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1.
Proc Natl Acad Sci U S A ; 102(51): 18620-5, 2005 Dec 20.
Article in English | MEDLINE | ID: mdl-16352709

ABSTRACT

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, delta9-tetrahydrocannabinol, acts by binding to brain CB1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.


Subject(s)
Antidepressive Agents/pharmacology , Arachidonic Acids/metabolism , Benzamides/pharmacology , Brain/drug effects , Brain/metabolism , Carbamates/pharmacology , Norepinephrine/metabolism , Serotonin/metabolism , Animals , Behavior, Animal/drug effects , Cannabinoid Receptor Agonists , Dronabinol/pharmacology , Endocannabinoids , Hydrolysis/drug effects , Male , Mice , Mice, Inbred C57BL , Neurons/drug effects , Neurons/metabolism , Polyunsaturated Alkamides , Rats , Receptors, Cannabinoid/metabolism
2.
J Neuroendocrinol ; 17(3): 179-85, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15796770

ABSTRACT

Women are twice as likely to suffer from mood disorders than men. Moreover, a growing body of evidence suggests a reciprocal modulation between sex steroids and the serotonin (5-HT) system. A previous study from our laboratory has shown that the progesterone metabolites 5beta-pregnane-3,20-dione (5beta-DHP) and 5alpha-pregnan-3alpha-ol,20-one (3alpha,5alpha-THP), as well as dehydroepiandrosterone (DHEA), increase the firing activity of dorsal raphe nucleus (DRN) 5-HT neurones in female rats. The present study was undertaken to assess the effects of these steroids in male rats, as well as the effects of testosterone and 17beta-oestradiol (17beta-E) in both sexes, and finally to evaluate gender differences in the modulation of the 5-HT neuronal firing activity by these different neuroactive steroids. Male rats were treated i.c.v., for 7 days, with a dose of 50 microg/kg/day of one of the following steroids: progesterone, 5beta-DHP, 3alpha,5alpha-THP, DHEA, testosterone, 17beta-hydroxy-5alpha-androstan-3-one (5alpha-DHT) and 17beta-E. Some rats also received a 3-day administration of testosterone (50 microg/kg/day, i.c.v). Females were treated in the same fashion with testosterone and 17beta-E. Extracellular unitary recordings of 5-HT neurones, obtained in vivo in the DRN of these rats, revealed that testosterone and 17beta-E increased the firing activity of 5-HT neurones in both males and females. In males, the effect of testosterone could already be seen after 3 days of treatment. Neither castration nor any treatment with other steroids significantly modified the firing rate of male 5-HT neurones. Taken together with previous findings, the results of the present study indicate both similarities and differences between sexes in the modulation of 5-HT neurones by some steroids. This could prove important in understanding gender differences in mood disorders.


Subject(s)
Action Potentials/physiology , Estradiol/physiology , Neurons/metabolism , Raphe Nuclei/metabolism , Serotonin/metabolism , Testosterone/physiology , Analysis of Variance , Animals , Electrophysiology , Estradiol/administration & dosage , Female , Gonadal Steroid Hormones/administration & dosage , Gonadal Steroid Hormones/physiology , Injections, Intraventricular , Male , Patch-Clamp Techniques , Raphe Nuclei/cytology , Rats , Rats, Sprague-Dawley , Sex Factors , Testosterone/administration & dosage
3.
J Endocrinol ; 182(1): 11-21, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15225127

ABSTRACT

Important gender differences in mood disorders result in a greater susceptibility for women. Accumulating evidence suggests a reciprocal modulation between the 5-hydroxytryptamine (5-HT) system and neuroactive steroids. Previous data from our laboratory have shown that during pregnancy, the firing activity of 5-HT neurons increases in parallel with progesterone levels. This study was undertaken to evaluate the putative modulation of the 5-HT neuronal firing activity by different neurosteroids. Female rats received i.c.v. for 7 days a dose of 50 micro g/kg per day of one of the following steroids: progesterone, pregnenolone, 5beta-pregnane-3,20-dione (5beta-DHP), 5beta-pregnan-3alpha-ol,20-one, 5beta-pregnan-3beta-ol,20-one, 5alpha-pregnane-3,20-dione, 5alpha-pregnan-3alpha-ol,20-one (allopregnanolone, 3alpha,5alpha-THP), 5alpha-pregnane-3beta-ol,20-one and dehydroepiandrosterone (DHEA). 5beta-DHP and DHEA were also administered for 14 and 21 days (50 micro g/kg per day, i.c.v.) as well as concomitantly with the selective sigma 1 (sigma1) receptor antagonist NE-100. In vivo, extracellular unitary recording of 5-HT neurons performed in the dorsal raphe nucleus of these rats revealed that DHEA, 5beta-DHP and 3alpha,5alpha-THP significantly increased the firing activity of the 5-HT neurons. Interestingly, 5beta-DHP and DHEA showed different time-frames for their effects with 5beta-DHP having its greatest effect after 7 days to return to control values after 21 days, whereas DHEA demonstrated a sustained effect over the 21 day period. NE-100 prevented the effect of DHEA but not of 5beta-DHP, thus indicating that its sigma1 receptors mediate the effect of DHEA but not that of 5beta-DHP. In conclusion, our results offer a cellular basis for potential antidepressant effects of neurosteroids, which may prove important particularly for women with affective disorders.


Subject(s)
Dihydrotestosterone/analogs & derivatives , Gender Identity , Gonadal Steroid Hormones/pharmacology , Neurons/metabolism , Raphe Nuclei/drug effects , Serotonin/metabolism , Synaptic Transmission/drug effects , 5-alpha-Dihydroprogesterone/pharmacology , Animals , Anisoles/pharmacology , Antipsychotic Agents/pharmacology , Dehydroepiandrosterone/pharmacology , Dihydrotestosterone/pharmacology , Female , Finasteride/pharmacology , Neurons/drug effects , Ovariectomy , Pregnenolone/pharmacology , Progesterone/pharmacology , Propylamines/pharmacology , Protein Isoforms/pharmacology , Raphe Nuclei/physiology , Rats , Rats, Sprague-Dawley , Receptors, sigma/antagonists & inhibitors , Time Factors
4.
Neuropharmacology ; 43(7): 1119-28, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12504918

ABSTRACT

Gender differences in susceptibility to affective disorders are well documented. The ovarian steroids, estrogen (E) and progesterone (P), may modulate the function of the serotonergic (5-HT) system, implicated in the etiology and treatment of affective disorders. We tested the hypothesis that ovarian steroid modulation of 5-HT function could result in a modification of the 5-HT neuronal firing activity. Extracellular unitary recordings of dorsal raphe nucleus 5-HT neurons were obtained in male rats and in female rats during natural E and P fluctuations. The average firing activity of 5-HT neurons was significantly higher in males (41%) than in freely cycling (CF) and in ovariectomized (OVX) females. During pregnancy, it increased gradually and by up to 136% on gestational day 17, then declined before parturition. In the postpartum period (PP), the firing rate decreased markedly compared to P17 but remained 63% higher than in CF. During pregnancy, the firing rate variations were closely correlated with P plasmatic levels. Finally no modification of the basal firing activity of locus coeruleus noradrenergic neurons was found in any group tested. Our results thus reveal a gender and pregnancy-dependent modulation of 5-HT firing rate that would impact 5-HT-mediated neurotransmission.


Subject(s)
Neurons/physiology , Pregnancy/physiology , Raphe Nuclei/physiology , Serotonin/physiology , Sex Characteristics , Action Potentials/physiology , Animals , Estrogens/blood , Female , Male , Ovariectomy , Pregnancy/blood , Progesterone/blood , Rats , Rats, Sprague-Dawley
5.
Br J Pharmacol ; 134(3): 691-9, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11588125

ABSTRACT

1. Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma(1) and sigma(2). Although the endogenous ligand is yet to be elucidated, the sigma(1) receptor has recently been cloned. 2. Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown. 3. The goal of the present study was to assess the effects of various sigma(1) ligands on the firing activity of serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats. 4. The sigma(1) ligands (+)-pentazocine and 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP) (2 mg kg(-1) day(-1)) increased markedly 5-HT firing activity after 2 days of treatment and maintained the same increased firing rate after long-term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)-pentazocine was prevented by the co-administration of N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine (NE-100) (10 mg kg(-1) day(-1)) a selective sigma(1) antagonist, confirming the sigma(1) receptor's modulation of these effects. In contrast, the sigma(1) ligands (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) and 2-(4-morpholinoethyl 1-phenyl-cyclohexane-1-carboxylate hydrochloride (PRE-084) had no effect. 5. Following a 21-day treatment with (+)-pentazocine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4-IBP and may represent a depolarization block. 6. These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the 'antidepressant effects' reported and provide evidence toward sigma(1) ligands as potential antidepressants with a rapid onset of action.


Subject(s)
Neurons/physiology , Receptors, sigma/agonists , Receptors, sigma/antagonists & inhibitors , Serotonin/physiology , Action Potentials/drug effects , Action Potentials/physiology , Analgesics, Opioid/administration & dosage , Animals , Cinnamates/administration & dosage , Cyclopropanes/administration & dosage , Ligands , Male , Morpholines/administration & dosage , Neurons/drug effects , Pentazocine/administration & dosage , Raphe Nuclei/drug effects , Raphe Nuclei/physiology , Rats , Rats, Sprague-Dawley , Receptors, sigma/physiology
6.
Synapse ; 42(2): 95-103, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11574946

ABSTRACT

Rat bilateral olfactory bulbectomy (OBX) serves as a useful model in the study of depression and the mechanisms of action of antidepressant treatments. Considering the evidence of NMDA receptors involvement in depression, the present study was undertaken in order to investigate the time-course effects of OBX on the NMDA receptor function. Following bilateral olfactory bulbectomy, rats display an increase in locomotor activity and changes in other types of behavior in a novel environment. Autoradiographic experiments using the noncompetitive NMDA antagonist [(125)I]-iodo-MK-801 as the labeling agent showed that this increase in behavioral activities corresponds to a decrease in [(125)I]-iodo-MK-801 binding in a number of brain regions. In most regions, this reduction reached significance by the third week following OBX. However, in some cortical areas-a nucleus of the thalamus (AV) and one of the amygdala (LA)-this reduction was already significant in the first or second week following OBX and lasted throughout the 4 weeks of the study. We also compared the behavioral modifications induced by a challenge injection of MK-801 (0.2 mg/kg i.p.) in OBX and sham-operated rats. This challenge is known to induce hyperlocomotion and a number of stereotypies in naive rats. These effects were drastically reduced in OBX as compared to sham-operated rats. These data are consistent with the above-mentioned decrease in cerebral binding of MK-801 to NMDA receptors.


Subject(s)
Brain/metabolism , Depression/metabolism , Glutamic Acid/metabolism , Neural Inhibition/physiology , Receptors, GABA-A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Binding Sites/drug effects , Binding Sites/physiology , Brain/drug effects , Brain/physiopathology , Denervation , Depression/physiopathology , Disease Models, Animal , Dizocilpine Maleate/pharmacokinetics , Dose-Response Relationship, Drug , Down-Regulation/physiology , Excitatory Amino Acid Antagonists/pharmacokinetics , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Iodine Radioisotopes/pharmacokinetics , Male , Neural Inhibition/drug effects , Neurons/drug effects , Neurons/metabolism , Olfactory Bulb/physiopathology , Olfactory Bulb/surgery , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects
7.
Neuropsychopharmacology ; 24(5): 511-21, 2001 May.
Article in English | MEDLINE | ID: mdl-11282251

ABSTRACT

Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-HT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant. The aim of this study was to assess the effects of duloxetine on the 5-HT and NE reuptake processes in healthy human volunteers. Twenty-seven healthy young males without a history of psychiatric disorder were randomly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 100 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to assess the NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) was measured. Determination of the whole blood 5-HT content was used to evaluate the 5-HT reuptake blockade. These measurements were performed at baseline and repeated after 7 and 14 days of drug intake. Both duloxetine, at doses of 20 to 60 mg/day, and clomipramine significantly interfered with the 5-HT reuptake process, as demonstrated by marked decreases in blood 5-HT concentrations. However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that it represents the threshold regimen for NE reuptake inhibition.


Subject(s)
Adrenergic Uptake Inhibitors/administration & dosage , Brain Chemistry/drug effects , Depression/drug therapy , Norepinephrine/blood , Selective Serotonin Reuptake Inhibitors/administration & dosage , Serotonin/metabolism , Thiophenes/administration & dosage , Adolescent , Adrenergic Uptake Inhibitors/adverse effects , Adrenergic Uptake Inhibitors/pharmacokinetics , Adult , Blood Pressure/drug effects , Blood Pressure/physiology , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Brain Chemistry/physiology , Clomipramine/administration & dosage , Clomipramine/adverse effects , Clomipramine/pharmacokinetics , Depression/metabolism , Depression/physiopathology , Dose-Response Relationship, Drug , Duloxetine Hydrochloride , Humans , Male , Reference Values , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Thiophenes/adverse effects , Thiophenes/pharmacokinetics , Tyramine/administration & dosage , Tyramine/adverse effects , Tyramine/pharmacokinetics
8.
Synapse ; 39(4): 323-31, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11169783

ABSTRACT

Recently, in an attempt to isolate the nonopioid sigma receptor, Su and colleagues purified a protein from rat liver and brain which appeared to resemble the original sigma opioid receptor as proposed by Martin in 1976, and for which the nonopiate sigma-1 ligand (+)pentazocine presents a high affinity. Previous in vivo electrophysiological studies from our laboratory have demonstrated that several selective sigma-1 ligands potentiate the neuronal response to NMDA. The goal of the present series of experiments was to assess the effects of some selective sigma-1 ligands on the potentiation of the NMDA response and to determine if this potentiation was mediated by the naloxone-sensitive sigma receptor. Extracellular unitary recordings from pyramidal neurons of the CA3 region of the rat dorsal hippocampus were obtained. The sigma-1 ligands BD 737, L 687-384, and JO-1784 (igmesine), administered intravenously at low doses, potentiated the NMDA response but the opiate antagonist naloxone failed to reverse this potentiation. However, the potentiation of the NMDA response induced by the sigma-1 ligand (+)pentazocine was suppressed by naloxone but not by the mu antagonist cyprodime hydrobomide, the kappa antagonist DIPPA nor by the delta antagonist naltrindole. (+/-) Cyclazocine, which presents a high affinity for the above-mentioned sigma-opiate receptor acted as an antagonist by suppressing the potentiation of the NMDA response induced by both JO-1784 and (+)pentazocine. These results suggest that the effects induced by some sigma-1 ligands may, in fact, be sensitive to naloxone while others may not. The original classification of sigma receptors as opiates might have been partly accurate.


Subject(s)
Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Pentazocine/pharmacology , Receptors, sigma/agonists , Action Potentials/drug effects , Animals , Cinnamates/administration & dosage , Cinnamates/pharmacology , Cyclazocine/administration & dosage , Cyclazocine/pharmacology , Cyclohexylamines/administration & dosage , Cyclohexylamines/pharmacology , Cyclopropanes/administration & dosage , Cyclopropanes/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Injections, Intravenous , Male , N-Methylaspartate/pharmacology , Pentazocine/administration & dosage , Piperidines/administration & dosage , Piperidines/pharmacology , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Pyrrolidines/administration & dosage , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley
9.
Neuropsychopharmacology ; 23(3): 294-306, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10942853

ABSTRACT

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT(1A) receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA(3) pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective beta-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT(1A) receptors was suggested by its complete reversal by the 5-HT(1A) antagonist WAY 100635 (100 microg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day x 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day x 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT(1A) receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT(1A) autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Cyclohexanols/pharmacology , Pindolol/pharmacology , Receptors, Neurotransmitter/drug effects , Receptors, Serotonin/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , 5,7-Dihydroxytryptamine/pharmacology , Animals , Cyclohexanols/administration & dosage , Drug Synergism , Electrophysiology , Extracellular Space/drug effects , Extracellular Space/metabolism , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/metabolism , Injections, Intravenous , Male , Paroxetine/pharmacology , Piperazines/pharmacology , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Pyridines/pharmacology , Raphe Nuclei/cytology , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Neurotransmitter/metabolism , Receptors, Serotonin, 5-HT1 , Serotonin Agents/pharmacology , Serotonin Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/administration & dosage , Venlafaxine Hydrochloride
10.
Neuropharmacology ; 39(10): 1800-12, 2000 Jul 24.
Article in English | MEDLINE | ID: mdl-10884561

ABSTRACT

The effect of a 21-day treatment with the dual 5-HT and NE reuptake blocker venlafaxine (delivered s.c. by osmotic minipumps) was assessed on the time required for a 50% recovery (RT(50)) of the firing activity of dorsal hippocampus CA(3) pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NE. The RT(50) values for 5-HT were increased by both 10 and 40 mg/kg/day regimens of venlafaxine, whereas those for NE were increased only by the 40 mg/kg/day regimen, indicative of a greater potency of venlafaxine in blocking 5-HT reuptake. The sensitivity of the postsynaptic 5-HT(1A) and alpha(2)-adrenergic receptors was altered by neither regimen of venlafaxine. Using a paradigm by which the 5-HT(1A) antagonist WAY 100635 can induce a disinhibition of firing activity of CA(3) pyramidal neurons, it was demonstrated that the high, but not the low, dose of venlafaxine led to an enhanced tonic activation of postsynaptic 5-HT(1A) receptors in the dorsal hippocampus. The duration of the suppressant effect of the firing activity of CA(3) hippocampus pyramidal neurons produced by the electrical stimulation of the ascending 5-HT pathway was significantly reduced when the frequency of the stimulation was enhanced from 1 Hz to 5 Hz in control rats and in rats treated with 10 mg/kg/day, but not with 40 mg/kg/day of venlafaxine. Hence, venlafaxine induced a desensitization of the terminal 5-HT(1B) autoreceptor only at the high dose. A 2-day treatment with 10 mg/kg/day of venlafaxine induced a suppression of the firing activity of 5-HT neurons of the dorsal raphe. The firing activity of these neurons was back to control level in rats that had been treated for 21 days with the same dose of venlafaxine. The suppressant effect of the i.v. administration of the 5-HT autoreceptor agonist LSD on the firing activity of dorsal raphe 5-HT neurons was reduced in rats that had been treated for 21 days with 10 mg/kg/day of venlafaxine. A 2-day treatment with 40 mg/kg/day of venlafaxine, unlike the 10 mg/kg/day regimen, induced a marked suppression of the firing activity of locus coeruleus NE neurons. However, in contrast to 5-HT neurons, NE neurons did not recover their firing activity after a 21-day treatment. Taken together, the results from this study indicate that the low dose of venlafaxine blocked selectively the reuptake of 5-HT, whereas the high dose blocked the reuptake of both 5-HT and NE. Moreover, an enhancement of serotonergic neurotransmission by venlafaxine was only achieved under conditions whereby the desensitization of the terminal 5-HT(1B) autoreceptor is appended to that of the somatodendritic 5-HT(1A) receptor.


Subject(s)
Cyclohexanols/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Autoreceptors/drug effects , Autoreceptors/physiology , Dendrites/drug effects , Dendrites/physiology , Dose-Response Relationship, Drug , Electric Stimulation , Electrophysiology , Locus Coeruleus/cytology , Locus Coeruleus/drug effects , Locus Coeruleus/physiology , Male , Neurons/drug effects , Neurons/physiology , Norepinephrine/metabolism , Norepinephrine/pharmacology , Piperazines/pharmacology , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Pyridines/pharmacology , Raphe Nuclei/cytology , Raphe Nuclei/drug effects , Raphe Nuclei/physiology , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/physiology , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Receptors, Serotonin, 5-HT1 , Serotonin/metabolism , Serotonin/pharmacology , Serotonin Antagonists/pharmacology , Synapses/drug effects , Time Factors , Venlafaxine Hydrochloride
11.
Neuropharmacology ; 39(10): 1813-22, 2000 Jul 24.
Article in English | MEDLINE | ID: mdl-10884562

ABSTRACT

The effects of long-term administrations of a low (10 mg/kg/day) and a high (40 mg/kg/day) dose of the dual 5-HT and NE reuptake inhibitor venlafaxine (delivered s.c. by osmotic minipumps for 21 days) were assessed on the electrically-evoked release of tritium from hippocampal slices preloaded with either [(3)H]5-HT or [(3)H]NE, 48 h after the removal of the minipump. The high, but not the low, dose regimen of venlafaxine enhanced the electrically-evoked release of [(3)H]5-HT while treatment with the high dose of venlafaxine failed to alter the electrically-evoked release of [(3)H]NE. The inhibitory effect of the 5-HT(1B) agonist CP 93,129 on the electrically evoked release of [(3)H]5-HT was unaltered by the low dose regimen of venlafaxine while it was attenuated in rats treated with the high dose of venlafaxine, indicative of a functional desensitization of the terminal 5-HT(1B) autoreceptor. Unexpectedly, neither regimen of venlafaxine altered the inhibitory effect of UK 14,304 on the electrically evoked release of both [(3)H]5-HT and [(3)H]NE, indicating that neither the alpha(2)-adrenergic auto- nor heteroreceptors were desensitized. Finally, the functions of the 5-HT and NE reuptake process were assessed. None of the treatment regimens altered the basal uptake of [(3)H]5-HT from hippocampal or mesencephalic slices nor that of [(3)H]NE from hippocampal slices. Finally, the enhancing effect of 1 microM of paroxetine in the perfusion medium on the electrical release of [(3)H]5-HT was unaltered in hippocampal slices prepared from rats that had been treated for 21 days with 40 mg/kg/day of venlafaxine. Taken together, these results indicate that, in terms of alteration of the sensitivity of the terminal 5-HT(1B) autoreceptor, alpha(2)-adrenergic auto-and heteroreceptors, the effects of long-term administration of venlafaxine are no different than those observed with classical SSRI's.


Subject(s)
Cyclohexanols/pharmacology , Membrane Transport Proteins , Nerve Tissue Proteins , Selective Serotonin Reuptake Inhibitors/pharmacology , Symporters , Adrenergic alpha-Agonists/pharmacology , Animals , Autoreceptors/drug effects , Autoreceptors/physiology , Brimonidine Tartrate , Carrier Proteins/drug effects , Carrier Proteins/physiology , Cricetinae , Dose-Response Relationship, Drug , Hippocampus/drug effects , Hippocampus/physiology , In Vitro Techniques , Male , Membrane Glycoproteins/drug effects , Membrane Glycoproteins/physiology , Norepinephrine/metabolism , Norepinephrine Plasma Membrane Transport Proteins , Pyridines/pharmacology , Pyrroles/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/physiology , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins , Serotonin Receptor Agonists/pharmacology , Time Factors , Tritium , Venlafaxine Hydrochloride
12.
J Clin Psychopharmacol ; 19(5): 401-6, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10505581

ABSTRACT

This was an 8-week, multicenter, open-label study of the efficacy and tolerability of venlafaxine in patients with treatment-resistant depression conducted in Canada. Inpatients or outpatients aged 18 to 70 years with major depression were eligible if they had a 21-item Hamilton Rating Scale for Depression (HAM-D-21) score of 2 > or = 18 and a documented history of unsatisfactory improvement after a minimum of 8 weeks of treatment with an adequate dose of an antidepressant. Treatment with venlafaxine was started at 37.5 mg twice daily, and the dose could be titrated upward to a maximum of 375 mg/day during the first 4 weeks on the basis of the investigator's assessment of clinical response and tolerability. Of the 159 patients enrolled, 152 were evaluable for efficacy. The mean daily venlafaxine dose was 260 mg/day. The mean HAM-D-21 score decreased by 52%, and the mean Montgomery-Asberg Depression Rating Scale score decreased by 50% from baseline to day 56. A response (50% improvement from baseline) was achieved by 58% of patients on the HAM-D-21, and a remission (> or = 75% improvement in the HAM-D-21) was observed in 28% at day 56. By day 56, 88% of patients had improved from baseline on the Clinical Global Impression Improvement scale. Only 8% of the patients discontinued for adverse events. The most common adverse events were headache, insomnia, nausea, constipation, diaphoresis, and xerostomia. In conclusion, these results suggest that venlafaxine is effective and well tolerated for the management of patients with treatment-resistant major depression.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Cyclohexanols/therapeutic use , Depressive Disorder/drug therapy , Adolescent , Adult , Aged , Antidepressive Agents, Second-Generation/adverse effects , Canada , Cyclohexanols/adverse effects , Depressive Disorder/psychology , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Venlafaxine Hydrochloride
13.
Br J Pharmacol ; 127(8): 1769-76, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10482906

ABSTRACT

1. Sigma (sigma) receptors have recently been cloned, though their endogenous ligand(s) remain unidentified. However, some neuroactive steroids, such as progesterone, have a high affinity for these receptors. Some sigma ligands, such as DTG, (+)-pentazocine and DHEA, act as sigma 'agonists' by potentiating the neuronal response to NMDA. Others, such as haloperidol, NE-100 and progesterone, act as sigma 'antagonists' by reversing the potentiations induced by sigma 'agonists'. 2. We compared the effects of sigma 'agonists' in four series of female rats: in controls, at day 18 of pregnancy, at day 5 post-partum, and in ovariectomized rats following a 3-week treatment with a high dose of progesterone. 3. In pregnant rats and following a 3-week treatment with progesterone, 10 fold higher doses of DTG, (+)-pentazocine and DHEA were required to elicit a selective potentiation of the NMDA response comparable to that obtained in control females. Conversely, at day 5 post-partum and following the 3-week treatment with a progesterone and after a 5-day washout, the potentiation of the NMDA response induced by the sigma 'agonist' DTG was greater than in control females. 4. The present data suggest that endogenous progesterone acts as an 'antagonist' at sigma receptors. The resulting changes in the function of sigma receptors during pregnancy and post-partum may be implicated in emotional phenomena occurring during these periods.


Subject(s)
Adjuvants, Immunologic/pharmacology , Analgesics, Opioid/pharmacology , Anticonvulsants/pharmacology , Dehydroepiandrosterone/pharmacology , Guanidines/pharmacology , Pentazocine/pharmacology , Receptors, sigma/drug effects , Action Potentials/drug effects , Action Potentials/physiology , Animals , Female , Hippocampus/drug effects , Hippocampus/physiology , Ovariectomy , Postpartum Period/drug effects , Postpartum Period/physiology , Pregnancy , Progesterone/blood , Progesterone/pharmacology , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/physiology , Receptors, sigma/physiology
14.
Synapse ; 32(3): 198-211, 1999 Jun 01.
Article in English | MEDLINE | ID: mdl-10340630

ABSTRACT

Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine displayed similar potency for suppressing the firing activity of dorsal raphe 5-HT neurons (ED50: 233 and 211 microg/kg i.v., respectively), while venlafaxine was three times less potent than desipramine (ED50: 727 and 241 microg/kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5-HT1A receptor antagonist WAY 100635 (100 microg/kg, i.v.) reversed the suppressant effect of venlafaxine and paroxetine on the firing activity of 5-HT neurons and the alpha2-adrenoceptor antagonist piperoxane (1 mg/kg, i.v.) reversed those of venlafaxine and desipramine on the firing activity of NE neurons. The ED50 of venlafaxine on the firing activity of 5-HT neurons was not altered (ED50: 264 microg/kg) in noradrenergic-lesioned rats, while the suppressant effect of venlafaxine on the firing activity of NE neurons was greater in serotonergic-lesioned rats (ED50: 285 microg/kg). Taken together, these results suggest that, in vivo, venlafaxine blocks both reuptake processes, its potency to block the 5-HT reuptake process being greater than that for NE. Since the affinities of venlafaxine for the 5-HT and NE reuptake carriers are not in keeping with its potencies for suppressing the firing activity of 5-HT and NE neurons, the suppressant effect of venlafaxine on the firing activity of 5-HT and NE neurons observed in vivo may not be mediated solely by its action on the [3H]cyanoimipramine and [3H]nisoxetine binding sites. In an attempt to unravel the mechanism responsible for this peculiarity, in vitro superfusion experiments were carried out in rat brain slices to assess a putative monoamine releasing property for venlafaxine. (+/-)Fenfluramine and tyramine substantially increased the spontaneous outflow of [3H]5-HT and [3H]NE, respectively, while venlafaxine was devoid of such releasing properties.


Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Cyclohexanols/pharmacology , Neurons/drug effects , Norepinephrine/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , Action Potentials/drug effects , Adrenergic Uptake Inhibitors/antagonists & inhibitors , Adrenergic Uptake Inhibitors/metabolism , Animals , Binding Sites , Cyclohexanols/antagonists & inhibitors , Cyclohexanols/metabolism , Desipramine/antagonists & inhibitors , Desipramine/metabolism , Desipramine/pharmacology , Fenfluramine/metabolism , Fenfluramine/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , In Vitro Techniques , Locus Coeruleus/cytology , Locus Coeruleus/drug effects , Locus Coeruleus/metabolism , Male , Neurons/metabolism , Neurons/physiology , Paroxetine/antagonists & inhibitors , Paroxetine/metabolism , Paroxetine/pharmacology , Piperazines/pharmacology , Piperoxan/pharmacology , Pyridines/pharmacology , Raphe Nuclei/cytology , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/antagonists & inhibitors , Selective Serotonin Reuptake Inhibitors/metabolism , Tyramine/metabolism , Tyramine/pharmacology , Venlafaxine Hydrochloride
15.
Eur J Pharmacol ; 368(2-3): 183-96, 1999 Mar 05.
Article in English | MEDLINE | ID: mdl-10193654

ABSTRACT

Extracellular single-unit recordings and iontophoresis were used to examine the effects of different selective sigma receptor ligands on dopaminergic and glutamatergic N-methyl-D-aspartate (NMDA) neurotransmissions both in origin (A10 and A9 areas) and terminal (nucleus accumbens and caudate nucleus) regions of the rat mesolimbic and nigrostriatal dopaminergic systems. The selective sigma1 receptor ligands 2-[4-(4-methoxy-benzyl)piperazin-1-yl-methyl]4-oxo[4H]-benzo-th iazolin-2-one (S-21377), systemically administered (1.2 mg/kg, i.v., cumulative dose), and 2[(4-benzyl piperazin-1-yl) mothyl] naphthalene, dichiorydrate (S-21378), iontophoretically applied, slightly increased the spontaneous firing rate and potentiated the NMDA-induced neuronal activation of dopaminergic neurons in the A9 and A10 regions. (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-butyl-2-N (JO-1784), another selective sigma1 receptor ligand produced no or little effect in these areas. The systemic administration of the selective sigma2 receptor ligand 1,4-bis-spiro[isobenzofuran-1(3H), 4'-piperidin-1'yl]butane (Lu 29-252) (2 mg/kg, i.v., cumulative dose) did not modify the firing activity of A9 and A10 dopaminergic neurons, but significantly potentiated the NMDA-induced increase in firing activity of A10 dopaminergic neurons. None of the sigma receptor ligands tested had any effects on the dopamine-induced suppression of firing. In the nucleus accumbens, the systemic administration of (JO-1784), (40 microg/kg, i.v.), (+)-pentazocine (30 microg/kg, i.v.), another selective sigma1 receptor ligand, and of the non selective sigma1 receptor ligand di-tolyl-guanidine (DTG) (20 microg/i.v.) produced a significant increase of NMDA-induced neuronal activation. Microiontophoretic applications of JO-1784 also potentiated the NMDA response. They also increased significantly the suppressant effect of dopamine on NMDA and kainate-induced activations of accumbens neurons. In the caudate nucleus, (+)-pentazocine, but not JO-1784, potentiated slightly the neuronal response to NMDA. None of the sigma receptor ligands tested did modify significantly the responses of caudate and accumbens neurons to kainate. These findings suggest that at least two subtypes of sigma1 receptors may affect differentially the glutamate NMDA neurotransmission in the terminal and origin regions of the mesolimbic and nigrostriatal dopaminergic systems. These results also demonstrate the existence of a functional interaction between sigma2 and NMDA receptors in the A10 region.


Subject(s)
Dopamine/physiology , Excitatory Amino Acids/physiology , Receptors, Cell Surface/physiology , Receptors, sigma/physiology , Synaptic Transmission/physiology , Analgesics, Opioid/pharmacology , Animals , Caudate Nucleus/drug effects , Caudate Nucleus/physiology , Cinnamates/pharmacology , Cyclopropanes/pharmacology , Electrophysiology , Glutamic Acid/physiology , Guanidines/pharmacology , Kainic Acid/pharmacology , Male , N-Methylaspartate/pharmacology , N-Methylaspartate/physiology , Neurons/drug effects , Neurons/physiology , Nucleus Accumbens/drug effects , Nucleus Accumbens/physiology , Pentazocine/pharmacology , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Receptors, Neurotransmitter/physiology , Receptors, sigma/agonists , Spiro Compounds/pharmacology , Substantia Nigra/drug effects , Substantia Nigra/physiology , Thiazoles/pharmacology , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/physiology , Sigma-1 Receptor
16.
Br J Pharmacol ; 125(3): 526-32, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9806336

ABSTRACT

1. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in the rat, to compare the effects of venlafaxine on 5-HT and NA reuptake to those of the selective 5-HT reuptake inhibitor paroxetine and the selective NA reuptake inhibitor desipramine. 2. Administered acutely, venlafaxine dose-dependently prolonged the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NA. Venlafaxine and paroxetine increased with a similar potency the RT50 values for 5-HT, while desipramine was more potent than venlafaxine at increasing the RT50 values for NA. Moreover, venlafaxine demonstrated a greater potency at increasing the RT50 values for 5-HT compared to that of NA. 3. A two-day treatment with venlafaxine (delivered s.c. by osmotic minipumps) increased the RT50 values for both 5-HT and NA applications. The RT50 values for 5-HT were significantly increased at a dose of 10 mg kg(-1) day(-1), whereas those for NA were increased at a dose of 20 mg kg(-1) day(-1), consistent with the data obtained following the acute administration of venlafaxine. 4. Taken together, these results indicate that, in vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NA reuptake process. This dual action, combined with the differential potency of venlafaxine, might constitute the biological substratum responsible for its apparent unique clinical efficacy in major depression.


Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Cyclohexanols/pharmacology , Norepinephrine/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , Animals , Depression/drug therapy , Desipramine/pharmacology , Hippocampus/drug effects , Injections, Intravenous , Iontophoresis , Male , Paroxetine/pharmacology , Rats , Rats, Sprague-Dawley , Venlafaxine Hydrochloride
17.
Eur J Pharmacol ; 349(1): 129-32, 1998 May 15.
Article in English | MEDLINE | ID: mdl-9669506

ABSTRACT

In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [3H]cyanoimipramine and [3H]nisoxetine, respectively. The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine had a high affinity for the norepinephrine transporter. Duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed a high affinity for both the 5-HT and the norepinephrine transporters. Interestingly, venlafaxine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed only a moderate affinity for the 5-HT transporter (Ki = 74 nM) and a very low affinity for the norepinephrine transporter (Ki = 1.26 microM). The relatively low affinities of venlafaxine contrast with its potent in vivo 5-HT and norepinephrine reuptake blocking properties. These results raise the possibility that the in vivo effects on the 5-HT and norepinephrine reuptake observed with venlafaxine may not be mediated solely by its binding to the [3H]cyanoimipramine and [3H]nisoxetine binding sites.


Subject(s)
Antidepressive Agents, Second-Generation/metabolism , Carrier Proteins/metabolism , Cyclohexanols/metabolism , Membrane Glycoproteins/metabolism , Membrane Transport Proteins , Nerve Tissue Proteins , Neurotransmitter Uptake Inhibitors/metabolism , Norepinephrine/metabolism , Serotonin/metabolism , Symporters , Animals , Binding, Competitive , Brain/metabolism , Fluoxetine/analogs & derivatives , Fluoxetine/metabolism , Imipramine/analogs & derivatives , Imipramine/metabolism , Male , Norepinephrine/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/metabolism , Serotonin Plasma Membrane Transport Proteins , Selective Serotonin Reuptake Inhibitors/metabolism , Venlafaxine Hydrochloride
18.
Synapse ; 29(1): 62-71, 1998 May.
Article in English | MEDLINE | ID: mdl-9552175

ABSTRACT

It has now been accepted for several years that sigma (sigma) receptors exist in, at least, two distinct entities denoted sigma1 and sigma2. Previous electrophysiological studies from our laboratory have demonstrated that several selective sigma1 ligands potentiate the neuronal response to NMDA. The nonselective sigma1/sigma2 ligand DTG also potentiates the NMDA response. However, when DTG is administered at doses between 3 and 40 microg/kg, the increase of NMDA-induced activation turns to an epileptoid activity. Until recently, the physiological role of sigma2 receptors had been less studied due to the lack of selective sigma2 ligands. The goal of the present electrophysiological studies was to assess the effect of the intravenous administration of new selective sigma2 ligands on the neuronal response to NMDA in the CA3 region of the rat dorsal hippocampus. Lu 28-179 and BD 1008 potentiated dose-dependently the NMDA response and generated bell-shaped dose-response curves. These ligands failed to generate any epileptoid activity on their own but the subsequent administration of a low dose of a sigma1 agonist (JO-1784) induced an epileptoid activity. Interestingly, the potentiations of the NMDA response induced by Lu 28-179 or BD 1008 were not reversed by haloperidol, by the neurosteroid progesterone, nor by the selective sigma1 antagonist NE-100. Ibogaine, a high affinity sigma2 ligand, slightly increases the NMDA response, which was reversed by progesterone. These data suggest that, similarly to sigma1 ligands, sigma2 agonists potentiate the NMDA response and that the coactivation of sigma1 and sigma2 receptors could be necessary to induce an epileptoid activity. They also suggest that haloperidol may not act as a sigma2 antagonist and that several subtypes of sigma2 receptors could exist.


Subject(s)
N-Methylaspartate/pharmacology , Neurons/drug effects , Receptors, sigma/metabolism , Animals , Electrophysiology , Ethylamines/pharmacology , Hippocampus/cytology , Hippocampus/physiology , Ibogaine/pharmacology , Indoles/pharmacology , Injections, Intravenous , Ligands , Male , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Spiro Compounds/pharmacology
20.
Br J Pharmacol ; 120(7): 1351-9, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9105712

ABSTRACT

1. Long-term treatments with the sigma ligand haloperidol decrease the density of sigma receptors in mammalian CNS. We have shown that sigma ligands, such as di(2-tolyl)guanidin (DTG), potentiate dose-dependently, with bell-shaped dose-response curves, the neuronal response of pyramidal neurones to N-methyl-D-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. sigma Ligands producing such a potentiation were denoted 'agonists'. This potentiation was suppressed by low doses of other sigma ligands denoted 'antagonists'. High doses of DTG and JO-1784 did not modify the NMDA response but acted as 'antagonists' by suppressing the potentiation induced by sigma 'agonists'. 2. Following a 21-day treatment with haloperidol as well as with high doses of DTG or JO-1784, after a 48 h washout, the acute administration of sigma 'agonists' failed to induce any potentiation of the NMDA response. Following a 21 day treatment with a low dose of DTG or JO-1784, after a 48 h washout, the neuronal response to microiontophoretic applications of NMDA was markedly increased. A 21 day treatment with low or high doses of (+)-pentazocine, after a 48 h washout, did not produce any change. 3. Following a two day treatment with a high dose of haloperidol, DTG, JO-1784 and (+)-pentazocine, after a 24 h washout, the potentiation of the NMDA response induced by the acute administration of the sigma 'agonists' was unchanged. 4. With the minipumps on board, with DTG and JO-1784, a dose-dependent enhancement of the NMDA response was seen but no effect was observed in the groups of rats treated at the same doses with haloperidol or (+)-pentazocine. 5. The present data suggest that long-term treatments with sigma 'antagonists' induce a desensitization of the th receptors, whereas long-term treatments with th 'agonists' induce a supersensitivity of the th receptors.


Subject(s)
Hippocampus/drug effects , N-Methylaspartate/pharmacology , Receptors, sigma/drug effects , Animals , Cinnamates/pharmacology , Cyclopropanes/pharmacology , Guanidines/pharmacology , Haloperidol/pharmacology , Hippocampus/metabolism , Male , Pentazocine/pharmacology , Rats , Rats, Sprague-Dawley
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