Tyrosine dephosphorylation underlies DHPG-induced LTD.

A form of long-term depression (LTD) of synaptic transmission can be induced by bath application of the group I metabotropic glutamate (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). The mechanisms responsible for the induction and expression of DHPG-induced LTD in the CA1 region of the hippocampus are currently the subject of intense investigation. Here we show that two protein tyrosine kinase (PTK) inhibitors (10 microM lavendustin A or 30 microM genistein) have little effect on DHPG-induced LTD.

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release.

Objective And Design: It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAO(A) and MAO(B) in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites.

Results: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAO(A) and MAO(B), their respective target enzymes, with IC(50) values of 2.

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine.

Objective And Design: This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue.

Results: In vitro, phentermine was without effect on basal [3H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 microM) evoked a 131% increase in [3H]5HT release. In combination, the two drugs did not alter [3H]5HT release beyond that caused by dexfenfluramine alone.

Protein phosphatase inhibitors facilitate DHPG-induced LTD in the CA1 region of the hippocampus.

We have shown earlier that activation of metabotropic glutamate (mGlu) receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus. In an attempt to determine the signal transduction mechanisms involved in this form of synaptic plasticity, we have tested the effects of a range of inhibitors on DHPG-induced LTD. In vitro grease-gap electrophysiological recordings were performed in the rat hippocampal CA1 region.

Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats.

The acute effects of systemic administration of the anti-obesity agent sibutramine on extracellular dopamine (DA) in the nucleus accumbens of freely moving rats were studied using in vivo microdialysis and compared with the actions of phentermine and d-amphetamine at doses 1x and 3x their respective 2 h ED(50) values to reduce food intake in rats. At the lower dose, sibutramine did not elevate extracellular DA concentrations; however, at the higher dose (6.0 mg kg(-1), i.

Further evidence that behavioral tests and neuropeptide mRNA and tissue level alterations can differentiate between typical and atypical antipsychotic drugs.

This study was designed to compare some behavioral and biochemical effects of chronic treatment with a range of antipsychotic drugs. Gene expression of enkephalin, chromogranin A, chromogranin B, and secretogranin II and their respective peptide products were studied with in situ hybridization and radioimmunoassays after daily oral administration of haloperidol, clozapine, risperidone, or zotepine for 21 days. In behavioral tests, significant catalepsy was induced by haloperidol only.

A comparison of the acute effects of zotepine and other antipsychotics on rat cortical dopamine release, in vivo.

The acute effects of systemic administration of the antipsychotic drug, zotepine, on extracellular dopamine (DA) in the frontal cortex of freely-moving rats were studied using in vivo microdialysis and compared with the actions of clozapine, olanzapine and haloperidol. Treatment with zotepine (1.0 mg/kg, i.

An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus.

Previously, we have found that activation of mGlu receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-DHPG, can induce long-term depression (LTD) in the CA1 region of the hippocampus and that, once established, this synaptic depression can be reversed by application of the mGlu receptor antagonist, (S)-MCPG [Palmer et al., 1997. Neuropharmacology 36, 1517-1532].

A CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus.

We have shown previously that activation of mGlu receptors using a group I specific mGlu receptor agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus (Palmer et al., 1997). We now report that DHPG-induced LTD is facilitated by treatment with KN-62, an inhibitor of certain Ca2+/calmodulin-dependent protein kinases (CaMKs), including CaMKII.

Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats.

The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.

Preferential blockade of cholecystokinin-8S-induced increases in aspartate and glutamate levels by the CCK(B) receptor antagonist, L-365,260, in rat brain.

In the present studies, the ability of a locally delivered cholecystokinin (CCK) receptor agonist and systemically delivered antagonists to modulate extracellular levels of aspartate and glutamate in the frontal cortex of anaesthetised rats and frontal cortex and caudate-putamen of freely moving rats was investigated using an in vivo microdialysis technique. In the anaesthetised rats, local application of sulphated CCK octapeptide (CCK-8S, 10 microM) into the frontal cortex enhanced extracellular aspartate levels to a maximum of 265+/-16% of the basal levels, whereas glutamate levels were increased to a maximum of 168+/-7% of the basal levels. Given 40 min prior to the cortical perfusion of 10 microM of CCK-8S, the CCK(B) receptor antagonist, L-365,260 (20 mg/kg, s.

An assessment of the peripheral antinociceptive potential of remoxipride, clonidine and fentanyl in sheep using the forelimb tourniquet.

A modification of the intravenous regional anaesthesia technique was used to assess the peripheral antinociceptive effect of remoxipride, clonidine and fentanyl. Drugs administered intravenously via peripheral catheters were restricted to the distal limb and nociceptive threshold test site by prior inflation of a tourniquet proximal to both the catheter and a threshold-testing device. Lignocaine (1 mg/kg) induced peripheral antinociception during tourniquet inflation.

Investigation into the antinociceptive potential of remoxipride administered intrathecally in sheep.

Systemic administration of remoxipride, a dopamine (D2) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of remoxipride. Remoxipride (17.

Diastereoselective synthesis of all four isomers of 3-(4-chlorophenyl) glutamic acid: identification of the isomers responsible for the potentiation of L-homocysteic acid-evoked depolarizations in neonatal rat motoneurons.

All four isomers of 3-(4-chlorophenyl)glutamic acid (5-8) were prepared by diastereoselective synthesis. Addition of (6S)-(+)-bis-lactim ether 15 to cis-4-chlorocinnamate 12 gave a mixture comprising mainly the (2R,3S)- and (2R,3R)-isomers 5 and 6, respectively (in a ratio of 56:40), while addition of (6R)-(-)-bis-lactim ether 16 to 4-chlorocinnamate 12 gave a mixture comprising mainly the (2S,3R)- and (2S,3S)-isomers 8 and 7, respectively (in a ratio of 56:42). The four stereoisomers (5-8) were therefore conveniently prepared by addition of either 3-lithio-(6S)- or -(6R)-bis-lactim ether (15 or 16, respectively) to 4-chlorocinnamate 12 and separation of the resultant mixtures of diastereoisomers (23-26) by flash silica gel chromatography.

Prevention by (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin of both catalepsy and the rises in rat striatal dopamine metabolism caused by haloperidol.

1. The influence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on haloperidol-induced increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), was measured in three microdissected brain regions of the rat following a quantitative assessment of catalepsy. 2.

The neurotransmitter candidature of sulphur-containing excitatory amino acids in the mammalian central nervous system.

While L-glutamate (L-Glu) is considered to be the predominant excitatory amino acid transmitter in the mammalian CNS, other amino acids have come under scrutiny as possible rivals for such a role. These include four sulphur-containing analogues of L-Glu and L-aspartate known as the SAAs. The L-Glu analogues are L-homocysteic acid and L-homocysteine sulphinic acid, while the L-aspartate analogues are L-cysteic acid and L-cysteine sulphinic acid.

Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats.

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores.

Differential actions of 3-(4-chlorophenyl) glutamic acid stereoisomers and L-trans-pyrrolidine-2,4-dicarboxylic acid upon L-homocysteic acid- and L-glutamic acid-induced responses from rat spinal motoneurones.

The four recently synthesized stereoisomers of 3-(4-chlorophenyl) glutamic acid (chlorpheg) were individually examined for their abilities to potentiate depolarizations of neonatal rat motoneurones evoked by L-homocysteic acid (L-HCA, 10 microM). This property had previously been observed using the racemate and is believed to be mediated by uptake inhibition. Both the (2S,3S)- and (2S,3R)- isomers were selective potentiators of L-HCA- (vs L-Glu) induced depolarizations although the (2S,3S)- isomer was more effective.

The actions of a range of excitatory amino acids at (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-depolarizing receptors on neonatal rat motoneurones.

Depolarizations induced by a range of amino acids including some sulphur-containing excitatory transmitter candidates were evoked from motoneurones in the neonatal rat spinal cord under conditions that precluded activation of known ionotropic glutamate receptors. The responses could be partially and differentially depressed by continuous application of several metabotropic glutamate receptor (mGluR) antagonists or by receptor desensitization with the mGluR agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. In most cases [the exceptions being (1S,3R)-ACPD and to a lesser extent, quisqualate], the major component of these depolarizations was resistant to antagonism by phenylglycine-derived mGluR antagonists or desensitization of (1S,3R)-ACPD-sensitive receptors.

Hippocampal slices do not appear to accumulate low micromolar concentrations of quisqualate by an active uptake mechanism.

The ability of hippocampal slices to accumulate quisqualate by an active uptake process was investigated. All amino acid concentrations were measured by HPLC. Incubation of hippocampal slices for 4 min with 16 microM quisqualate at 25 degrees C led to measurable amounts of quisqualate within supernatant layers derived from slice homogenates.

Haloperidol-induced increases in rat amygdaloid dopamine metabolism: evidence for independence from postsynaptic feedback mechanisms.

The present study assessed the role of postsynaptic dopamine (DA) receptors in mediating the actions of focal injections of the classical antipsychotic drug, haloperidol, on DA metabolism in the rat amygdala (AMYG) and caudate-putamen (CP) using a high-performance liquid chromatographic assay. One hour after unilateral injection of haloperidol into either site, significant elevations of the DA metabolite, homovanillic acid, were observed in both ipsilateral (+33%) and contralateral (+81%) hemispheres of the CP and in the ipsilateral (+107%) and contralateral AMYG (+121%). Such increased DA metabolism persisted in these regions if focal injections of muscimol (intended to eliminate transmission in postsynaptic output neurones) had been made into either brain area immediately prior to the focal haloperidol injection.

The influence of assay conditions on measurement of excitatory dibasic sulphinic and sulphonic alpha-amino acids in nervous tissue.

Major improvements to the HPLC separation of fluorescent derivatives of excitatory sulphur-containing amino acids have been made. Quisqualate was used as the internal standard since no endogenous derivatives coeluted with it. The artefactual generation of sulphinic and sulphonic amino acids from the oxidation of cysteine (56 microM) and homocysteine (1.

Lesions of the Cerebral Cortex and Caudate-Putamen Enhance GABA Function in the Rat Superior Colliculus.

Unilateral lesions of the rat frontal cortex were made either alone or in combination with the caudate-putamen in order to examine (a) their morphological influence on the substantia nigra and (b) their neurochemical influence on GABA function in the superior colliculus. One to two months following the combined lesion, neuronal somata in the ipsilateral pars reticulata of the substantia nigra were clearly hypertrophied (+ 30%). Morphological changes in the substantia nigra were not evident contralaterally or in animals bearing only cortical lesions.