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Papers by alvaro diaz

Research paper thumbnail of The endocannabinoid system in mental disorders: Evidence from human brain studies

Biochemical pharmacology, Jan 17, 2018

Mental disorders have a high prevalence compared with many other health conditions and are the le... more Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, th...

Research paper thumbnail of Targeting β-Catenin in GLAST-Expressing Cells: Impact on Anxiety and Depression-Related Behavior and Hippocampal Proliferation

Molecular neurobiology, Jan 8, 2018

β-catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood ... more β-catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood disorders, associated to neurogenesis and neuroplasticity. Decreased β-catenin protein levels have been observed in the hippocampus and prefrontal cortex of depressed subjects. Additionally, the antidepressants exert, at least in part, their neurogenic effects by increasing β-catenin levels in the subgranular zone of the hippocampus. To further understand the role of β-catenin in depression and anxiety, we generated two conditional transgenic mice in which β-catenin was either inactivated or stabilized in cells expressing CreERT under the control of the astrocyte-specific glutamate transporter (GLAST) promoter inducible by tamoxifen, which presents high expression levels on the subgranular zone of the hippocampus. Here, we show that β-catenin inactivation in GLAST-expressing cells enhanced anxious/depressive-like responses. These behavioral changes were associated with impaired hippocamp...

Research paper thumbnail of Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation

ACS chemical neuroscience, Nov 18, 2017

Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although th... more Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT1AR activation might predispose to a high ...

Research paper thumbnail of Effects of spinal administration of amitryptiline, venlafaxine and fluoxetine on C-fibre and A-fibre evoked responses of dorsal horn neurones

Research paper thumbnail of Chronic (-) cannabidiol improves depressive-like behaviors in OBX mice likely via 5-HT1A and CB1 receptor modulation

Comunicacion presentada al: "First Joint Spanish-Italian Meeting on Cannabinoid Research&quo... more Comunicacion presentada al: "First Joint Spanish-Italian Meeting on Cannabinoid Research" celebrado del 29 de noviembre al 1 de diciembre de 2012 en Madrid.

Research paper thumbnail of Sex differences in hippocampal functionality in mice overexpressing postsynaptic 5-HT1A receptors

Ministerio de Ciencia e Innovacion (SAF07-61862; SAF2011-25020). Deutscher Akademischer Austausch... more Ministerio de Ciencia e Innovacion (SAF07-61862; SAF2011-25020). Deutscher Akademischer Austausch Dienst (DAAD; D/11/ 42325)

Research paper thumbnail of Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation

Pain, 1997

The effects of the intrathecal (i.t.) administration of different voltage-sensitive calcium chann... more The effects of the intrathecal (i.t.) administration of different voltage-sensitive calcium channel (VSCC) blockers were studied in the formalin model of inflammation. The responses of convergent dorsal horn neurones after the subcutaneous injection of formalin (5% formaldehyde, 50 ml volume) were recorded extracellularly in rats under halothane anaesthesia. Administration of the L-type calcium channel blocker verapamil, 5 and 50 mg, before formalin injection had no effect on either the first or second phase of the formalin response. Pre-treatment with the N-type calcium channel blocker q-Conotoxin-GVIA, 0.1 and 0.4 mg, reduced both phases of the formalin response. The low dose of q-Conotoxin-GVIA significantly inhibited the first phase response whereas the high dose significantly reduced the second phase. Pre-treatment with the P-type calcium channel blocker q-Agatoxin-IVA, 0.125 and 0.5 mg, did not cause a significant inhibition of the first phase whereas a marked dose-related reduction in the second phase of formalin response was found with the high dose producing 95% inhibition. These results demonstrate that spinal N-and P-type, but not L-type, VSCCs are involved in the inflammation-evoked hyperexcitability of dorsal horn neurones after peripheral formalin injection. Since selective antagonists for each type of VSCC had differential effects on the formalin response, it is suggested that each type of VSCC could be preferentially regulating or coupled to the release of certain neurotransmitters in the enhanced nociceptive transmission at the spinal level following formalin inflammation.

Research paper thumbnail of WAY100635 prevents the changes induced by fluoxetine upon the 5-HT1A receptor functionality

Neuropharmacology, 2008

5-HT1A receptor-mediated signalling in rat brain was evaluated after chronic administration (14 d... more 5-HT1A receptor-mediated signalling in rat brain was evaluated after chronic administration (14 days; s.c.) of the selective serotonin reuptake inhibitor (SRRI) fluoxetine (10 mg/kg/day) alone, or in combination with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg/day). The density of 5-HT1A binding sites was unchanged following fluoxetine, WAY100635, or the combination of fluoxetine and WAY100635. However, the net stimulation of [35S]GTPgammaS binding induced by the 5-HT1A agonist 8-OH-DPAT was significantly attenuated in dorsal raphe nucleus (DRN), but not in hippocampus, after chronic fluoxetine. Moreover, depending of the area analysed, the basal binding of [35S]GTPgammaS was differentially affected by this treatment: increased in DRN and decreased in hippocampal dentate gyrus. Interestingly, the changes in [35S]GTPgammaS basal binding and on 5-HT1A receptors functionality were prevented by the concomitant administration of WAY100635. The inhibition of dorsal raphe firing by...

Research paper thumbnail of Calcium Channel Antagonists and the Control of Pain

Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery, Second Edition, 2003

Research paper thumbnail of Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT4 receptor agonist RS67333

The International Journal of Neuropsychopharmacology, 2011

It has been recently suggested that activation of 5-HT 4 receptors might exert antidepressant-lik... more It has been recently suggested that activation of 5-HT 4 receptors might exert antidepressant-like effects in rats after 3 d treatment, suggesting a new strategy for developing faster-acting antidepressants. We studied the effects of 3 d and 7 d treatment with the 5-HT 4 receptor partial agonist RS67333 (1.5 mg/kg.d) in behavioural tests of chronic efficacy and on neuroplastic-associated changes, such as adult hippocampal neurogenesis, expression of CREB, BDNF, b-catenin, AKT and 5-HT 4 receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, b-catenin expression and pCREB/CREB ratio after 3 d treatment. This short-term treatment also reduced immobility time in the forced swim test (FST), together with a partial reversion of the anhedonic-like state (sucrose consumption after chronic corticosterone). Administration of RS67333 for 7 d resulted in a higher increase in the rate of hippocampal cell proliferation, a significant desensitization of 5-HT 4 receptor-coupled adenylate cyclase activity and a more marked increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT) : these changes reached the same magnitude as those observed after 3 wk administration of classical antidepressants. Consistently, a positive behavioural response in the novelty suppressed feeding (NSF) test and a complete reversion of the anhedonic-like state (sucrose consumption) were also observed after 7 d treatment. These results support the antidepressant-like profile of RS67333 with a shorter onset of action and suggest that this time period of administration (3-7 d) could be a good approximation to experimentally predict the onset of action of this promising strategy.

Research paper thumbnail of Serotonin 5-HT4 Receptors: A New Strategy for Developing Fast Acting Antidepressants?

Current Pharmaceutical Design, 2014

Research paper thumbnail of Neural Plasticity and Proliferation in the Generation of Antidepressant Effects: Hippocampal Implication

Neural Plasticity, 2013

It is widely accepted that changes underlying depression and antidepressant-like effects involve ... more It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as...

Research paper thumbnail of Neurotransmisión serotoninérgica

Neurofarmacología Contemporánea, 2011

Research paper thumbnail of Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment

Psychopharmacology, 2013

Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug... more Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT(1B) receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial. The aim of this study was to evaluate the effect of venlafaxine (10 mg kg⁻¹ day⁻¹, p.o.) after 21 days of treatment on the density of 5-HT(1B) receptors and their functionality in rat brain. Effects of chronic venlafaxine were evaluated at different levels of 5-HT(1B) receptor by using receptor autoradiography, [³⁵S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT(1B) agonist. Our results show that venlafaxine induced an increase in sensitivity of 5-HT(1B) receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density. These results demonstrate that adaptive changes on 5-HT(1B) receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.

Research paper thumbnail of Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

Research paper thumbnail of Opioid tolerance and supersensitivity induce regional changes in the autoradiographic density of dihydropyridine-sensitive calcium channels in the rat central nervous system

Pain, 2000

Chronic opioid administration induces adaptations in neurones resulting in opioid tolerance and d... more Chronic opioid administration induces adaptations in neurones resulting in opioid tolerance and dependence. The changes in dihydropyridine (DHP)-sensitive Ca 21 channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the m-opioid receptor agonist sufentanil were analyzed in the central nervous system (CNS) of rats. Autoradiographic assays were performed with [ 3 H]PN-200-110 (isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate). Chronic s.c. infusion of sufentanil (2 mg/h) for 7 days, which has been shown to induce tolerance to the opioid antinociceptive effect, produced an upregulation of DHP binding sites. The highest increases in density were localized in regions involved in nociceptive transmission and perception, such as the dorsal horn of the spinal cord, the dorsal raphe nucleus, the central grey matter, the thalamic nuclei, and the somatosensory cortex. Animals were rendered supersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 mg/h) and nimodipine (1 mg/h) for 7 days. Under these conditions, a greater increase in the number of DHP binding sites was observed in the spinal cord, central grey matter, dorsal raphe nucleus, and somatosensory neocortex, when compared to the sufentanil group. The role of an increased in¯ux through L-type channels in opioid tolerance is reinforced, whereas their persistent blockade is essential for the expression of opioid supersensitivity.

Research paper thumbnail of Regionally specific age-dependent decline in α2-adrenoceptors: An autoradiographic study in human brain

Neuroscience Letters, 1991

Research paper thumbnail of Differential adaptive changes on serotonin and noradrenaline transporters in a rat model of peripheral neuropathic pain

Neuroscience Letters, 2012

Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in ... more Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in several animal models of neuropathic pain. In the present work, we have analyzed the density of brain and spinal serotonin and noradrenaline transporters (5-HTT and NAT) in a rat model of neuropathic pain, the spinal nerve ligation (SNL). Quantitative autoradiography revealed a significant decrease in the density of 5-HTT ([ 3 H]citalopram binding) at the level of the lumbar spinal cord following 2 weeks of neuropathic surgery (lamina V, −40%: 6.01 ± 0.64 nCi/mg tissue in sham-animals vs 3.59 ± 1.56 in SNL-animals; lamina X, −30%: 9.10 ± 2.00 vs 6.40 ± 1.93 and lamina IX, −22%: 12.01 ± 2.41 vs 9.42 ± 1.58). By contrast, NAT density ([ 3 H]nisoxetine binding) was significantly increased (lamina I-II, +34%: 2.20 ± 0.45 vs 2.96 ± 0.65;

Research paper thumbnail of Transient localization of 5-HT1A receptors in human cerebellum during development

Neuroscience Letters, 1994

The appearance and distribution of 5-HTIA receptors in the human cerebellum during the ontogeneti... more The appearance and distribution of 5-HTIA receptors in the human cerebellum during the ontogenetic development was studied in samples from a group of fetal, neonatal and adult cases, by means of quantitative autoradiography and membrane binding. [3H]8-OH-DPAT was used as a ligand. High densities of 5-HTtA receptors were found during the fetal and neonatal stages over the whole cerebellar cortex, with a slight predominance in the external part, in a band which included the molecular layer. In contrast, the adult cerebellum was nearly devoid of such sites. This tinding supports a role for 5-HT~.~ receptors in the regulation of development in the human cerebellum.

Research paper thumbnail of Supersensitivity to μ-opioid receptor-mediated inhibition of the adenylyl cyclase pathway involves pertussis toxin-resistant Gα protein subunits

Neuropharmacology, 2008

Sustained administration of opioids leads to antinociceptive tolerance, while prolonged associati... more Sustained administration of opioids leads to antinociceptive tolerance, while prolonged association of L-type Ca2+ channel blockers (e.g. nimodipine) with opioids results in increased antinociceptive response. Herein, we investigated the changes in mu-opioid receptor signalling underlying this shift from analgesic tolerance to supersensitivity. Thus, the interaction of mu-opioid receptors with G proteins and adenylyl cyclase was examined in lumbar spinal cord segments of rats. In control animals, the mu-opioid selective agonists, sufentanil and DAMGO, stimulated [35S]5'-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding and inhibited forskolin-stimulated adenylyl cyclase activity, through a mechanism involving pertussis toxin (PTX) sensitive G alpha(i/o) subunits. Seven days of chronic sufentanil treatment developed antinociceptive tolerance associated with a reduction in mu-agonist-induced [35S]GTP gamma S binding, mu-agonist-induced adenylyl cyclase inhibition, and co-precipitation of G alpha o, G alpha i2 G alpha z and G alpha q11 subunits with mu-opioid receptors. In contrast, combined nimodipine treatment with sufentanil over the same period increased the sufentanil analgesic response. This antinociceptive supersensitivity was accompanied by a significant increase of mu-agonist-induced inhibition of adenylyl cyclase that was resistant to the antagonism by PTX. In good agreement, co-precipitation of the PTX-resistant, G alpha z and G alpha q/11 subunits with mu-opioid receptors was not lowered. On the other hand, the PTX-sensitive subunits, G alpha i2 and G alpha o, as well as agonist-stimulated [35S]GTP gamma S binding were still reduced. Our results demonstrate that mu-opioid analgesic tolerance follows uncoupling of spinal mu-opioid receptors from their G proteins and linked effector pathways. Conversely, the enhanced analgesic response following combined nimodipine treatment with sufentanil is associated with adenylyl cyclase supersensitivity to the opioid inhibitory effect through a mechanism involving PTX-resistant G protein subunits.

Research paper thumbnail of The endocannabinoid system in mental disorders: Evidence from human brain studies

Biochemical pharmacology, Jan 17, 2018

Mental disorders have a high prevalence compared with many other health conditions and are the le... more Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, th...

Research paper thumbnail of Targeting β-Catenin in GLAST-Expressing Cells: Impact on Anxiety and Depression-Related Behavior and Hippocampal Proliferation

Molecular neurobiology, Jan 8, 2018

β-catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood ... more β-catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood disorders, associated to neurogenesis and neuroplasticity. Decreased β-catenin protein levels have been observed in the hippocampus and prefrontal cortex of depressed subjects. Additionally, the antidepressants exert, at least in part, their neurogenic effects by increasing β-catenin levels in the subgranular zone of the hippocampus. To further understand the role of β-catenin in depression and anxiety, we generated two conditional transgenic mice in which β-catenin was either inactivated or stabilized in cells expressing CreERT under the control of the astrocyte-specific glutamate transporter (GLAST) promoter inducible by tamoxifen, which presents high expression levels on the subgranular zone of the hippocampus. Here, we show that β-catenin inactivation in GLAST-expressing cells enhanced anxious/depressive-like responses. These behavioral changes were associated with impaired hippocamp...

Research paper thumbnail of Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation

ACS chemical neuroscience, Nov 18, 2017

Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although th... more Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT1AR activation might predispose to a high ...

Research paper thumbnail of Effects of spinal administration of amitryptiline, venlafaxine and fluoxetine on C-fibre and A-fibre evoked responses of dorsal horn neurones

Research paper thumbnail of Chronic (-) cannabidiol improves depressive-like behaviors in OBX mice likely via 5-HT1A and CB1 receptor modulation

Comunicacion presentada al: "First Joint Spanish-Italian Meeting on Cannabinoid Research&quo... more Comunicacion presentada al: "First Joint Spanish-Italian Meeting on Cannabinoid Research" celebrado del 29 de noviembre al 1 de diciembre de 2012 en Madrid.

Research paper thumbnail of Sex differences in hippocampal functionality in mice overexpressing postsynaptic 5-HT1A receptors

Ministerio de Ciencia e Innovacion (SAF07-61862; SAF2011-25020). Deutscher Akademischer Austausch... more Ministerio de Ciencia e Innovacion (SAF07-61862; SAF2011-25020). Deutscher Akademischer Austausch Dienst (DAAD; D/11/ 42325)

Research paper thumbnail of Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation

Pain, 1997

The effects of the intrathecal (i.t.) administration of different voltage-sensitive calcium chann... more The effects of the intrathecal (i.t.) administration of different voltage-sensitive calcium channel (VSCC) blockers were studied in the formalin model of inflammation. The responses of convergent dorsal horn neurones after the subcutaneous injection of formalin (5% formaldehyde, 50 ml volume) were recorded extracellularly in rats under halothane anaesthesia. Administration of the L-type calcium channel blocker verapamil, 5 and 50 mg, before formalin injection had no effect on either the first or second phase of the formalin response. Pre-treatment with the N-type calcium channel blocker q-Conotoxin-GVIA, 0.1 and 0.4 mg, reduced both phases of the formalin response. The low dose of q-Conotoxin-GVIA significantly inhibited the first phase response whereas the high dose significantly reduced the second phase. Pre-treatment with the P-type calcium channel blocker q-Agatoxin-IVA, 0.125 and 0.5 mg, did not cause a significant inhibition of the first phase whereas a marked dose-related reduction in the second phase of formalin response was found with the high dose producing 95% inhibition. These results demonstrate that spinal N-and P-type, but not L-type, VSCCs are involved in the inflammation-evoked hyperexcitability of dorsal horn neurones after peripheral formalin injection. Since selective antagonists for each type of VSCC had differential effects on the formalin response, it is suggested that each type of VSCC could be preferentially regulating or coupled to the release of certain neurotransmitters in the enhanced nociceptive transmission at the spinal level following formalin inflammation.

Research paper thumbnail of WAY100635 prevents the changes induced by fluoxetine upon the 5-HT1A receptor functionality

Neuropharmacology, 2008

5-HT1A receptor-mediated signalling in rat brain was evaluated after chronic administration (14 d... more 5-HT1A receptor-mediated signalling in rat brain was evaluated after chronic administration (14 days; s.c.) of the selective serotonin reuptake inhibitor (SRRI) fluoxetine (10 mg/kg/day) alone, or in combination with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg/day). The density of 5-HT1A binding sites was unchanged following fluoxetine, WAY100635, or the combination of fluoxetine and WAY100635. However, the net stimulation of [35S]GTPgammaS binding induced by the 5-HT1A agonist 8-OH-DPAT was significantly attenuated in dorsal raphe nucleus (DRN), but not in hippocampus, after chronic fluoxetine. Moreover, depending of the area analysed, the basal binding of [35S]GTPgammaS was differentially affected by this treatment: increased in DRN and decreased in hippocampal dentate gyrus. Interestingly, the changes in [35S]GTPgammaS basal binding and on 5-HT1A receptors functionality were prevented by the concomitant administration of WAY100635. The inhibition of dorsal raphe firing by...

Research paper thumbnail of Calcium Channel Antagonists and the Control of Pain

Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery, Second Edition, 2003

Research paper thumbnail of Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT4 receptor agonist RS67333

The International Journal of Neuropsychopharmacology, 2011

It has been recently suggested that activation of 5-HT 4 receptors might exert antidepressant-lik... more It has been recently suggested that activation of 5-HT 4 receptors might exert antidepressant-like effects in rats after 3 d treatment, suggesting a new strategy for developing faster-acting antidepressants. We studied the effects of 3 d and 7 d treatment with the 5-HT 4 receptor partial agonist RS67333 (1.5 mg/kg.d) in behavioural tests of chronic efficacy and on neuroplastic-associated changes, such as adult hippocampal neurogenesis, expression of CREB, BDNF, b-catenin, AKT and 5-HT 4 receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, b-catenin expression and pCREB/CREB ratio after 3 d treatment. This short-term treatment also reduced immobility time in the forced swim test (FST), together with a partial reversion of the anhedonic-like state (sucrose consumption after chronic corticosterone). Administration of RS67333 for 7 d resulted in a higher increase in the rate of hippocampal cell proliferation, a significant desensitization of 5-HT 4 receptor-coupled adenylate cyclase activity and a more marked increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT) : these changes reached the same magnitude as those observed after 3 wk administration of classical antidepressants. Consistently, a positive behavioural response in the novelty suppressed feeding (NSF) test and a complete reversion of the anhedonic-like state (sucrose consumption) were also observed after 7 d treatment. These results support the antidepressant-like profile of RS67333 with a shorter onset of action and suggest that this time period of administration (3-7 d) could be a good approximation to experimentally predict the onset of action of this promising strategy.

Research paper thumbnail of Serotonin 5-HT4 Receptors: A New Strategy for Developing Fast Acting Antidepressants?

Current Pharmaceutical Design, 2014

Research paper thumbnail of Neural Plasticity and Proliferation in the Generation of Antidepressant Effects: Hippocampal Implication

Neural Plasticity, 2013

It is widely accepted that changes underlying depression and antidepressant-like effects involve ... more It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as...

Research paper thumbnail of Neurotransmisión serotoninérgica

Neurofarmacología Contemporánea, 2011

Research paper thumbnail of Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment

Psychopharmacology, 2013

Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug... more Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT(1B) receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial. The aim of this study was to evaluate the effect of venlafaxine (10 mg kg⁻¹ day⁻¹, p.o.) after 21 days of treatment on the density of 5-HT(1B) receptors and their functionality in rat brain. Effects of chronic venlafaxine were evaluated at different levels of 5-HT(1B) receptor by using receptor autoradiography, [³⁵S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT(1B) agonist. Our results show that venlafaxine induced an increase in sensitivity of 5-HT(1B) receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density. These results demonstrate that adaptive changes on 5-HT(1B) receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.

Research paper thumbnail of Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

Research paper thumbnail of Opioid tolerance and supersensitivity induce regional changes in the autoradiographic density of dihydropyridine-sensitive calcium channels in the rat central nervous system

Pain, 2000

Chronic opioid administration induces adaptations in neurones resulting in opioid tolerance and d... more Chronic opioid administration induces adaptations in neurones resulting in opioid tolerance and dependence. The changes in dihydropyridine (DHP)-sensitive Ca 21 channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the m-opioid receptor agonist sufentanil were analyzed in the central nervous system (CNS) of rats. Autoradiographic assays were performed with [ 3 H]PN-200-110 (isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate). Chronic s.c. infusion of sufentanil (2 mg/h) for 7 days, which has been shown to induce tolerance to the opioid antinociceptive effect, produced an upregulation of DHP binding sites. The highest increases in density were localized in regions involved in nociceptive transmission and perception, such as the dorsal horn of the spinal cord, the dorsal raphe nucleus, the central grey matter, the thalamic nuclei, and the somatosensory cortex. Animals were rendered supersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 mg/h) and nimodipine (1 mg/h) for 7 days. Under these conditions, a greater increase in the number of DHP binding sites was observed in the spinal cord, central grey matter, dorsal raphe nucleus, and somatosensory neocortex, when compared to the sufentanil group. The role of an increased in¯ux through L-type channels in opioid tolerance is reinforced, whereas their persistent blockade is essential for the expression of opioid supersensitivity.

Research paper thumbnail of Regionally specific age-dependent decline in α2-adrenoceptors: An autoradiographic study in human brain

Neuroscience Letters, 1991

Research paper thumbnail of Differential adaptive changes on serotonin and noradrenaline transporters in a rat model of peripheral neuropathic pain

Neuroscience Letters, 2012

Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in ... more Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in several animal models of neuropathic pain. In the present work, we have analyzed the density of brain and spinal serotonin and noradrenaline transporters (5-HTT and NAT) in a rat model of neuropathic pain, the spinal nerve ligation (SNL). Quantitative autoradiography revealed a significant decrease in the density of 5-HTT ([ 3 H]citalopram binding) at the level of the lumbar spinal cord following 2 weeks of neuropathic surgery (lamina V, −40%: 6.01 ± 0.64 nCi/mg tissue in sham-animals vs 3.59 ± 1.56 in SNL-animals; lamina X, −30%: 9.10 ± 2.00 vs 6.40 ± 1.93 and lamina IX, −22%: 12.01 ± 2.41 vs 9.42 ± 1.58). By contrast, NAT density ([ 3 H]nisoxetine binding) was significantly increased (lamina I-II, +34%: 2.20 ± 0.45 vs 2.96 ± 0.65;

Research paper thumbnail of Transient localization of 5-HT1A receptors in human cerebellum during development

Neuroscience Letters, 1994

The appearance and distribution of 5-HTIA receptors in the human cerebellum during the ontogeneti... more The appearance and distribution of 5-HTIA receptors in the human cerebellum during the ontogenetic development was studied in samples from a group of fetal, neonatal and adult cases, by means of quantitative autoradiography and membrane binding. [3H]8-OH-DPAT was used as a ligand. High densities of 5-HTtA receptors were found during the fetal and neonatal stages over the whole cerebellar cortex, with a slight predominance in the external part, in a band which included the molecular layer. In contrast, the adult cerebellum was nearly devoid of such sites. This tinding supports a role for 5-HT~.~ receptors in the regulation of development in the human cerebellum.

Research paper thumbnail of Supersensitivity to μ-opioid receptor-mediated inhibition of the adenylyl cyclase pathway involves pertussis toxin-resistant Gα protein subunits

Neuropharmacology, 2008

Sustained administration of opioids leads to antinociceptive tolerance, while prolonged associati... more Sustained administration of opioids leads to antinociceptive tolerance, while prolonged association of L-type Ca2+ channel blockers (e.g. nimodipine) with opioids results in increased antinociceptive response. Herein, we investigated the changes in mu-opioid receptor signalling underlying this shift from analgesic tolerance to supersensitivity. Thus, the interaction of mu-opioid receptors with G proteins and adenylyl cyclase was examined in lumbar spinal cord segments of rats. In control animals, the mu-opioid selective agonists, sufentanil and DAMGO, stimulated [35S]5'-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding and inhibited forskolin-stimulated adenylyl cyclase activity, through a mechanism involving pertussis toxin (PTX) sensitive G alpha(i/o) subunits. Seven days of chronic sufentanil treatment developed antinociceptive tolerance associated with a reduction in mu-agonist-induced [35S]GTP gamma S binding, mu-agonist-induced adenylyl cyclase inhibition, and co-precipitation of G alpha o, G alpha i2 G alpha z and G alpha q11 subunits with mu-opioid receptors. In contrast, combined nimodipine treatment with sufentanil over the same period increased the sufentanil analgesic response. This antinociceptive supersensitivity was accompanied by a significant increase of mu-agonist-induced inhibition of adenylyl cyclase that was resistant to the antagonism by PTX. In good agreement, co-precipitation of the PTX-resistant, G alpha z and G alpha q/11 subunits with mu-opioid receptors was not lowered. On the other hand, the PTX-sensitive subunits, G alpha i2 and G alpha o, as well as agonist-stimulated [35S]GTP gamma S binding were still reduced. Our results demonstrate that mu-opioid analgesic tolerance follows uncoupling of spinal mu-opioid receptors from their G proteins and linked effector pathways. Conversely, the enhanced analgesic response following combined nimodipine treatment with sufentanil is associated with adenylyl cyclase supersensitivity to the opioid inhibitory effect through a mechanism involving PTX-resistant G protein subunits.