Garcia-Alloza, M. (Mónica)
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- Involvement of the Serotonergic System in Cognitive and Behavioral Symptoms of Alzheimer's Disease(Bentham Science Publishers, 2005) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Garcia-Alloza, M. (Mónica); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)Alzheimer's disease (AD) is a chronic progressive disorder characterized by dementia, but often featuring behavioral and psychological syndromes (BPSD), such as depression, overactivity, psychosis or aggressive behavior. Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. Neurochemically, the classical hallmark of AD is the disruption of basal forebrain cholinergic pathways and consequent cortical cholinergic denervation of the neocortex and hippocampus. However, it is conceivable that, according to the complexity and diversity of BPSD, more than one transmitter system may contribute to a particular behavioral syndrome. The serotonergic system has been implicated not only in cognitive processes, but also in depression, psychosis or aggression. In AD, extensive serotonergic denervation has been reported. In particular, there is growing interest in the pathological functions and implication in BPSD of 5-HT6 receptors, due to its high affinity for antipsychotic drugs and its distribution in the brain. In this study we will review the present knowledge of the involvement of the serotonergic system and its receptors in cognitive deficits and BPSD. From the currently available data, it is possible to conclude that pharmacological manipulation of serotonergic system may improve not only cognitive function but behavioral disturbances in dementia.
- Involvement of an altered 5-HT -{6} receptor function in behavioral symptoms of Alzheimer's disease(Ios Press, 2008) Chuang, T.T. (Tsu T.); Ramirez, M.J. (María Javier); Tsang, S.W.T.Y. (Shirley W.T.Y.); Chen, C.P. (Christopher P.); Francis, P.T. (Paul T.); Garcia-Alloza, M. (Mónica); Lai, M.K. (Mitchell K.); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT_{6} receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02 +/- 27.53 pmol/mg prot.) compared to controls (823.33 +/-196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT_{6} receptor density was significantly lower (p< 0.01) in AD (6.67 +/- 0.83) compared to controls (16.67 +/- 3.33). Splitting these results by sex, 5-HT_{6} receptor activation was significantly lower (p< 0.01) in AD females compared to males (121.67 +/- 30.02 vs. 231.67 +/- 34.17 pmol/mg prot). 5-HT_{6} density and 5-HT levels were significantly correlated (p < or = 0.01) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT_{6} activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD.
- Involvement of the GABAergic system in depressive symptoms of Alzheimer's disease(Elsevier, 2005) Ramirez, M.J. (María Javier); Tsang, S.W.T.Y. (Shirley W.T.Y.); Chen, C.P. (Christopher P.); Francis, P.T. (Paul T.); Garcia-Alloza, M. (Mónica); Lai, M.K. (Mitchell K.); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)Cognitive and neuropsychiatric (BPSD) symptoms seen in Alzheimer's disease (AD) probably result from differential neurotransmitter alterations. The involvement of the glutamatergic and GABAergic system in cognitive and behavioral and psychological symptoms of dementia (BPSD) has been studied in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed with the Mini-Mental State Examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD. In addition to cholinergic deficits, significant decreases in gamma-amino butyric acid (GABA) content, with no changes in glutamate content, were found in frontal and temporal cortex. Both GABA levels and the glutamate/GABA ratio showed significant correlations with depression in AD. In the temporal cortex, higher densities of GABA(A)/benzodiazepine receptors also correlated with more severe depression. It can be suggested that in a situation of cholinergic deficit, such as AD, an imbalance between the excitatory glutamatergic tone and inhibitory GABAergic tone may be responsible for non-cognitive behavioral disturbances.
- Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release(Blackwell Publishing, 2006) Hirst, W.D. (Warren D.); Ramirez, M.J. (María Javier); Garcia-Alloza, M. (Mónica); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5-HT6 receptor antagonists led us to study the relationship between 5-HT6 receptors and cholinergic neurotransmission. A selective cholinergic lesion, induced by injection of the immunotoxin 192-IgG-Saporin into the nucleus basalis magnocellularis, failed to alter the density of 5-HT6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5-HT6 receptors are not located on cholinergic neurons. The 5-HT6 receptor antagonist SB-357134 (0.001-1 microM) induced a concentration-dependant K+-evoked [3H]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB-357134, up to 1 microM, stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 microM) blocked the SB-357134-induced K+-stimulated [3H]ACh release, and simultaneous administration of MK-801 (1 microM) and SB-357134 (0.05 microM) elicited an increase in K+-evoked ACh release. In the striatum, SB-357134, 1 microM, decreased dopamine release, and the increase in K+-evoked [3H]ACh release induced by 5-HT6 receptor blockade was reversed by the D1 receptor antagonist, SCH23390 (1 microM). In both the frontal cortex and striatum, bicuculline, 1 microM, showed no effect on SB-357134-evoked [3H]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5-HT6 receptor functions.
- Altered NCAM expression associated with the cholinergic system in Alzheimer's disease(Ios Press, 2010) Aisa, B. (Bárbara); Ramirez, M.J. (María Javier); Chen, C.P. (Christopher P.); Francis, P.T. (Paul T.); Garcia-Alloza, M. (Mónica); Lai, M.K. (Mitchell K.); Solas, M. (Maite); Gil-Bea, F.J. (Francisco J.)Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.
- Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease(Elsevier, 2005) Diez-Ariza, M. (Mónica); Ramirez, M.J. (María Javier); Chen, C.P. (Christopher P.); Francis, P.T. (Paul T.); Garcia-Alloza, M. (Mónica); Lasheras, B. (Berta); Gil-Bea, F.J. (Francisco J.)Neuropsychiatric symptoms seen in Alzheimer's disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic-serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.
- Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation(Elsevier, 2004) Ramirez, M.J. (María Javier); Garcia-Alloza, M. (Mónica); Lasheras, B. (Berta); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz); Dominguez, J. (Jon)We have studied the effects of concomitant blockade of 5-HT(3) and GABA(A) receptors on acetylcholine (ACh) release in the frontal cortex of rats with a selective cholinergic lesion. Lesions were performed by microinjection of the cholinergic toxin 192 IgG-saporin into the nucleus basalis magnocellularis. Single treatment with either the 5-HT(3) receptor antagonist ondansetron, 0.1 microg/kg, or the GABA(A) receptor benzodiazepine site antagonist flumazenil, 10 mg/kg, did not affect ACh release. However, the combined ondansetron + flumazenil administration significantly increased ACh release to a similar extent as a depolarising stimulus with K(+), 100 mM, at both 7 and 30 days post-lesion. Cortical perfusion with the combined ondansetron + flumazenil treatment also increased [(3)H]ACh efflux "in vitro" 30 days after lesion, suggesting that local events within the frontal cortex may participate in the interaction of ondansetron with GABAergic neurons, modulating ACh release in situations of cholinergic hypoactivity. No differences in the expression of 5-HT(3) and GABA(A) receptors in the frontal cortex were found after the cholinergic lesion. These results suggest that a combined ondansetron + flumazenil treatment would contribute to restoring a diminished cholinergic function and may provide a basis for using this treatment in the therapy of cognitive disorders associated with degeneration of the cholinergic system.
- Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit(Elsevier, 2005) Ramirez, M.J. (María Javier); Garcia-Alloza, M. (Mónica); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz); Dominguez, J. (Jon)Cognitive deficits in neuropsychiatric disorders, such as Alzheimer's disease (AD), have been closely related to cholinergic deficits. We have compared different markers of cholinergic function to assess the best biomarker of cognitive deficits associated to cholinergic hypoactivity. In post-mortem frontal cortex from AD patients, acetylcholine (ACh) levels, cholinacetyltransferase (ChAT) and acetylcholinesterase (AChE) activity were all reduced compared to controls. Both ChAT and AChE activity showed a significant correlation with cognitive deficits. In the frontal cortex of rats with a selective cholinergic lesion, all cholinergic parameters measured (ACh levels, ChAT and AChE activities, "in vitro" and "in vivo" basal ACh release) were significantly reduced. AChE activity was associated to ChAT activity, and even more, to "in vivo" and "in vitro" basal ACh release. Quantification of AChE activity is performed by an easy and cheap method and therefore, these results suggest that determination of AChE activity may be used as an effective first step method to evaluate cholinergic deficits.
- Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory(Lippincott Williams and Wilkins, 2006) Diez-Ariza, M. (Mónica); Ramirez, M.J. (María Javier); Garcia-Alloza, M. (Mónica); Zaldua, N. (Natalia); Lasheras, B. (Berta); Gil-Bea, F.J. (Francisco J.); Marcos, B. (Beatriz)The cholinergic system has been widely implicated in cognitive processes and cholinergic loss is a classical hallmark in Alzheimer disease. Increasing evidence supports a role of the serotonergic system in cognition, possibly through a modulation of cholinergic activity. We compared selective cholinergic denervation by administration of the immunotoxin 192 IgG-saporin in the nucleus basalis of Meynert (NBM) with intracerebroventricular (ICV) lesions of the basal forebrain in male rats 7 days after lesioning. NBM lesions induced significant changes in cholinergic markers in the frontal cortex, whereas ICV lesions produced significant decreases in cholinergic markers both in the frontal cortex and hippocampus. Only ICV lesions lead to memory impairments in passive avoidance and Morris water maze tasks. Both models lead to reductions of serotonin levels in the frontal cortex. Similar changes in 5-hydroxytriptophan levels were observed, suggesting a downregulation of the rate-limiting enzyme for the synthesis of serotonin along with the cholinergic deficit. Neither 5-HT1A nor 5-HT1B receptors seem to mediate this process. These data imply that the serotonergic system in the frontal cortex can compensate for diminished cholinergic function and support the investigation of the serotonergic system as a therapeutic target to treat Alzheimer disease.