Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11.

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

Ginkgo biloba leaf extract (EGb 761®) and its specific acylated flavonol constituents increase dopamine and acetylcholine levels in the rat medial prefrontal cortex: possible implications for the cognitive enhancing properties of EGb 761®.

Experimental and clinical data suggest that the Ginkgo biloba standardized extract EGb 761® exerts beneficial effects in conditions which are associated with impaired cognitive function. However, the neurochemical correlates of these memory enhancing effects are not yet fully clarified. The aim of this study was to examine the effect of repeated oral administration of EGb 761® and some of its characteristic constituents on extracellular levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT), acetylcholine (ACh) and the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the medial prefrontal cortex (mPFC) of awake rats by use of in vivo microdialysis technique. Subacute (14 days, once daily), but not acute, oral treatment with EGb 761® (100 and 300 mg/kg) or the flavonoid fraction, which represents about 24% of the whole extract caused a significant and dose-dependent increase in extracellular DA levels in the mPFC. Repeated administration of EGb 761® also caused a modest but significant increase in the NA levels, whereas the concentrations of 5-HT and those of the metabolites DOPAC, HVA and 5-HIAA were not affected. The same treatment regimen was used in a subsequent study with the aim of investigating the effects of two Ginkgo-specific acylated flavonols, 3-O-(2''-O-(6'''-O-(p-hydroxy-trans-cinnamoyl)-ß-D-glucosyl)-α-L-rhamnosyl)quercetin (Q-ag) and 3-O-(2''-O-(6'''-O-(p-hydroxy-trans-cinnamoyl)-ß-D-glucosyl)-α-L-rhamnosyl)kaempferol (K-ag). Both compounds together represent about 4.5% of the whole extract. Repeated oral treatment with Q-ag (10 mg/kg) for 14 days caused a significant increase in extracellular DA levels of 159% and extracellular acetylcholine (ACh) levels of 151% compared to controls. Similarly, administration of K-ag (10 mg/kg) induced a significant rise of DA levels to 142% and ACh levels to 165% of controls, whereas treatment with isorhamnetin, an O-methylated aglycon component of EGb 761® flavonol glycosides had no effect. None of the tested flavonoids had a significant effect on extracellular DOPAC and HVA levels. The present findings provide evidence that the subacute treatment with EGb 761® and its flavonol constituents increases DA and ACh release in the rat mPFC, and suggest that the two Ginkgo-specific acylated flavonol glycosides Q-ag and K-ag are active constituents contributing to these effects. As seen for isorhamnetin, the effect on neurotransmitter levels seems not to be a general effect of flavonols but rather to be a specific action of acylated flavonol glycosides which are present in EGb 761®. The direct involvement of these two flavonol derivatives in the increase of dopaminergic and cholinergic neurotransmission in the prefrontal cortex may be one of the underlying mechanisms behind the reported effects of EGb 761® on the improvement of cognitive function.

Determination of histamine in microdialysis samples from Guinea pig skin by high-performance liquid chromatography with fluorescence detection.

AIM: To develop a sensitive and selective liquid-chromatographic method for the determination of histamine in microdialysis samples from guinea pig skin following allergenic provocation. METHODS: The novel fluorescence derivatization method is based on an intramolecular excimer-forming reaction between 2 amino moieties of histamine and 2 molecules of 4-(1-pyrene)butanoyl chloride (PBC) yielding the corresponding dipyrene-labeled derivative. RESULTS: The PBC derivative of histamine was separated within 20 min, and the detection limit (signal-to-noise ratio = 3) of histamine was 0.6 fmol/20 µl volume injected. The basal extracellular levels of histamine in guinea pig skin microdialysates were 20.6 ± 1.7 fmol/10 µl. Subcutaneous administration of histamine liberator compound 48/80 (3 mg/kg) increased the extracellular histamine levels in the skin dialysates by about 860%, whereas ovalbumin challenge (2 mg/kg i.v.) in the sensitized guinea pigs increased the extracellular histamine levels by about 3,030%. CONCLUSION: The novel technique for histamine determination in microdialysis samples from the guinea pig skin may be utilized in preclinical research of antihistaminergic drugs and evaluation of allergenic properties of various dermal preparations such as transdermal drug delivery systems.

Galanin differentially regulates acetylcholine release in ventral and dorsal hippocampus: a microdialysis study in awake rat.

The purpose of the present study was to investigate, by use of in vivo microdialysis technique, the regulatory role of galanin on acetylcholine (ACh) release in the CA1, CA3, and dentate gyrus (DG) subregions of rat dorsal and ventral hippocampus. In the ventral hippocampus, local infusions of galanin (1.5 nmol) into CA1, and CA3, but not DG (3 nmol), decreased basal ACh release to 58.6% and 68.4%, respectively. In addition, local infusion of galanin (1.5 nmol) into the ventral DG, and CA3 areas decreased basal ACh levels in the CA1 to 51.2% and 84%, respectively. This observation implies that the effects of galanin are unlikely to be mediated via galanin autoreceptors on the cholinergic terminals, but rather via mechanisms involving galanin internalization and modulation of hippocampo-septo-hippocampal loops, attenuation of the excitability of the principal cells, or indirect modulation by galanin-containing vasopressin terminals to the ventral and/or dorsal hippocampus. In the dorsal hippocampus, galanin infusion (1.5 nmol) into the CA1 region increased ACh release to 128.2% of the control levels, but infusions of galanin had no effects in the CA3 and DG. In all cases, the ACh levels returned to basal values within 100 min after the galanin infusion. It is concluded that the attenuating effects of galanin on ACh release in the ventral hippocampus and increase in ACh release in the dorsal hippocampus are in line and support the current view on molecular and functional distinction between the ventral hippocampus being involved preferentially in motivational and emotional behavior, whereas the dorsal hippocampus is primarily implicated in cognitive processes of learning and memory.

Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation.

Dysregulated cholinergic neurotransmission has been implicated in the pathophysiology of schizophrenia, particularly negative symptoms and cognitive deficits. The aim of the present study was to evaluate the role of neocortical cholinergic innervation and of the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on social interaction and novel object recognition (NOR), a declarative memory task. The cholinergic corticopetal projection was lesioned by local infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis of adult male Lister hooded rats. Behavior was assessed 2.5 weeks later in a social interaction paradigm followed by the NOR task. We found that selective cholinergic denervation of neocortex led to a significant reduction in duration of social interaction, specifically active social interaction. Acute administration of PCP (1.0 mg/kg, s.c.) caused a marked decrease of active social interaction, such that there was no longer a difference between intact and denervated animals. Neither cholinergic denervation alone, nor PCP (1.0 mg/kg, s.c.) alone blocked the ability of rats to recognize a novel object. However, when animals lacking cortical cholinergic innervation were challenged by PCP, they were no longer able to recognize a novel object. This study indicates that rats lacking cholinergic innervation of neocortex have impaired social interaction and specifically that the duration of active contact is shortened. Animals with severe cortical cholinergic hypofunction maintain the ability to perform in a declarative memory test, although the task is carried out less intensively. However, a provocation of psychosis-like behavior by a dose of PCP that does not by itself impair performance in normal animals, will abolish the ability to recognize novel objects in animals lacking cortical cholinergic innervation. The present findings support a possible role for cortical cholinergic hypofunction in the negative and cognitive symptoms of schizophrenia, and the potential for cholinergic augmentation as part of the pharmacological profile of antipsychotic drugs.

Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats.

BACKGROUND AND PURPOSE: The designer drug 1-(4-methylphenyl)-2-methylaminopropan-1-one (4-methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5-HT in the nucleus accumbens of awake rats and compare these effects with those induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and amphetamine. EXPERIMENTAL APPROACH: Microdialysis sampling was performed while simultaneously recording locomotor activity in rats and the monoamines were determined by HPLC with electrochemical detection. KEY RESULTS: Mephedrone (3 mg·kg(-1) s.c.) and (+)-amphetamine (1 mg·kg(-1) s.c.) caused rapid increases in extracellular DA levels of 496% and 412%, respectively, whereas MDMA (3 mg·kg(-1) s.c.) showed only a moderate effect (235%). The corresponding 5-HT levels increased to 941% (mephedrone) and 911% (MDMA), but only to 165% following amphetamine. The calculated t(1/2) values for elimination rate of mephedrone, MDMA and amphetamine-induced increases in extracellular DA levels were 25, 303 and 51 min, the corresponding t(1/2) values for 5-HT were 26, 48 and 84 min, respectively. Locomotor activity was increased most by amphetamine, whereas both mephedrone and MDMA showed about three times lower and shorter-lasting effects. CONCLUSIONS AND IMPLICATIONS: The neurochemical and functional properties of mephedrone resemble those of MDMA, but it also shows an amphetamine-like effect in that it evokes a rapid release and elimination of DA in the brain reward system, a feature that may contribute to its potent reinforcing properties.

Diffusion and clearance of superparamagnetic iron oxide nanoparticles infused into the rat striatum studied by MRI and histochemical techniques.

The purpose of the present study was to investigate, by MRI and histochemical techniques, the diffusion and clearance abilities of superparamagnetic iron oxide nanoparticles (SPION) coated with dextran (Dextran-SPION) and gold (Au-SPION) following their local infusions into the rat brain. In separate groups of anesthetized rats, the Dextran-SPION and Au-SPION were infused at concentrations of 0.01, 0.1, 1 and 5 µg Fe/0.5 µl and at the flow rate of 0.5 µl min(-1) into the left and right striata, respectively. Repetitive T2-weighted spin-echo MRI scans were performed at time intervals of 1, 6, 12, 24, 48, 72 h, and one, two and eight weeks after inoculation. Following infusion of Dextran-SPION (0.1 µg and 1 µg Fe), the maximal distribution volume was observed at about 12-24 h after inoculation and two weeks later the Fe signals were undetectable for the lower dose. On the other hand, Au-SPION remained tightly localized in the closest vicinity of the infusion site as revealed by unchanged MRI signal intensities and strong histochemical staining of Fe(2+) and Fe(3+) ions in the corresponding brain slices. Immunohistochemical staining of astrocytic and microglial reactions revealed that there were no marked differences in GFAP, VIM or OX-42 labeling observed between the nanoparticle types, however the astrocytic reaction was more pronounced in rats receiving nanoparticles compared to the control (aCSF-infused) rats. In conclusion, the present data demonstrate that the viral-sized Dextran-SPION were able to diffuse freely through the interstitial space of the brain being progressively cleared out from the infusion site within two weeks. Thus, Dextran-SPION could be beneficially used in MRI-guided diagnostic applications such as in experimental oncology or as labels and carriers for targeted drug delivery, whereas Au-SPION could be used for labeling and tracking the transplanted stem cells in experimental MRI.

The Ginkgo biloba extract EGb 761(R) and its main constituent flavonoids and ginkgolides increase extracellular dopamine levels in the rat prefrontal cortex.

BACKGROUND AND PURPOSE: Experimental and clinical data suggest that extracts of Ginkgo biloba improve cognitive function. However, the neurochemical correlates of these effects are not yet fully clarified. The purpose of this study was to examine the effects of acute and repeated oral administration of the standardized extract EGb 761((R)) on extracellular levels of dopamine, noradrenaline and serotonin (5-HT), and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC) and striatum of conscious rats. EXPERIMENTAL APPROACH: Monoamines and their metabolites were monitored by the use of microdialysis sampling and HPLC with electrochemical or fluorescence detection. KEY RESULTS: A single oral dose of EGb 761 (100 mg.kg(-1)) had no effect on monoamine levels. However, following chronic (100 mg.kg(-1)/14 days/once daily) treatment, the same dose significantly increased extracellular dopamine and noradrenaline levels, while 5-HT levels were unaffected. Chronic treatment with EGb 761 showed dose-dependent increases in frontocortical dopamine levels and, to a lesser extent, in the striatum. The extracellular levels of HVA and DOPAC were not affected by either acute or repeated doses. Treatment with the main constituents of EGb 761 revealed that the increase in dopamine levels was mostly caused by the flavonol glycosides and ginkgolide fractions, whereas bilobalide treatment was without effect. CONCLUSIONS AND IMPLICATIONS: The present results demonstrate that chronic but not acute treatment with EGb 761 increased dopaminergic transmission in the PFC. This finding may be one of the mechanisms underlying the reported effects of G. biloba in improving cognitive function.

MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.

The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson's disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postural instability in PD. L-DOPA induces different locomotor responses depending on the age: in young MitoPark mice the L-DOPA-induced motor activation is small; middle-aged MitoPark mice respond in a dose-dependent manner to L-DOPA, whereas aged MitoPark mice display a double-peaked locomotor response to a high dose of L-DOPA that includes an intermittent period of very low motor activity, similar to the 'on-off' phenomenon in PD. To correlate behavior with biochemical data, we analyzed monoamine levels in three different brain areas that are highly innervated by the DA system: striatum, anterior cortex and olfactory bulb. DA levels declined earlier and faster in striatum than in cortex; only at the latest time-point analyzed, DA levels were found to be significantly lower than control levels in the olfactory bulb. Interestingly, the ratio between homovanillic acid (HVA) and DA differed between regions over time. In striatum and olfactory bulb, the ratio increased steeply indicating increased DA turnover. In contrast, the ratio decreased over time in cortex, revealing important differences between DA cells in substantia nigra and the ventral tegmental area.

Continuous delivery of rotigotine decreases extracellular dopamine suggesting continuous receptor stimulation.

Rotigotine, a non-ergolinic dopamine receptor agonist for treatment of Parkinson's disease was continuously administered over 48 h (0.5 mg/kg s.c., slow release formulation) to conscious rats striatally implanted with a microdialysis probe. Subsequently, the levels of rotigotine increased to a maximum of 3.42 + 2.1 nmol/l and remained at a level of 2.81 +/- 0.82 nmol/l for 48 h. Concomitantly, the dopamine levels consistently decreased to 20% of the control level. This suggests that the sustained administration of rotigotine provides stable extracellular drug levels in the striatum resulting in continuous stimulation of dopamine receptors.

Indices glicémicos de formulas enterales de uso habitual / Glycemic index of enteral formulas of habitual use

Las fórmulas enterales completas contienen todos los nutrientes para asegurar una adecuada nutrición, con frecuencia son administradas como suplementos orales para aumentar el aporte calórico - proteico de los pacientes. El objetivo del estudio fue conocer el índice glicémic (IG) de éstas fórmulas. Material y métodos: para determinar el IG de las fórmulas enterales se estudiaron 30 sujetos sanos entre 18 y 48 años, sin sobrepeso y sin historia de diabetes mellitus e ingesta de fármacos. Se dividieron aleatoriamente en cuatro grupos, a cada uno se administró 50 gramos de hidratos de carbono contenidos en las fórmulas enterales: Nutricomp ADN, Nutricomp Renal, Nutricomp fibra y Nutricomp diabético y se comparó con la administración de 50 gramos de glucosa. El estudio se realizó en orden aleatorio y en ocasiones separadas, después de una noche de ayuno...

Indices glicémicos de formulas enterales de uso habitual / Glycemic index of enteral formulas of habitual use

Las fórmulas enterales completas contienen todos los nutrientes para asegurar una adecuada nutrición, con frecuencia son administradas como suplementos orales para aumentar el aporte calórico - proteico de los pacientes. El objetivo del estudio fue conocer el índice glicémic (IG) de éstas fórmulas. Material y métodos: para determinar el IG de las fórmulas enterales se estudiaron 30 sujetos sanos entre 18 y 48 años, sin sobrepeso y sin historia de diabetes mellitus e ingesta de fármacos. Se dividieron aleatoriamente en cuatro grupos, a cada uno se administró 50 gramos de hidratos de carbono contenidos en las fórmulas enterales: Nutricomp ADN, Nutricomp Renal, Nutricomp fibra y Nutricomp diabético y se comparó con la administración de 50 gramos de glucosa. El estudio se realizó en orden aleatorio y en ocasiones separadas, después de una noche de ayuno...(AU)

Indices glicémicos de formulas enterales de uso habitual / Glycemic index of enteral formulas of habitual use

Las fórmulas enterales completas contienen todos los nutrientes para asegurar una adecuada nutrición, con frecuencia son administradas como suplementos orales para aumentar el aporte calórico - proteico de los pacientes. El objetivo del estudio fue conocer el índice glicémic (IG) de éstas fórmulas. Material y métodos: para determinar el IG de las fórmulas enterales se estudiaron 30 sujetos sanos entre 18 y 48 años, sin sobrepeso y sin historia de diabetes mellitus e ingesta de fármacos. Se dividieron aleatoriamente en cuatro grupos, a cada uno se administró 50 gramos de hidratos de carbono contenidos en las fórmulas enterales: Nutricomp ADN, Nutricomp Renal, Nutricomp fibra y Nutricomp diabético y se comparó con la administración de 50 gramos de glucosa. El estudio se realizó en orden aleatorio y en ocasiones separadas, después de una noche de ayuno...(AU)

Derivatization chemistries for determination of serotonin, norepinephrine and dopamine in brain microdialysis samples by liquid chromatography with fluorescence detection.

The present paper provides an overview on currently developed derivatization chemistries and techniques for determination of monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA) in microdialysis samples by microbore liquid chromatography with fluorescence detection. In mild alkaline conditions, 5-hydroxyindoles and catecholamines react with benzylamine (BA), forming highly fluorescent 2-phenyl-4,5-pyrrolobenzoxazoles and 2-phenyl(4,5-dihydropyrrolo) [2,3-f]benzoxazoles, respectively. However, for derivatization of DA a higher fluorescence intensity was achieved for reaction with 1,2-diphenylethylenediamine (DPE) rather than with BA, therefore for simultaneous determination of 5-HT, NE and DA in brain microdialysates, a two-step derivatization with BA followed by DPE was developed. The detection limits for 5-HT, NE and DA were 0.2, 0.08 and 0.13 fmol, respectively, in an injection volume of 20 microL, which corresponds to concentrations of 30, 12 and 19.5 pm, respectively in standard solution prior to derivatization. The experimental data presented demonstrate the ability of the technique to simultaneously monitor neuronally releasable pools of monoamine neurotransmitters in the rat and mouse brains at basal conditions and following pharmacological treatments or physiological stimuli. These techniques play an important role in drug discovery and clinical investigation of psychiatric and neurological diseases such as depression, schizophrenia and Parkinson's disease.

Nutrición enteral en cáncer gástrico / Enteral nutrition in gastric cancer

La nutrición enteral es una técnica terapéutica ampliamente utilizada para aportar nutrientes de forma efectiva a los pacientes que tienen incapacidad de recibir sus requerimientos nutricionales por la via oral y constituye una buena alternativa a la nutrición parenteral. El objetivo del estudio fue evaluar el impacto de la nutrición enteral sobre el estado nutricional en un grupo de pacientes operados de cáncer gástrico. Material y métodos: 30 pacientes portadores de cáncer gástrico resecables con edad promedio de 67±15 años fueron estudiados con parámetros antropométricos y bioquímicos que evalúan el estado nutricional en el período preoperatorio y postoperatorio. Durante la cirugía se instaló una sonda nasoyeyunal por la cual recibieron nutrición enteral en el postoperatorio. Se determinó el aporte real de nutrientes que recibieron los pacientes y la frecuencia de complicaciones postoperatorias...

Effect of water stress on lupin stem protein analysed by two-dimensional gel electrophoresis.

Lupinus albus plants can withstand severe drought stress and show signs of recovery 24 h after rewatering (RW). Two-dimensional gel electrophoresis was used to evaluate the effect of water deficit (WD) on the protein composition of the two components of the lupin stem (stele and cortex). This was performed at three distinct stress levels: an early stage, a severe WD, and early recovery. Protein characterisation was performed through mass spectrometric partial sequencing. Modifications in the protein expression were first noticed at 3 days of withholding water, when the plant water status was still unaffected but some decrease in the relative soil water content had already occurred. An increase in serine proteases, possibly associated with WD sensing, was an early alteration induced by WD. When the stress severity increased, a larger number of stem proteins were affected. Immunophilin, serine protease and cysteine protease (well-known components of animal sensing pathways) were some of these proteins. The simultaneous expression of proteases and protease inhibitors that reacted differently to the stress level and to RW was found. Although the level of protease inhibitors was significantly raised, RW did not cause de novo expression of proteins. Many amino acid sequences did not match known sequences of either protein or expressed sequence tag databases. This emphasises the largely unknown nature of stem proteins. Nevertheless, some important clues regarding the way the lupin plant copes with WD were revealed.

Effects of isoflurane on prefrontal acetylcholine release and hypothalamic Fos response in young adult and aged rats.

This experiment investigated the influence of age on prefrontal acetylcholine (ACh) release and Fos response in the hypothalamic paraventricular nucleus and the nucleus tractus solitarius (NTS) of rats following isoflurane anesthesia. It is known that isoflurane decreases acetylcholine release in most brain regions. In the present study, we found that the level of prefrontal acetylcholine was significantly lower in 28-month-old rats (14% of baseline) than in 3-month-old rats (38% of baseline) during 2 h of isoflurane anesthesia (P < 0.05). The old rat group showed significantly greater Fos induction in the paraventricular nucleus compared to the young adult rat group (P < 0.05), indicating that the old rats were subjected to stress. No difference in Fos response was noted in the nucleus tractus solitarius. The old rats displayed a significant increase in feeding behavior during the 3-h recovery period (P < 0.05), but there was no difference in overall acetylcholine levels. Taken together, these findings suggest that isoflurane anesthesia influences old rats more profoundly than young adult rats with regard to reductions in acetylcholine release and stress responses. This may have implications for understanding the development of postoperative delirium in aged patients.

The role of alpha1- and alpha2-adrenoreceptors on venlafaxine-induced elevation of extracellular serotonin, noradrenaline and dopamine levels in the rat prefrontal cortex and hippocampus.

The role of adrenergic alpha1- and alpha2-adrenoreceptors in augmentation of venlafaxine-induced elevation of extracellular serotonin (5-HT),noradrenaline (NA) and dopamine (DA) levels in the rat prefrontal cortex (PFC) and hippocampus (HIPP) was studied by in vivo microdialysis in anaesthetized rats. The alpha1-adrenoreceptor antagonist prazosin given alone (0.3 mg/kg, s.c.) induced only a moderate reduction of hippocampal 5-HT and NA levels. The alpha2-adrenoreceptor antagonist idazoxan (1.5 mg/kg, s.c.) causes moderate increases in the levels of 5-HT and DA in the PFC. The mixed 5-HT and NA reuptake inhibitor venlafaxine (10 mg/kg, i.p.) increased the efflux of 5-HT, NA and DA almost equally, to approximately 200% of the control levels in the PFC. The levels of 5-HT increased to 310%, an effect approximately twice the effect on NA in the HIPP. Venlafaxine also produced a moderate increase in DA levels in the PFC but had no effect in the HIPP. Pre-treatment with prazosin caused a significant attenuation of the venlafaxine induced 5-HT effect in the PFC, and a moderate increase in DA levels in the HIPP. Prazosin had no significant effect on the venlafaxine-induced increase of the NA levels in PFC or HIPP. A combined treatment of venlafaxine with idazoxan increased the venlafaxine NA and DA effects in PFC by a factor of two and resulted in a very robust five-fold augmentation of NA and DA concentrations in the HIPP. In summary, idazoxan was found to produce a potent enhancement of the venlafaxine effect to increase extracellular NA and DA levels in the PFC and, in particular, in the HIPP. Idazoxan had no effect on venlafaxine-induced elevation of extracellular 5-HT levels in either PFC or HIPP and prazosin induced a decrease of 5-HT in the PFC. The present data suggest that blockade of alpha2-adrenoreceptors may play an important role in augmentation of the effects of mixed monoamine reuptake inhibitors.

Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition.

The cholinergic neurons in the septohippocampal projection are implicated in hippocampal functions such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide galanin, co-localized with acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial learning assessed by the Morris water maze test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal cholinergic function. To test these hypotheses, compounds were microinjected into the medial septum and hippocampal ACh release was assessed by microdialysis probes in the ventral hippocampus of the rat. Blockade of septal muscarinic transmission by intraseptal scopolamine increased hippocampal ACh release suggesting that septal cholinergic neurons are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also increased hippocampal ACh release. Despite this increase, both scopolamine and carbachol tended to impair hippocampus-dependent spatial learning. This finding also suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting that septal galanin, contrary to earlier claims, does not inhibit but excites septohippocampal cholinergic neurons. Galanin receptor stimulation combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.

Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease.

Behavioral and microdialysis studies have been performed on antagonistic A(2A)/D(2) interactions in animal models of Parkinson's Disease. The behavioral analysis involved studies on locomotor activity in reserpinized mice, haloperidol-induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis studies were indirectly performed on the striatopallidal GABA neurons by studying extracellular glutamate levels in the striatum and globus pallidus of the awake freely moving rat. The striatum was perfused with A(2A) and/or D(2) agonists via reverse microdialysis. The results show that the A(2A) antagonists SCH58261 and KF17837 can increase locomotor activity in reserpinized mice and produce contralateral rotational behavior only after administration of subthreshold doses of l-DOPA or the D(2) like agonist quinpirole. Furthermore, antagonizing the A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D(2) heterodimers where A(2A) R inhibits the D(2) R transduction and D(2) inhibits the adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that the A(2A) agonist CGS21680 striatally coperfused with the D(2) agonist quinpirole more potently counteract the D(2) agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A(2A)/D(2) interaction. In the DA denervated but not in the control striatum the A(2A) agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A(2A) R located on the striatal glutamate terminals, where also D(2) like R exist, here probably as D(4). Thus, the signaling of this A(2A) R may be set free by the loss of D(4) tone on the AC activated by A(2A) in this postulated A(2A)/D(4) heteromer on the glutamate terminals. Taken together, the results indicate that the antiparkinsonian actions of A(2A) antagonists probably are produced by blockade of A(2A) R in the A(2A)/D(2) heterodimers mainly located in the striatopallidal GABA neurons.