Barriers to promote cardiovascular health in community pharmacies: a systematic review.

Community pharmacists play an important role in the provision of health promotion services, and community pharmacies are considered as a potentially ideal site for cardiovascular health promotion. Information based on a systematic review of barriers to promoting cardiovascular health in community pharmacy is currently lacking. We have sought to identify the most important barriers to cardiovascular health promotion in the community pharmacy. We have systematically searched PubMed and International Pharmaceutical Abstracts for a period of 15 years from 1 April 1998 to 1 April 2013, contacted subject experts and hand-searched bibliographies. We have included peer-reviewed articles, with English abstracts in the analysis, if they reported community pharmacists' perceptions of the barriers to cardiovascular health promotion activities in a community pharmacy setting. Two reviewers have independently extracted study characteristics and data. We identified 24 studies that satisfy the eligibility criteria. The main barriers to cardiovascular health promotion in the community pharmacy included pharmacist-related factors; practice site factors; financial factors; legal factors; and patient-related factors. This review will help to provide reliable evidence for health promotion practitioners of the barriers to promoting cardiovascular health in the community pharmacy setting. This knowledge is valuable for the improvement of cardiovascular health promotion in this setting and guiding future research.

[Evaluation of a nutritional intervention among elderly people: the Edumay project]. / Evaluación de una intervención nutricional en personas mayores: el proyecto Edumay.

BACKGROUND: The adherence to a Mediterranean Dietary Pattern is associated with a morbi-mortality reduction, and with a better quality of life. OBJECTIVES: To evaluate a nutritional intervention among independent elderly people enrolled in an educational program to increase the knowledge of the food and daily diets, promoting a healthy dietary pattern. METHODS: Quasi-experimental design conducted in elderly participants who lived in foster home apartments owned by the City Council of Pamplona (n = 41). The intervention was based on six group sessions and an individual motivational session in a period of three months. Adherence to Mediterranean diet was evaluated through a 14-point scale previously validated. RESULTS: Eighty point five per cent of participants were women, with a median age of 79 years, the majority of them widowed (48.8%) and with primary education (58.5%). After the nutritional intervention the percentage of participants who consumed two or more servings of vegetables increased significantly versus the control group (p = 0.042). Similarly, in comparison with the control group, there was an increase in the percentage of participants who consumed three servings per week of legumes (p = 0.042), three or more servings per week of nuts (p = 0.003), and those who consumed preferably meat from chicken, turkey, or rabbit instead of veal, pork, hamburgers, or sausages (p = 0.011). DISCUSSION: An intervention based on individual and group sessions improved significantly several parameters of a Mediterranean dietary pattern.

INTRODUCCIÓN: La adhesión a un patrón de Dieta Mediterránea está asociado a una reducción de la morbi-mortalidad, y a una mejora de la calidad de vida. OBJETIVOS: Evaluar una intervención nutricional en personas mayores independientes a través de un programa de educación que favorezca el conocimiento de los alimentos y la confección de dietas adecuadas, promocionando un patrón de dieta saludable. MÉTODOS: Estudio cuasi-experimental realizado en un colectivo de personas mayores que residen en apartamentos tutelados del Ayuntamiento de Pamplona (n = 41). La intervención consistió en seis sesiones de educación grupal y una entrevista motivacional individual en un periodo de tres meses. Se evaluó la adhesión a la Dieta Mediterránea a través de un cuestionario de 14 puntos previamente validado. RESULTADOS: El 80,5% de los participantes fueron mujeres, con una mediana de edad de 79 años, en gran proporción viudas (48,8%) y con estudios primarios (58,5%). Tras la intervención nutricional el porcentaje de participantes que consumió dos o más raciones de verduras u hortalizas aumentó significativamente con respecto al grupo control (p = 0,042). De forma similar en comparación con el grupo control hubo un mayor incremento en el porcentaje de individuos que consumían 3 raciones de legumbres a la semana (p = 0,042), 3 o más veces por semana frutos secos (p = 0,003) y que tomaban preferentemente carne de pollo, pavo o conejo en vez de ternera, cerdo, hamburguesas o salchichas (p = 0,011). DISCUSIÓN: Una intervención basada en educación nutricional individual y grupal consiguió una mejora significativa en diversos parámetros de adhesión a un patrón de Dieta Mediterránea.

Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvement of the HPA axis.

Adverse experiences early in life may sensitize specific neurocircuits to subsequent stressors. We have evaluated in maternal separation (MS) rats, an animal paradigm of early-life stress, the effects of a selective cholinergic lesion on cognitive function as well as susceptibility of cholinergic neurons to the lesion. MS rats subjected to a cholinergic lesion by administration of the immunotoxin 192 IgG-saporin, showed significant decreases in both choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity compared to control lesioned rats. Morris water maze results revealed a significant impairment in learning and memory function in MS adult rats and further cognitive deficits after the lesion. The lesion of cholinergic neurons induced a significant decrease in glucocorticoid receptor density in MS rats, accompanied by increases in CRF mRNA expression. Decreases in NGF and increases in NGF-p75NTR expression have also been found in MS rats. Our results suggest that vulnerability of basal forebrain cholinergic nerve cells might be affected by the HPA axis. The present data are discussed not only in terms of conditions that occur during ageing or Alzheimer disease, but also regarding a purported involvement of the cholinergic system in the regulation of HPA axis activity.

Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: implications for spatial memory.

Early stressful adverse situations may increase the vulnerability to cognitive deficits and psychiatric disorders, such as depression. Maternal separation (MS) has been used as an animal model to study changes in neurochemistry and behavior associated with exposure to early-life stress. This study investigated the effects of neonatal stress (MS) on the expression of synaptic plasticity markers in the hippocampus and a purported relationship to cognitive processes. Spatial learning (Morris water maze) significantly increased the expression of total levels of the neural cell adhesion molecule (NCAM), as well as its three major isoforms (NCAM-120, -140, and -180) both in the control and MS groups. Interestingly, these increases in NCAM expression after learning were lower in MS animals when compared with control rats. MS induced a significant decrease in total levels of NCAM, and specifically, in the NCAM-140 isoform expression. In the hippocampus of MS rats there was a significant decrease in brain-derived neurotrophic factor and synaptophysin mRNA densities. Cell proliferation, measured as BrdU-positive cells, was also decreased in the dentate gyrus of MS rats. Altogether these results suggest that MS can alter normal brain development, providing a potential mechanism by which early environmental stressors may influence vulnerability to show cognitive impairments later in life.

Phosphodiesterase 5 inhibitors prevent 3,4-methylenedioxymethamphetamine-induced 5-HT deficits in the rat.

Phosphodiesterase 5 (PDE5) inhibitors are often used in combination with club drugs such as 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). We investigated the consequences of such combination in the serotonergic system of the rat. Oral administration of sildenafil citrate (1.5 or 8 mg/kg) increased brain cGMP levels and protected in a dose-dependent manner against 5-hydroxytryptamine depletions caused by MDMA (3 x 5 mg/kg, i.p., every 2 h) in the striatum, frontal cortex and hippocampus without altering the acute hyperthermic response to MDMA. Intrastriatal administration of the protein kinase G (PKG) inhibitor, KT5823 [(9S, 10R, 12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester)], suppressed sildenafil-mediated protection. By contrast, the cell permeable cGMP analogue, 8-bromoguanosine cyclic 3',5'-monophosphate, mimicked sildenafil effects further suggesting the involvement of the PKG pathway in mediating sildenafil protection. Because mitochondrial ATP-sensitive K(+) channels are a target for PKG, we next administered the specific mitochondrial ATP-sensitive K(+) channel blocker, 5-hydroxydecanoic acid, 30 min before sildenafil. 5-hydroxydecanoic acid completely reversed the protection afforded by sildenafil, thereby implicating the involvement of mitochondrial ATP-sensitive K(+) channels. Sildenafil also increased Akt phosphorylation, and so the possible involvement of the Akt/endothelial nitric oxide synthase (eNOS)/sGC signalling pathway was analysed. Neither the phosphatidylinositol 3-kinase inhibitor, wortmannin, nor the selective eNOS inhibitor, L-N5-(1-iminoethyl)-L-ornithine dihydrochloride, reversed the protection afforded by sildenafil, suggesting that Akt/eNOS/sGC cascade does not participate in the protective mechanisms. Our data also show that the protective effect of sildenafil can be extended to vardenafil, another PDE5 inhibitor. In conclusion, sildenafil protects against MDMA-induced long-term reduction of indoles by a mechanism involving increased production of cGMP and subsequent activation of PKG and mitochondrial ATP-sensitive K(+) channel opening.

On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats.

The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15 mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2 mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5 mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 degrees C but not in those treated at 15 degrees C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100 microM for 5h) combined with tyrosine (0.5 mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.

The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity.

RATIONALE: A close relationship appears to exist between 3,4-methylenedioxymethamphetamine (MDMA)-induced changes in core body temperature and long-term serotonin (5-HT) loss. OBJECTIVE: We investigated whether changes in core body temperature affect MDMA metabolism. MATERIALS AND METHODS: Male Wistar rats were treated with MDMA at ambient temperatures of 15, 21.5, or 30 degrees C to prevent or exacerbate MDMA-induced hyperthermia. Plasma concentrations of MDMA and its main metabolites were determined for 6 h. Seven days later, animals were killed and brain indole content was measured. RESULTS: The administration of MDMA at 15 degrees C blocked the hyperthermic response and long-term 5-HT depletion found in rats treated at 21.5 degrees C. At 15 degrees C, plasma concentrations of MDMA were significantly increased, whereas those of three of its main metabolites were reduced when compared to rats treated at 21.5 degrees C. By contrast, hyperthermia and indole deficits were exacerbated in rats treated at 30 degrees C. Noteworthy, plasma concentrations of MDMA metabolites were greatly enhanced in these animals. Instrastriatal perfusion of MDMA (100 microM for 5 h at 21 degrees C) did not potentiate the long-term depletion of 5-HT after systemic MDMA. Furthermore, interfering in MDMA metabolism using the catechol-O-methyltransferase inhibitor entacapone potentiated the neurotoxicity of MDMA, indicating that metabolites that are substrates for this enzyme may contribute to neurotoxicity. CONCLUSIONS: This is the first report showing a direct relationship between core body temperature and MDMA metabolism. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use, as hyperthermia is often associated with MDMA use in humans.

Minoxidil prevents 3,4-methylenedioxymethamphetamine-induced serotonin depletions: role of mitochondrial ATP-sensitive potassium channels, Akt and ERK.

Preconditioning has emerged as a valid strategy against different neurotoxic insults. Although the mechanisms underlying preconditioning are not fully understood, the activation of ATP-sensitive potassium (KATP) channels has been proposed to play a pivotal role in neuronal preconditioning. In the present work we examine whether minoxidil a KATP channel activator protects against the long-term toxicity caused by the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) in rats. Our data show that intrastriatal administration of minoxidil prevents MDMA-induced long-term indole depletions in the rat striatum. This effect was not related to an effect on core temperature, as pre-treatment with minoxidil did not significantly alter MDMA-induced hyperthermia. Taking into account that minoxidil opens both sarcolemmal and mitochondrial KATP channels, we examined the role of each type of channels in the protective effects of minoxidil using specific inhibitors. The administration of HMR-1098, a blocker of the sarcolemmal KATP channels, along with minoxidil did not affect the protection afforded by the latter. On the contrary the selective mitochondrial KATP channel blocker 5-hydroxydecanoic acid completely reversed the protection afforded by minoxidil, thereby implicating the involvement of mitochondrial (but not sarcolemmal) KATP channels. Furthermore our data show the participation of Akt and extracellular signal-regulated kinases in minoxidil-afforded protection. Intrastriatal administration of wortmannin or PD98059 (inhibitors of phosphatidylinositol-3-kinase and mitogen-activated protein kinase/extracellular regulated protein kinase, respectively), along with minoxidil abolished the protective effect of minoxidil against the serotonergic toxicity caused by MDMA. These results demonstrate that minoxidil by opening mitochondrial KATP channels completely prevents MDMA toxicity and that Akt and MAP kinases are involved in minoxidil-afforded neuroprotection.

Factors that influence under-reporting of suspected adverse drug reactions among community pharmacists in a Spanish region.

BACKGROUND: The spontaneous reporting system is the most efficient warning system of adverse drug reactions (ADRs). Pharmacists can play an important role in the detection and reporting of ADRs. The factors that affect under-reporting among these professionals are unknown in Spain. OBJECTIVE: To identify the factors that influence community pharmacists' ADR under-reporting in Navarra, a Northern Spanish region. METHODS: A case-control study was conducted on a population of 802 community pharmacists working in Navarra. Cases were pharmacists who had reported at least two ADRs to the region's drug surveillance unit between 2003 and 2005 and who agreed to participate in the study (18/20; 90%). A random sample of 60 controls was selected from the 762 pharmacists who had not reported any ADR during the same period of time. RESULTS: Factors positively associated with ADR reporting were age, years of work experience as a pharmacist, participation in educational activities related to the detection and resolution of drug-related problems, the habit of detecting ADRs as part of pharmacists' duties, having the basic knowledge needed to report ADRs, and disagreement with the common belief among healthcare professionals that 'to report an ADR it is necessary to be sure that the reaction is related to the use of a particular drug'. The most frequently mentioned reasons for not reporting ADRs were the ADR is not serious, the ADR is already known, uncertainty concerning the causal relationship between the ADR and the drug, forgetting to report the ADR and a lack of time. CONCLUSIONS: Pharmacists' knowledge, beliefs, behaviour and motivation play an important role in ADR reporting. Under-reporting might be improved through activities focused on modifying such factors.

Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats.

Exposure to early stressful adverse life events may increase vulnerability to psychopathology in adult life. There are important memory disturbances in stress-related psychiatric disorders. Therefore, there is much interest in understanding the mechanisms responsible for interactions between stress and cognition. Male Wistar rats that experienced 3-h daily separations from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood a depressive-like behaviour in the forced swimming test, increased hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stressors and elevated CRF mRNA in the paraventricular nucleus of the hypothalamus (PVN). In the hippocampus of MS rats, there was a lower glucocorticoid receptor density. MS produced significant learning impairments both in the Morris water maze and in the novel object recognition test (NORT). The glucocorticoid receptor antagonist mifepristone and the beta-adrenoceptor antagonist propranolol were able to completely reverse the increased immobility time in the forced swimming test and the memory deficits in the NORT observed in MS rats. Our data support the hypothesis that elevated secretion of glucocorticoids may be associated to behavioural and cognitive deficits in MS rats. The stress hyperresponsiveness observed in MS rats could be attributed, at least in part, to an impaired feedback sensitivity mediated by hippocampal glucocorticoid receptors. It can also be suggested the possible involvement of the noradrenergic system in cognitive impairments mediated by glucocorticoids in the MS model.

Studies on the mechanisms underlying amiloride enhancement of 3,4-methylenedioxymethamphetamine-induced serotonin depletion in rats.

Amiloride and several of its congeners known to block the Na(+)/Ca(2+) and/or Na(+)/H(+) antiporters potentiate methamphetamine-induced neurotoxicity without altering methamphetamine-induced hyperthermia. We now examine whether amiloride also exacerbates 3,4-methylenedioxymethamphetamine (MDMA)-induced long-term serotonin (5-HT) loss in rats. Amiloride (2.5 mg/kg, every 2 h x 3, i.p.) given at ambient temperature 30 min before MDMA (5 mg/kg, every 2 h x 3, i.p.), markedly exacerbated long-term 5-HT loss. However, in contrast to methamphetamine, amiloride also potentiated MDMA-induced hyperthermia. Fluoxetine (10 mg/kg i.p.) completely protected against 5-HT depletion caused by the MDMA/amiloride combination without significantly altering the hyperthermic response. By contrast, the calcium channel antagonists flunarizine or diltiazem did not afford any protection. Findings with MDMA and amiloride were extended to the highly selective Na(+)/H(+) exchange inhibitor dimethylamiloride, suggesting that the potentiating effects of amiloride are probably mediated by the blockade of Na(+)/H(+) exchange. When the MDMA/amiloride combination was administered at 15 degrees C hyperthermia did not develop and brain 5-HT concentrations remained unchanged 7 days later. Intrastriatal perfusion of MDMA (100 microM for 8 h) in combination with systemic amiloride caused a small depletion of striatal 5-HT content in animals made hyperthermic but not in the striatum of normothermic rats. These data suggest that enhancement of MDMA-induced 5-HT loss caused by amiloride or dimethylamiloride depends on their ability to enhance MDMA-induced hyperthermia. We hypothesise that blockade of Na(+)/H(+) exchange could synergize with hyperthermia to render 5-HT terminals more vulnerable to the toxic effects of MDMA.

Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory.

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.

Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions.

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.

Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation.

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.

GABA(A) receptor antagonists enhance cortical acetylcholine release induced by 5-HT(3) receptor blockade in freely moving rats.

ACh release from the rat frontal cortex was increased by both local, 0.1-1 microM, and systemic, 0.1-10 microg/kg, administration of the 5-HT(3) receptor antagonist ondansetron, reaching a maximum peak of 143% over basal values. Bicuculline, 1-10 microM, and flumazenil, 5-10 mg/kg, antagonists at different sites of the GABA(A) receptor, also enhanced ACh release, with maximum effects of 85 and 124% above baseline, respectively. GABA(A) receptor antagonists potentiated the effect induced by ondansetron on ACh release, reaching a peak increase of 238% (with bicuculline) and 259% (with flumazenil) over basal levels. These results suggest an interaction of ondansetron with GABAergic neurons modulating ACh release in the rat frontal cortex in vivo.

Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT(1A) receptors.

It has been proposed that 5-HT(1A) receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT(1A) receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]thiophene derivatives to arylpiperazines, typical 5-HT(1A) receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT(1A) receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT(1A) receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K(i) < 50 nM) and the 5-HT(1A) receptors (K(i) < 20 nM) were further explored for their ability to stimulate [(35)S]GTPgammaS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [(35)]GTPgammaS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT(1A) receptors, respectively. Compound 8g exhibited agonist activity (EC(50) = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,l antagonized the R(+)-8-OH-DPAT-stimulated GTPgammaS binding. Functional characterization was performed by measuring the antagonism to 8-OH-DPAT-induced hypothermia in mice.

Antidepressant-like activity of VN2222, a serotonin reuptake inhibitor with high affinity at 5-HT1A receptors.

It has been suggested that drugs combining serotonin (5-hydroxytryptamine, 5-HT) transporter blockade and 5-HT1A autoreceptor antagonism could be a novel strategy for a shorter onset of action and higher therapeutic efficacy of antidepressants. The present study was aimed at characterizing the pharmacology of 1-(3-benzo[b]tiophenyl)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanol (VN2222) a new synthetic compound with high affinity at both the 5-HT transporter and 5-HT1A receptors and devoid of high affinity at other receptors studied, with the only exception of alpha1-adrenoceptors. In keeping with the binding affinity at the 5-HT transporter, VN2222 inhibited 5-HT uptake in vitro both in rat cortical synaptosomes and in mesencephalic cultures and also in vivo when administered locally into the rat ventral hippocampus. After systemic administration, VN2222 exhibited an inverted U-shape effect so the inhibition of [3H]5-HT uptake ex vivo and the increase in 5-HT extracellular levels in microdialysis experiments was observed at low doses of 0.01-0.1 mg/kg whereas higher doses were ineffective. In studies related to 5-HT1A receptor function, 0.01-0.1 microM VN2222 produced a partial inhibition of forskolin-stimulated cAMP formation behaving as a weak agonist of 5-HT1A receptors. In body temperature studies, 5 mg/kg VN2222 produced a mild hypothermic effect in mice, suggesting a weak agonist activity at presynaptic 5-HT1A receptors; much lower doses (0.01-0.5 mg/kg) partially antagonized the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) possibly through 5-HT transporter blockade. In the learned helplessness test in rats, an animal model for antidepressants, 1-5 mg/kg VN2222 reduced significantly the number of escape failures. Consequently, VN2222 is a new compound with a dual effect on the serotonergic system, as 5-HT uptake blocker and 5-HT1A receptor partial agonist, and with a remarkable activity in an animal model of depression with high predictive validity.