrograms kg-1, i.p.) which did not recover until between day 36 and day 80 of the study. 5. It was concluded that repeated treatment with 8-OH-DPAT produced adaptive changes which resulted in a reduction in the dynamic range of 5-HT1A receptor-mediated transmission in the hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMedDate not supplied

Group 1 metabotropic glutamate receptors contribute to slow-onset potentiation in the rat CA1 region in vivo.

It has been demonstrated in the CA1 region of the hippocampus in vitro, and in the dentate gyrus and CA1 region in vivo, that application of the metabotropic glutamate receptor (mGluR) agonist, 1S, 3R-amino cyclopentane 2,3-dicarboxylic acid triggers a slow-onset potentiation of synaptic transmission in the hippocampus. This study examined the involvement of group 1 and 2 mGluRs in this phenomenon in the CA1 region of freely moving rats. Drugs were applied via the lateral cerebral ventricle, and measurements were obtained from the CA1 region via permanently implanted electrodes. The group 1 mGluR agonists, 3,5-dihydroxyphenylglycine (DHPG, 20-100 nmol/5 microl) and trans-azetidine-2,4-dicarboxylic acid (ADA, 100 nmol-1 micromol/5 microl) induced a dose-dependent potentiation of basal synaptic transmission. The mGluR antagonist R,S-alpha-methyl-carboxyphenylglycine (MCPG, 1 micromol), and the group 1 mGluR antagonist, S-4-carboxyphenylglycine (4CPG, 100 nmol) completely inhibited the effects of both DHPG and ADA. The group 2 mGluR agonist, (S)-4-carboxy-3-hydroxy phenylglycine (4C3H-PG, 50-200 nmol/5 microl) induced a dose-dependent decrease of basal synaptic transmission. These results suggest that in the CA1 region in vivo, slow-onset potentiation may be mediated by group 1 mGluRs.

Animals↗

PubMedDate not supplied

A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning.

Metabotropic glutamate receptors (mGluRs) have been implicated in long-term potentiation and in learning and memory formation. In this study, we tested the effects of group I mGluR inhibition on synaptic plasticity and learning of rats at different levels of organization (1) in the hippocampal slice preparation; (2) in freely moving animals implanted with chronic hippocampal electrodes; and (3) in different spatial learning paradigms. To allow a direct comparison of the effects obtained the same doses were used in all paradigms. Bath-application of the selective group I mGluR antagonist (S)4-carboxyphenylglycine (4-CPG) impaired a decremental long-term potentiation (LTP) induced by a weak tetanization paradigm, but failed to affect a robust LTP generated by strong tetanization. In contrast, 4-CPG impaired a robust LTP in freely moving animals if applied 30 min before tetanization. The same dose of 4-CPG only impeded spatial learning mildly in the eight-arm radial maze and had no effect on a simple configuration of the Y-maze spatial alternation task. In the more difficult configuration of this task, however, 4-CPG caused complete amnesia. The lack of state-dependent 4-CPG actions and the absence of any 4-CPG effects in the open-field test classify the obtained retention deficit as a selective impairment of memory storage. Our results indicate a specific role of group I mGluRs in certain types of synaptic plasticity and of spatial learning.

Animals↗