Extracellular Serotonin Levels Research Articles

Nitrous oxide increases serotonin release in the rat spinal cord

The mechanism of the antinociceptive action of nitrous oxide (N(2)O) is not fully understood. It was reported that N(2)O induces opioid peptide release in the rat midbrain, which can activate the descending inhibitory system in the spinal cord. Although effects of N(2)O on the noradrenergic descending inhibitory system have been established, effects of N(2)O on the serotonergic descending inhibitory system have not been extensively investigated. We measured the extracellular level of serotonin by using in vivo microdialysis in the dorsal horn of the spinal cord in rats. The serotonin release increased to 213.01 +/- 24.87% (mean +/- SEM) of the baseline level from 20 to 40 min after applying N(2)O, which was followed by a gradual decrease. It is suggested that the serotonergic descending pathway is activated by N(2)O.

Lack of development of behavioral sensitization to methylphenidate in mice: Correlation with reversible astrocytic activation

Methamphetamine is a powerfully addictive psychostimulant that dramatically affects the mammalian central nervous system. Methylphenidate has been shown to have psychostimulus effects similar to methamphetamine. In the present study, we compared several effects of methylphenidate to those of methamphetamine. The subcutaneous administration of either methamphetamine or methylphenidate increased extracellular dopamine levels in the nucleus accumbens of mice. Interestingly, methamphetamine, but not methylphenidate, also increased the extracellular serotonin levels in this area. Further, repeated treatment with methamphetamine induced the development of sensitization to hyperlocomotion, whereas methylphenidate failed to induce behavioral sensitization. Moreover, in vitro treatment with methamphetamine, but not methylphenidate, caused long-lasting astrocytic activation in limbic neuron/glia co-cultures. These findings suggest that, unlike methamphetamine, methylphenidate shows a lack of development of behavioral sensitization to its hyperlocomotion and induces reversible astrocytic activation.

Methamphetamine-induced hyperactivity and behavioral sensitization in PACAP deficient mice

Mice lacking the PACAP gene (PACAP −/−) display psychomotor abnormalities such as novelty-induced hyperactivity and jumping behavior, and they show different responses to amphetamine, a typical psychostimulant. The present study examined the possible role of endogenous PACAP in methamphetamine (METH)-induced hyperactivity and behavioral sensitization. The locomotor activity of hyperactive PACAP −/− mice was measured using the infrared photocell beam detection system, Acti-Track, after a habituation period. Single administration of METH (1 and 2 mg/kg) caused a robust increase in locomotor activity of mice, but this effect did not differ between wild-type and PACAP −/− mice. Repeated administration of METH (1 mg/kg) for 7 days enhanced METH-induced hyperactivity, and this sensitization was observed even when withdrawn for 7 days. There was no difference in the degree of development and expression of METH-induced behavioral sensitization between wild-type and PACAP −/− mice. In addition, there was no difference in METH-induced increases in extracellular serotonin and dopamine levels in the prefrontal cortex of the normal and sensitized mice between the two groups. These results suggest that endogenous PACAP is not involved in the locomotor stimulant activity of acute METH and repeated METH-induced behavioral and neurochemical sensitization.

GIRK Channels as a Target for SSRIs. Focus on “Reduced 5-HT1A- and GABAB Receptor Function in Dorsal Raphe Neurons Upon Chronic Fluoxetine Treatment of Socially Stressed Rats”

One of the most enigmatic problems in neurobiology is the apparent disconnect between rapid effects of serotonin reuptake inhibitors (SSRI) on extracellular serotonin (5-HT) levels and the slow onset of the therapeutic antidepressant effects of these drugs. Indeed, SSRIs increase extracellular 5-HT

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

Previous studies have shown that the dopamine (DA) uptake blocker methylphenidate, a psychostimulant widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), prevents the neurotoxic effects of the highly abused DA releaser methamphetamine. However, there is a lack of information about the pharmacological interactions of these two drugs at the behavioral level. When systemically administered within an interval of 2 h, previous administration of methylphenidate (10 mg/kg, intraperitoneal (i.p.)) did not modify locomotor activation induced by methamphetamine. On the other hand, previous administration of methamphetamine (1 mg/kg, i.p.) markedly potentiated methylphenidate-induced motor activation. With in vivo microdialysis experiments, methamphetamine and methylphenidate were found to increase DA extracellular levels in the nucleus accumbens (NAs). Methamphetamine, but not methylphenidate, significantly increased the extracellular levels of serotonin (5-HT) in the NAs. Methamphetamine-induced 5-HT release remained significantly elevated for more than 2 h after its administration, suggesting that the increased 5-HT could be responsible for the potentiation of methylphenidate-induced locomotor activation. In fact, previous administration of the 5-HT uptake blocker fluoxetine (10 mg/kg, i.p.) also potentiated the motor activation induced by methylphenidate. A selective 5-HT 1B receptor antagonist (GR 55562; 1 mg/kg), but not a 5-HT2 receptor antagonist (ritanserin; 2 mg/kg, i.p.), counteracted the effects of methamphetamine and fluoxetine on the motor activation induced by methylphenidate. Furthermore, a 5-HT 1B receptor agonist (CP 94253; 1-10 mg/kg, i.p.) strongly and dose-dependently potentiated methylphenidate-induced locomotor activation. The 5-HT 1B receptor-mediated modulation of methylphenidate-induced locomotor activation in rat could have implications for the treatment of ADHD.

MDMA attenuates THC withdrawal syndrome in mice

3, 4-Methylenedioxymethamphetamine (MDMA) and cannabis are widely abused illicit drugs that are frequently consumed in combination. Interactions between these two drugs have been reported in several pharmacological responses observed in animals, such as body temperature, anxiety, cognition, and reward. However, the interaction between MDMA and cannabis in addictive processes such as physical dependence has not been elucidated yet. In this study, the effects of acute and chronic MDMA were evaluated on the behavioral manifestations of Delta(9)-tetrahydrocannabinol (THC) abstinence in mice. THC withdrawal syndrome was precipitated by injecting the cannabinoid antagonist rimonabant (10 mg/kg, i.p.) in mice chronically treated with THC and receiving MDMA (2.5, 5 and 10 mg/kg i.p.) or saline just before the withdrawal induction or chronically after the THC administration. Both chronic and acute MDMA decreased in a dose-dependent manner the severity of THC withdrawal. In vivo microdialysis experiments showed that acute MDMA (5 mg/kg, i.p.) administration increased extracellular serotonin levels in the prefrontal cortex, but not dopamine levels in the nucleus accumbens. Our results also indicate that the attenuation of THC abstinence symptoms was not due to a direct interaction between rimonabant and MDMA nor to the result of the locomotor stimulating effects of MDMA. The modulation of the cannabinoid withdrawal syndrome by acute or chronic MDMA suggests a possible mechanism to explain the associated consumption of these two drugs in humans.

Differential effects of adjunctive methylphenidate and citalopram on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain

Several clinical studies have suggested that the combined treatment with methylphenidate and citalopram may accelerate the onset of antidepressant action and induce an improvement even in treatment-refractory patients. In the present study, in vivo microdialysis was used to monitor the extracellular levels of serotonin, noradrenaline and dopamine in the prefrontal cortex, hippocampus, nucleus accumbens and striatum of the rat. Administration of methylphenidate (2.5 mg/kg s.c.) with citalopram (5 mg/kg i.p.) compared to methylphenidate alone caused a marked enhancement of dopamine levels in the prefrontal cortex, n. accumbens and hippocampus, but not in the striatum. Citalopram-induced increase in serotonin levels was strongly enhanced by adjunctive methylphenidate in the hippocampus, but attenuated in the cortex. These findings suggest that the proposed augmentation effects of adjuvant methylphenidate to citalopram are most likely associated with enhanced dopamine transmission in the corticolimbic areas, whereas serotonin and noradrenaline levels show differential and region specific responses.

Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression

One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric acid (GABA). Furthermore, altered GABAergic function is also evident in depressed patients and in animal models of depression. Disturbed sleep is characteristic of patients with mood disorders. The most pronounced changes of the 5-HT firing activity occur during sleep. Hence, the present paper reports a study on simultaneously measurement of hippocampal levels of serotonin and GABA during waking and sleep in the chronic mild stress (CMS) animal model of depression. The neurotransmitter findings are accompanied by depression-like symptoms (e.g. sleep alterations and reduced sucrose intake, a putative indicator of anhedonia in rodents). Our results show that animals exposed to CMS had lower hippocampal GABA levels compared to controls. In addition, after CMS there was a lack of 5-HT stage-dependency. A subgroup (five out of eight animals) showed a consistent increase in 5-HT levels in slow wave sleep and REM sleep. We also observed that this increase occurred in those animals regarded as most anhedonic (lowest intake of sucrose solution). Moreover, REM sleep was positively correlated with anhedonia. No interaction between 5-HT and GABA was found in the hippocampus. The data suggest that both GABAergic and serotonergic systems may be simultaneously but independently involved in depression. The alteration in 5-HT function may represent a link between depression-like behaviour and sleep abnormalities found in depressed patients.

Neurochemical changes associated with chronic administration of typical anti-psychotics and its relationship with tardive dyskinesia

The therapeutic success of atypical antipsychotics has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptic-associated extrapyramidal side effects such as tardive dyskinesia. In the present study we planned to study time-dependent changes in extracellular levels of norepinephrine, dopamine and serotonin in cortical and subcortical (including striatum) regions of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements [VCMs], tongue protrusions and facial jerking) in rats treated chronically with typical neuroleptics (haloperidol and chlorpromazine). Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in a time-dependent increase in orofacial hyperkinetic movements. There were also significant changes in the extracellular levels of different neurotransmitters in different brain regions (cortical and subcortical regions) as measured by high-performance liquid chromatography/electrochemical detection (HPLC/ED). Both haloperidol and chlorpromazine produced time-dependent decreases in the levels of these neurotransmitters.

Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats

The sex difference in the emotional response to stress suggests a sex-specific stress response in the amygdala. To examine the sex difference in extracellular levels of serotonin (5HT) and dopamine (DA) in the basolateral amygdala (BLA) and their responses to restraint stress, in vivo microdialysis studies were performed in male and female rats. In experiment I, dialysates were collected from the BLA at 15-min intervals under the freely moving condition. Mean extracellular levels of 5HT or DA in the BLA were higher in male rats than in female rats. In experiment II, rats were subjected to restraint stress for 60 min to examine the stress response of 5HT or DA levels. Although restraint stress significantly increased extracellular 5HT levels in both sexes of rats, female rats showed a greater response than male rats. Moreover, restraint stress significantly increased extracellular DA levels in female rats, but not in male rats. In experiment III, rats were subjected to restraint stress for 30 min to examine behavioral responses to restraint stress. Although no sex difference was observed in the number of audible vocalizations, male rats defecated a larger number of fecal pellets than female rats. In experiment IV, rats were tested for freezing behavior to examine contextual fear responses. Conditioned male rats showed a longer freezing time than conditioned female rats. We found sex differences in the extracellular levels of 5HT and DA in the BLA and their responses to restraint stress, which may be involved in the sex-specific emotional response to stress in rats.

Serotonin and epilepsy

In recent years, there has been increasing evidence that serotonergic neurotransmission modulates a wide variety of experimentally induced seizures. Generally, agents that elevate extracellular serotonin (5-HT) levels, such as 5-hydroxytryptophan and serotonin reuptake blockers, inhibit both focal and generalized seizures, although exceptions have been described, too. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsions. Furthermore, it has been shown that several anti-epileptic drugs increase endogenous extracellular 5-HT concentration. 5-HT receptors are expressed in almost all networks involved in epilepsies. Currently, the role of at least 5-HT(1A), 5-HT(2C), 5-HT(3) and 5-HT(7) receptor subtypes in epileptogenesis and/or propagation has been described. Mutant mice lacking 5-HT(1A) or 5-HT(2C) receptors show increased seizure activity and/or lower threshold. In general, hyperpolarization of glutamatergic neurons by 5-HT(1A) receptors and depolarization of GABAergic neurons by 5-HT(2C) receptors as well as antagonists of 5-HT(3) and 5-HT(7) receptors decrease the excitability in most, but not all, networks involved in epilepsies. Imaging data and analysis of resected tissue of epileptic patients, and studies in animal models all provide evidence that endogenous 5-HT, the activity of its receptors, and pharmaceuticals with serotonin agonist and/or antagonist properties play a significant role in the pathogenesis of epilepsies.

Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system

We used a model of neuropathic pain consisting of rats with chronic constriction injury (CCI) of the sciatic nerve, in order to investigate whether endocannabinoid levels are altered in the dorsal raphe (DR) and to assess the effect of repeated treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate, a synthetic cannabinoid agonist, or N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404), an inhibitor of endocannabinoid reuptake, on DR serotonergic neuronal activity and on behavioural hyperalgesia. CCI resulted in significantly elevated anandamide but not 2-arachidonoylglycerol levels in the DR. Furthermore, as well as thermal and mechanical hyperalgesia, CCI caused serotonergic hyperactivity (as shown by the increase of basal activity of serotonergic neurones, extracellular serotonin levels and expression of 5-HT1A receptor gene). Repeated treatment with either (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate or AM404 reverted the hyperalgesia and enhanced serotonergic activity induced by CCI in a way attenuated by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide, a selective cannabinoid subtype 1 (CB1) receptor antagonist. Despite the elevated levels of anandamide following CCI, N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide did not produce hyperalgesia or any other effect on serotonergic neuronal activity when administered alone. Furthermore, the effects of AM404 were not accompanied by an increase in endocannabinoid levels in the DR. In conclusion, following CCI of the sciatic nerve, the endocannabinoid and serotonergic systems are activated in the DR, where repeated stimulation of CB1 receptors with exogenous compounds restores DR serotonergic activity, as well as thermal and mechanical nociceptive thresholds, to pre-surgery levels. However, an elevated level of endogenous anandamide in the DR does not necessarily contribute to the CB1-mediated tonic control of analgesia and serotonergic neuronal activity.

Reduced brain‐derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice

Brain-derived neurotrophic factor (BDNF) regulates monoamine neuronal growth, survival and function in development and throughout adulthood. At 18 months of age, mice with constitutive reductions in BDNF expression show decreased serotonin innervation in the hippocampus compared with age-matched wildtype mice. It is not known, however, whether age-accelerated loss of serotonergic innervation in BDNF(+/-) mice occurs in other brain regions, advances beyond 18 months or is associated with alterations in other neurotransmitter systems. In this study, immunocytochemistry was used to assess serotonergic and catecholaminergic innervation in 26-month-old BDNF(+/-) mice. Age-related loss of serotonin axons in the hippocampus was potentiated in BDNF(+/-) mice compared with wildtype mice at this late age, particularly in the CA1 subregion. By contrast, aging BDNF(+/-) mice showed increased serotonin innervation of the basomedial nucleus of the amygdala. In the noradrenergic system, BDNF(+/-) mice showed reduced numbers of cell bodies and fibers in the locus coeruleus compared with age-matched wildtype mice, whereas no changes were observed in dopaminergic innervation with respect to genotype. In vivo zero net flux microdialysis in awake mice showed a significant decrease in extracellular serotonin levels in the hippocampus in BDNF(+/-) mice at 20 months of age. Thus, reduced BDNF is associated with altered serotonergic and noradrenergic innervation in aging mice and, in particular, with accelerated loss of serotonergic innervation to the hippocampus that is manifest as a decrease in basal neurotransmission.

Irreversible blockade of monoamine oxidases reveals the critical role of 5‐HT transmission in locomotor response induced by nicotine in mice

Although nicotine is generally considered as the main compound responsible for addictive properties of tobacco, some experimental data indicate that nicotine does not exhibit all the characteristics of other substances of misuse such as psychostimulants and opiates. For example, nicotine generally fails to induce locomotor response in mice and self-administration of nicotine is difficult to obtain in rats. We have shown recently that a pretreatment with mixed irreversible monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and induces a robust self-administration of nicotine in rats. We show here that when mice were pretreated with enhancers of extracellular levels of noradrenaline, dopamine or serotonin (D-amphetamine, GBR12783 or para-chloro-amphetamine, respectively) and injected with nicotine (1 mg/kg), only those animals pretreated with para-chloro-amphetamine exhibited a specific locomotor response to nicotine. These data indicate a critical role of serotonin in nicotine-induced locomotor activity in mice. This was further confirmed in microdialysis experiments showing that nicotine induces an increase in extracellular serotonin levels in the ventral striatum in mice pretreated with tranylcypromine. This effect of nicotine on extracellular serotonin levels was absent in mice lacking the beta2-subunit of the nicotinic acetylcholine receptor. Our data suggest that mixed irreversible MAOIs contained in tobacco facilitate the effects of nicotine on serotonin release, thus allowing the locomotor and rewarding effects of nicotine.

Effects of acute and repeated administration of Hypericum perforatum extract (WS 5572®) and its main constituents on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain: A microdialysis study

Effects of acute and repeated administration of Hypericum perforatum extract (WS 5572®) and its main constituents on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain: A microdialysis study

Effects of chronic administration of Ginkgo biloba extract (EGb 761®) on levels of dopamine, noradrenaline and serotonin in the prefrontal cortex of the awake rat

The special Ginkgo biloba extract (EGb 761®) has been shown to exert beneficial effects in the therapy of age-related neurological disorders such as Parkinson's and Alzheimer's disease [1]. Besides neuroprotective effects, EGb 761® has been demonstrated to improve cognitive functions in animal models [2] and in clinical studies [3]. Thus, it was the aim of the present study to investigate whether EGb 761® influences monoamine levels in brain areas implicated in cognitive function, motivation and mood behaviour. For this purpose, the effect of sub-chronic (14 days) daily administration of EGb 761® on basal extracellular levels of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) were monitored by microdialysis in the prefrontal cortex of awake rats. Administration of EGb 761® at a dose of 100mg/kg p.o., caused a significant increase in DA levels during 40–180min, reaching a maximum level of 163% of the control group. The extracellular levels of NA increased only by about 120% and the concentrations of 5-HT were not changed from the pre-drug levels. These findings supports previous observations suggesting that Ginkgo biloba extracts could increase monoaminergic function via inhibition of MAO activity. However, the minimal effects on NA and 5-HT concentrations indicate that EGb 761® may affect brain monoaminergic system also through other mechanisms than direct inhibition of MAO activity. These results suggest that treatment with EGb 761® can lead to increased dopaminergic function in the prefrontal cortex which may be an underlying factor to clinically observed effects on improved cognitive function.

Mechanistic model of acute autoinhibitory feedback action after administration of SSRIs in rats: Application to escitalopram-induced effects on brain serotonin levels

This study presents the development and evaluation of a feedback turnover model that mimics drug-induced effects on brain extracellular levels of serotonin (5-HT) after acute administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram ( S-citalopram) in rats. The extracellular 5-HT output in the hippocampus was continuously monitored by intracerebral microdialysis in conjunction with serial arterial blood sampling for evaluation of escitalopram pharmacokinetics. 5-HT levels were significantly increased following administration of 2.5, 5 and 10 mg/kg of escitalopram and the 5-HT levels gradually declined to its baseline value within 360 min. However, at 5 and 10 mg/kg, the response–time curves were almost identical. This might be explained by activation of serotonergic autoreceptors exerting negative feedback, leading to a reduced release of new 5-HT into the synapse. The dynamics of escitalopram-evoked changes of 5-HT response was characterized by a turnover model, which included an inhibitory feedback moderator component. Thus, the response acted linearly on the production of the moderator, which acted inversely on the production of response. The plasma kinetics served as input to an inhibitory function acting on the loss of response. Simultaneous fitting of the model after three constant rate infusions demonstrated the flexibility of the system. The efficacy ( I max) and potency (IC 50) of inhibition of reuptake were 0.9 ± 0.03 and 4.4 ± 1.4 ng/ml, respectively, corresponding to an EC 50 of escitalopram about 30 ng/ml. In conclusion, the model lends itself to ‘what–if’ predictions at different drug exposure scenarios, and has potential for extrapolation of the pharmacodynamics of SSRIs in man.

Involvement of the somatostatin‐2 receptor in the anti‐convulsant effect of angiotensin IV against pilocarpine‐induced limbic seizures in rats

The anti-convulsant properties of angiotensin IV (Ang IV), an inhibitor of insulin-regulated aminopeptidase (IRAP) and somatostatin-14, a substrate of IRAP, were evaluated in the acute pilocarpine rat seizure model. Simultaneously, the neurochemical changes in the hippocampus were monitored using in vivo microdialysis. Intracerebroventricularly (i.c.v.) administered Ang IV or somatostatin-14 caused a significant increase in the hippocampal extracellular dopamine and serotonin levels and protected rats against pilocarpine-induced seizures. These effects of Ang IV were both blocked by concomitant i.c.v. administration of the somatostatin receptor-2 antagonist cyanamid 154806. These results reveal a possible role for dopamine and serotonin in the anti-convulsant effect of Ang IV and somatostatin-14. Our study suggests that the ability of Ang IV to inhibit pilocarpine-induced convulsions is dependent on somatostatin receptor-2 activation, and is possibly mediated via the inhibition of IRAP resulting in an elevated concentration of somatostatin-14 in the brain.

¿Son reversibles los efectos neurotóxicos de las drogas de síntesis?

La investigacion preclinica sobre las drogas de sintesis realizada en animales de laboratorio nos indica que las acciones neurotoxicas pueden ser de dos tipos: a corto plazo y reversibles y a largo plazo e irreversibles. En efecto su consumo se traduce enseguida en un aumento de las concentraciones extracelulares de serotonina y dopamina que parece conllevar una subida de la temperatura corporal, pero este efecto es reversible en un tiempo medio de 6 horas. Sin embargo, una segunda accion aparece entre un dia y una semana mas tarde, con consecuencias neurotoxicas que afectan sobre todo al sistema serotoninergico y a las terminaciones finas de las fibras nerviosas de serotonina que proceden de los nucleos del rafe dorsal, puede que sea por un incremento en la oxidacion de ciertos procesos celulares en esas neuronas. La suspension de la administracion de esas drogas hace que, a largo plazo, haya un nuevo crecimiento de las danadas terminaciones finas, pero con un patron de reinervacion distinto al que originalmente habia. Es probable que en humanos ocurra un proceso parecido, puesto que esto ocurren en primates no humanos. Tampoco conocemos las consecuencias psicologicas a largo plazo del dano neurotoxico que causan las drogas de sintesis en humanos incluida, en su caso, una posible reinervacion de las terminaciones serotoninergicas, si se abandona durante un tiempo considerable el consumo. Pero es sabido que la serotonina es un neurotransmisor implicado en numeros procesos cognitivos y emocionales y puede que sean la causa de las disfunciones psicologicas mantenidas que muestran los que han consumido drogas de sintesis.

Neurochemical changes in the RVM associated with peripheral inflammatory pain stimuli

A greater knowledge of the neurochemical changes occurring during pain states will undoubtedly aid in the discovery of effective pain pharmacotherapies. This study highlights the acute effects of inflammatory agents on neurochemical changes in the rostral ventromedial medulla (RVM), a supraspinal site involved in the processing of painful stimuli. Consistent with previous reports, a peripheral injection of 0.1 mg prostaglandin E 2 (PGE 2) into the intraplantar area of the rat paw produced thermal hypersensitivity that peaked 10 min after administration. In vivo microdialysis studies in the same animals revealed that this behavioral response correlated with a greater than 2-fold increase (230%) in extracellular serotonin (5-HT) levels in the RVM. In contrast, levels of other neurotransmitters measured, including norepinephrine and dopamine, were not altered in animals receiving this inflammatory agent. Similar to PGE 2, an intraplantar injection of capsaicin (0.1 mg) produced a robust thermal hypersensitivity that was paralleled by a 3-fold increase in levels of 5-HT in the RVM. The next series of experiments showed that acute administration of the opioid analgesic, morphine (5.6 mg/kg; IP), attenuated PGE 2-induced thermal hypersensitivity and reversed the increase in extracellular 5-HT observed in the RVM. Taken together, these findings extend previous reports of central neurochemical changes during inflammatory pain conditions and show that the combination of behavioral endpoints with microdialysis can yield important insights into the neurochemical environment of the pain circuitry.