Cannabis use influence on peripheral brain-derived neurotrophic factor levels in antipsychotic-naïve first-episode psychosis.

The objective of this study is to determine whether cannabis influences BDNF levels in patients with psychosis (FEP) and healthy volunteers (HV) to help understand the role of BDNF in psychosis. We assessed the association between BDNF and cannabis in a cohort of FEP antipsychotic-naïve patients and HV, whilst controlling for other potential confounding factors. 70 FEP drug-naive patients and 57 HV were recruited. A sociodemographic variable collection, structured clinical interview, weight and height measurement, substance use determination, and blood collection to determine BDNF levels by ELISA analysis were done. In FEP patients, cannabis use was associated with BDNF levels (high cannabis use was associated with lower BDNF levels). Moreover, cannabis use was statistically significantly associated with age (high use of cannabis was associated with younger age). In HV, no relationship between cannabis use and BDNF levels was observed. Otherwise, cannabis use was significantly associated with tobacco use, so that high cannabis users were also high tobacco users. This study showed a different association between cannabis use and BDNF levels in FEP patients compared with HV, particularly, with high doses of cannabis. These findings may help understand the deleterious effects of cannabis in some vulnerable individuals, as well as discrepancies in the literature.

Environmental enrichment in the absence of wheel running produces beneficial behavioural and anti-oxidative effects in rats.

The effects of early environmental enrichment (EE) when solving a simple spatial task in adult male rats were assessed. After weaning, rats were housed in pairs in enriched or standard cages (EE and control groups) for two and a half months. Then the rats were trained in a triangular-shaped pool to find a hidden platform whose location was defined in terms of two sources of information, a landmark outside the pool and a particular corner of the pool. As expected, enriched rats reached the platform faster than control animals. Enriched rats also performed better on a subsequent test trial without the platform with the geometry cue individually presented (in the absence of the landmark). Most importantly, the beneficial effects of the present protocol were obtained in the absence of wheel running. Additionally, the antioxidative effects in the hippocampus produced by the previous protocol are also shown.

Sex differences after environmental enrichment and physical exercise in rats when solving a navigation task.

The effects of early environmental enrichment (EE) and voluntary wheel running on the preference for using a landmark or pool geometry when solving a simple spatial task in adult male and female rats were assessed. After weaning, rats were housed in same-sex pairs in enriched or standard cages (EE and control groups) for two and a half months. Then the rats were trained in a triangular-shaped pool to find a hidden platform whose location was defined in terms of these two sources of information, a landmark outside the pool and a particular corner of the pool. As expected, enriched rats reached the platform faster than control animals, and males and females did not differ. Enriched rats also performed better on subsequent test trials without the platform with the cues individually presented (either pool geometry or landmark). However, on a preference test without the platform, a clear sex difference was found: Females spent more time in an area of the pool that corresponded to the landmark, whereas males spent more time in the distinctive corner of the pool. The present EE protocol did not alter females' preference for the landmark cue. The results agree with the claim that environmental enrichment is a consequence of a reduced anxiety response (measured by thigmotaxis) during cognitive testing. A possible implication of ancestral selection pressures is discussed.

Network analysis of gene expression in mice provides new evidence of involvement of the mTOR pathway in antipsychotic-induced extrapyramidal symptoms.

To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP-induced EPS and offers new and valuable markers for pharmacogenetic studies.

Role of oxidative stress and adenosine nucleotides in the liver of aging rats.

We studied the response of several parameters related to oxidative stress in the liver of aging rats. Male Wistar rats aged 1.5, 3, 18 and 24 months were used. Livers showed an increase in superoxide anion (O(2)(-)) concentration at 1.5 and 18 months of age compared to the 3-month-old group; a decrease in superoxide dismutase (SOD) was seen at 1.5 months and catalase concentrations remained unaltered throughout the aging process. Nitric oxide (NO) progressively declined with age; a significant decrease was particularly apparent at 18 and 24 months of age. Thiobarbituric acid reactive substances (TBARS) decreased significantly at 1.5 months, whereas it increased at 18 and 24 months of age. Concentrations of prostaglandin E(2) (PGE(2)), and adenine nucleotides, and their metabolites, remained unchanged throughout the aging process. Although the mitochondrial damage caused by oxidative stress can result in reduced ATP production and compromised cell function, our results on adenosine nucleotides and their metabolites support the notion that the integrity of mitochondria and enzymatic activity remain mostly unchanged with aging. In conclusion, we observed a significant decrease in the levels of NO in the older groups of rats and hence in its antioxidant activity. This could explain the observed increase in lipid peroxides which suggests an important role for NO in oxidative stress in the liver of older rats.

Toxicity and antioxidant activity in vitro and in vivo of two Fucus vesiculosus extracts.

The consumption of seaweeds has increased in recent years. However, their adverse and beneficial effects have scarcely been studied. Two extracts from the brown seaweed Fucus vesiculosus containing 28.8% polyphenols or 18% polyphenols plus 0.0012% fucoxanthin have been obtained and studied to determine their toxicity in mice and rats and also their antioxidant activity. Both extracts were shown to lack any relevant toxic effects in an acute toxicity test following a 4 week daily treatment in rats. The extracts exhibited antioxidant activity in noncellular systems and in activated RAW 264.7 macrophages, as well as in ex vivo assays in plasma and erythrocytes, after the 4 week treatment in rats. Our ex vivo results indicated that compounds from extract 2 may be more easily absorbed and that the antioxidants in their parent or metabolized form are more active. These findings support the view that the daily consumption of F. vesiculosus extract 2 (Healsea) would have potential benefits to humans.

Loss of adaptation to oxidative stress asa mechanism for aortic damage in aging rats

Cells are armed with a vast repertoire of antioxidant defence mechanisms to preventthe accumulation of oxidative damage. The cellular adaptive response is animportant antioxidant mechanism against physiological and pathophysiologicaloxidative alterations in a cell’s microenvironment. The aim of this paper was to study,in the rat aorta, whether this adaptive response and the inflammation associated withoxidative stress were expressed throughout the aging process. We examined the rataorta, as it is a very sensitive tissue to oxidative stress. Male Wistar rats of 1.5, 3, 12,18 and 24 months of age were used. Superoxide anion (O2-) generation; levels of twoantioxidant enzymes, superoxide dismutase (SOD) and catalase; and the levels ofprostaglandin E2 (PGE2), an inflammatory marker, were measured. The results forrats at different ages were compared with those for 3 months of age. A balancebetween production of O2- and SOD activity was found in the aorta of rats from 1.5to 12 months old. Oxidative stress was present in the aorta of old animals (18-24months), due to a failure in the mechanisms of adaptation to oxidative stress. Theobserved increase in PGE2 levels in these rats reflected an inflammatory response. Alltogether suggest that vascular oxidative stress and the inflammatory process observedin the old groups of rats could be closely related to vascular aging. Our results alsoremark the importance of the adaptative response to oxidative stress (AU)

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Loss of adaptation to oxidative stress as a mechanism for aortic damage in aging rats.

Cells are armed with a vast repertoire of antioxidant defence mechanisms to prevent the accumulation of oxidative damage. The cellular adaptive response is an important antioxidant mechanism against physiological and pathophysiological oxidative alterations in a cell's microenvironment. The aim of this paper was to study, in the rat aorta, whether this adaptive response and the inflammation associated with oxidative stress were expressed throughout the aging process. We examined the rat aorta, as it is a very sensitive tissue to oxidative stress. Male Wistar rats of 1.5, 3, 12, 18 and 24 months of age were used. Superoxide anion (O2(-)) generation; levels of two antioxidant enzymes, superoxide dismutase (SOD) and catalase; and the levels of prostaglandin E2 (PGE2), an inflammatory marker, were measured. The results for rats at different ages were compared with those for 3 months of age. A balance between production of O2(-) and SOD activity was found in the aorta of rats from 1.5 to 12 months old. Oxidative stress was present in the aorta of old animals (18-24 months), due to a failure in the mechanisms of adaptation to oxidative stress. The observed increase in PGE2 levels in these rats reflected an inflammatory response. All together suggest that vascular oxidative stress and the inflammatory process observed in the old groups of rats could be closely related to vascular aging. Our results also remark the importance of the adaptative response to oxidative stress.

Effects of phospholipid vesicles (liposomes) on cAMP levels in the rat cerebral cortex.

We studied the effects of two types of liposomes (cholate-free liposomes and cholate-containing liposomes) on control (in the presence of 3-isobutyl-1 methyl xanthine [IBMX], a phosphodiesterase inhibitor) and stimulated (IBMX plus isoprenaline) cyclic 3',5'-adenosine monophosphate (cAMP) accumulation in slices of rat cerebral cortex. Our purpose was to examine whether or not liposomes with different lipid constituents modify levels of cAMP in vitro. Liposomes at low concentrations had a significant inhibitory effect on cAMP accumulation in brain tissue. This inhibition was concentration-dependent. Cholate-containing liposomes had a greater inhibitory effect at higher concentrations. Liposomes also inhibited cAMP accumulation in a dose-dependent manner when the tissues were preincubated with ouabain, a Na(+)-K(+)-ATPase inhibitor. These results demonstrate that, in rat brain, liposomes alone modified important biochemical responses such as the adenylyl cyclase-cAMP system coupled to beta-adrenoceptors. The significance of these findings for the mechanism of the action of liposomes is discussed.

Influence of aging on thromboxane A2 and prostacyclin levels in rat hippocampal brain slices.

We have investigated the influence of age (3, 18, 24 months) on Thromboxane A2 (TXA2) and Prostacyclin (PGI2) levels in hippocampal slices from F344/NHSD rats. A significant increase in TXA2 and PGI2 levels was observed in 18 and 24 months old compared to 3 months old animals. A significant reduction in the ratio TXA2/PGI2 produced by a higher increase in PGI2 was observed in 24 month old animals. The reduction in the TXA2/PGI2 ratio has been related to vasodilatory and antiaggregating effects that may contribute to protect the brain against neuronal damage.

Early environmental stimulation produces long-lasting changes on beta-adrenoceptor transduction system.

Long-term behavioral and biochemical effects of exposure to differential early stimulation (postnatal handling and/or enriched environment) were studied in 18- to 20-month-old Sprague-Dawley rats. Postnatal handling treatment was given between 1 and 22 postnatal days. In the enriched environment procedure, the pups were maintained under enriched conditions from weaning until postnatal Day 100. At 18 months of age animals were tested for working memory in an object recognition test, based on the differential exploration of familiar and new objects. Animals reared in the enriched environment performed better in the working memory test than did control or postnatally handled rats. No interaction was observed between postnatal handling and environmental enrichment on cognitive parameters. At 20 months of age, the animals were sacrificed and cyclic AMP formation was determined under basal conditions and after activation of beta-adrenoceptors in cerebral cortex and hippocampus. Both postnatal handling and its combination with exposure to enriched environment significantly increased basal cyclic AMP accumulation in cerebral cortex, but not in the hippocampus. Environmental enrichment was able to induce a long-lasting modification in the responsiveness of the beta-adrenergic neurotransmitter system as reflected by a decreased cyclic AMP accumulation after beta-adrenoceptor activation by means of isoprenaline, in either anatomical structure. It is suggested that manipulations of the environment early in life leading to a reduction in age-related memory deficits produce subtle but long-lasting modifications of noradrenergic transmission.

Action on noradrenergic transmission of an anticholinesterase: 9-amino-1,2,3,4-tetrahydroacridine.

The mechanism by which 9-amino-1,2,3,4-tetrahydroacridine (THA) inhibits beta-adrenoceptor linked cyclic AMP formation and its possible relationship with the cholinergic system were studied. In addition, the effect of THA on alpha 1-adrenoceptor coupled transduction systems was also investigated. THA was not able to influence the concentration-response curve for forskolin indicating that it is not acting on the catalytic subunit of the adenylate cyclase complex. On the other hand a cholinergic component seems to participate in the action of THA on beta-adrenoceptor stimulated adenylate cyclase activity since the blockade of muscarinic receptors with atropine (10 microM) partially prevented the reduction in cyclic AMP formation attained by THA in the hippocampus, in isoprenaline-stimulated conditions. This effect is not reproducible by another potent anticholinesterase physostigmine. Moreover, THA at concentrations up to micromolar did not affect alpha 1-adrenoceptor stimulated cyclic AMP formation or phosphoinositide hydrolysis. In conclusion, the neuropharmacological profile of THA is not to be restricted to the cholinergic system and its effectiveness in improving age-associated cognitive deterioration may involve an action on the beta-adrenoceptor coupled signal transduction system. Moreover, the action of THA on the beta-adrenergic and cholinergic systems in the brain could be relevant to the amelioration of cognitive deterioration and could lead to the development of new therapeutic strategies.

Effects of age on alpha 1-adrenoceptor subtypes in the heart ventricular muscle of the rat.

The effects of ageing on alpha 1-adrenoceptor subtypes have been examined in heart ventricular muscle of young (2-3 months) and middle-aged (18 months) Sprague-Dawley rats. Radioligand binding studies with [3H]prazosin revealed an age-related loss of binding sites (Bmax 56.7 +/- 1.93 fmol (mg protein)-1 age 2 months vs 31.7 +/- 2.45 fmol (mg protein)-1 age 18 months) not followed by changes in the dissociation constant value (Kd 0.16 +/- 0.03 nM age 2 months and 0.10 +/- 0.03 nM age 18 months). Competition curves with WB 4101 showed two distinct sites with different affinities, the proportion of sites with high affinity being similar for both age groups (22.2 +/- 1.89% vs 17.8 +/- 1.96% for animals aged 2 and 18 months, respectively). Agonist displacement curves of [3H]prazosin indicate the existence of two different affinity sites for the agonist, that are maintained regardless of the ageing process (R(high) = 16.2 +/- 1.54% and R(low) = 83.8 +/- 1.89% in rats aged 2 months and R(high) = 16.3 +/- 3.23% and R(low) = 83.7 +/- 3.95% in rats aged 18 months). The fractional inactivation of alpha 1-adrenoceptors by chloroethylclonidine resulted in a loss of [3H]prazosin specific binding, and a percentage of 22.5 +/- 0.95 and 22.6 +/- 4.2 of remaining binding sites for the groups of 2 and 18 months of age, respectively. The percentage of chloroethylclonidine-insensitive [3H]prazosin binding sites was similar to those with high affinity for WB4101. The present study confirms a decline of alpha 1-adrenoceptors with increasing age and reveals that the equilibrium of the expression of the two existing subpopulations of the receptor is maintained during ageing.

Differential effects of physostigmine and 1,2,3,4-tetrahydro-9-aminoacridine on the beta-adrenoceptor transduction system.

The effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) and physostigmine on beta-adrenoceptor-linked cyclic AMP accumulation have been analyzed in vitro in rat cortex and hippocampus. A 10-min incubation with increasing concentrations of THA reduced isoprenaline (10 microM)-stimulated cyclic AMP accumulation in a concentration-dependent manner in cortical (IC50 = 1.31 +/- 0.13 microM) and hippocampal (IC50 = 0.02 +/- 0.003 microM) structures. Conversely, physostigmine did not modify cyclic AMP synthesis in any experimental condition. The action of THA was non-competitive since it induced a non-parallel shift to the right of the concentration-response curve for isoprenaline. The differential effects of THA and physostigmine on the beta-adrenoceptor transduction system may account for the difference in their ability to restore cognitive function.

Interactions of lithium with the adrenergic system in electrically-stimulated guinea pig myenteric plexus isolated preparations. Actions of a phosphodiesterase inhibitor.

The possible involvement of lithium in the mechanism of action of norepinephrine has been studied in electrically-stimulated preparations isolated from guinea pig myenteric plexus. Results show that concentrations of lithium above 0.5 x 10(-2) M significantly inhibit the norepinephrine effect. The results obtained when preparations were preincubated with alpha-adrenergic blocking agents (phenoxybenzamine and phentolamine) suggest a beta-adrenergic action of lithium since these substances induced 74% and 37% inhibition of the lithium effects, respectively. When preparations were preincubated with beta-adrenergic blocking agents (propranolol, toliprolol, atenolol and sotalol) the action of lithium was unchanged. A phosphodiesterase inhibitor also led to 50% inhibition of the lithium effects. These results, together with the fact that the adenylate cyclase cAMP system is linked directly to the beta-adrenoceptors, suggest that the inhibitory action of lithium on norepinephrine, in this preparation, is related to its beta-adrenergic action, which agrees with the results obtained in brain by other authors.

Post-train administration of 9-amino-1,2,3,4-tetrahydroacridine enhances passive avoidance retention and decreases beta-adrenoceptor-linked cyclic AMP formation in middle-aged rats.

The possible involvement of beta-adrenoceptor system in the effectiveness of 9-amino-1,2,3,4-tetrahydroacridine (THA) to attenuate retention deficits exhibited by middle-aged rats in a one-trial passive avoidance task has been investigated. THA (2.5 mg.kg-1), injected i.p. after training, induced a significant increase in test step-through latency (STL) in middle-aged rats. Post-training injection of THA reduced basal and isoprenaline stimulated cyclic AMP accumulation in cortex and hippocampus of every group of rats. It is suggested that the effect of THA on memory processes may involve an action on beta-adrenoceptor-linked cyclic AMP accumulation.

Demonstration of inhibition of cyclic AMP accumulation in brain by very low concentrations of lithium in the presence of alpha-adrenoceptor blockade.

In the present paper, we have studied the effect of lithium on cAMP levels induced by isoprenaline and norepinephrine in the presence of alpha- or beta-adrenoceptor antagonists. Our results show that low lithium concentrations, starting at 0.3 x 10(-3) M, have a significant inhibitory effect on cAMP content induced by isoprenaline in brain tissue pretreated with the alpha-adrenoceptor blocker phenoxybenzamine. On the other hand, the inhibitory effect of lithium on cAMP levels induced by norepinephrine when beta-adrenoceptors are blocked with propranolol, is observed at concentrations starting at 2.5 x 10(-3) M. These results show that in the presence of alpha blockade, low lithium concentrations which are within the therapeutic plasma range for treatment of manic patients, are able to act on an adenylate cyclase-cAMP system coupled to beta-adrenoceptors.

Acute effects of tetrahydroaminoacridine on beta-adrenoceptor-linked cyclic AMP accumulation in brain of young and middle-aged rats.

The effects of acute treatment with 1,2,3,4-tetrahydro-9-aminoacridine (THA), a 4-aminopyridine derivative clinically effective in Alzheimer's disease, on beta-adrenoceptor-linked cyclic AMP accumulation have been investigated in cortical and hippocampal structures of young and middle-aged rats. In a first series of experiments, pretreatment with 2.5 mg/kg THA decreased basal cyclic AMP accumulation. When a phosphodiesterase inhibitor was added to the preparation, THA again decreased cyclic AMP levels in young rats, but failed to significantly modify cyclic AMP accumulation in middle-aged animals. Finally, in isoprenaline-stimulated conditions, acute treatment with tacrine was able to diminish cyclic AMP accumulation in every group of rats. It is suggested that the neurochemical action of THA in mammalian brain is more complex than earlier has been anticipated and may involve an action on beta-adrenoceptors.

Chronic treatment of guinea pigs with lithium chloride: effects on myenteric plexus preparations and on cyclic AMP levels.

We studied the effects of lithium chloride, given i.p. in doses of 0.05, 1, 2, 4 and 8 mEq/kg twice daily for 14 days, on preparations of guinea pig myenteric plexus. The effects of lithium added to isolated myenteric plexus preparations derived from chronically treated animals showed that relatively low lithium concentrations produced a statistically significant decrease in the force of contraction, this effect being concentration-dependent. 3-Isobutyl-1-methylxanthine (IBMX) induced a statistically significant inhibition, between 30 and 50%, of the lithium effects. cAMP levels in animals treated chronically with lithium were studied, using an isotopic displacement technique. Our results show that only the highest dose of lithium (8 mEq/kg per day) significantly decreased basal levels of cAMP. In the presence of IBMX, low doses of lithium (1 mEq/kg per day) induced a very significant decrease in cAMP levels, but the inhibition remained constant, approximately 30-35%, at doses from 2 mEq/kg per day. In guinea pig myenteric plexus preparations from acutely treated animals, our results show a direct relationship between lithium concentration and inhibition of the cAMP accumulation induced by IBMX.