Post-Traumatic Craniocervical Disorders From a Postural Control Perspective: A Narrative Review.

Mild traumatic brain injury (mTBI) and whiplash injury (WI) may lead to long-term disabling consequences known as post-concussive syndrome (PCS) and whiplash-associated disorders (WADs). PCS and WAD patients commonly complain of conditions encompassing dizziness, vertigo, headache, neck pain, visual complaints, anxiety, and neurocognitive dysfunctions. A proper medical work-up is a priority in order to rule out any acute treatable consequences. However investigations may remain poorly conclusive. Gathered in the head and neck structures, the ocular sensorimotor, the vestibular, and the cervical proprioceptive systems, all involved in postural control, may be damaged by mTBI or WI. Their dysfunctions are associated with a wide range of functional disorders including symptoms reported by PCS and WAD patients. In addition, the stomatognathic system needs to be specifically assessed particularly when associated to WI. Evidence for considering the post-traumatic impairment of these systems in PCS and WAD-related symptoms is still lacking but seems promising. Furthermore, few studies have considered the assessment and/or treatment of these widely interconnected systems from a comprehensive perspective. We argue that further research focusing on consequences of mTBI and WI on the systems involved in the postural control are necessary in order to bring new perspective of treatment.

Clinical Neurochemistry of Subarachnoid Hemorrhage: Toward Predicting Individual Outcomes via Biomarkers of Brain Energy Metabolism.

The functional outcome of patients with subarachnoid hemorrhage is difficult to predict at the individual level. The monitoring of brain energy metabolism has proven to be useful in improving the pathophysiological understanding of subarachnoid hemorrhage. Nonetheless, brain energy monitoring has not yet clearly been included in official guidelines for the management of subarachnoid hemorrhage patients, likely because previous studies compared only biological data between two groups of patients (unfavorable vs favorable outcomes) and did not determine decision thresholds that could be useful in clinical practice. Therefore, this Viewpoint discusses recent findings suggesting that monitoring biomarkers of brain energy metabolism at the level of individuals can be used to predict the outcomes of subarachnoid hemorrhage patients. Indeed, by taking into account specific neurochemical patterns obtained by local or global monitoring of brain energy metabolism, it may become possible to predict routinely, and with sufficient sensitivity and specificity, the individual outcomes of subarachnoid hemorrhage patients. Moreover, combining both local and global monitoring improves the overall performance of individual outcome prediction. Such a combined neurochemical monitoring approach may become, after prospective clinical validation, an important component in the management of subarachnoid hemorrhage patients to adapt individualized therapeutic interventions.

Why Optogenetics Needs in Vivo Neurochemistry.

In neuroscience, the consequences of optogenetic manipulation are often studied using in vivo electrophysiology and by observing behavioral changes induced by light stimulation in genetically targeted rodents. In contrast, reports on the in vivo neurochemical effects of optogenetic stimulation are scarce despite the improving quality of analytical techniques available to monitor biochemical compounds involved in neurotransmission. This intriguing lack of neurochemical information suggests the existence of unknown or misunderstood factors hampering the expected rise of a novel specialty putatively be termed "neurochemical optogenetics".

Biochemical neuromonitoring of poor-grade aneurysmal subarachnoid hemorrhage: comparative analysis of metabolic events detected by cerebral microdialysis and by retrograde jugular vein catheterization.

OBJECTIVES: In severe aneurysmal subarachnoid hemorrhage (aSAH), pathological changes in cerebral energy metabolism can be detected either by local measurements using cerebral microdialysis (cMD) together with brain tissue oxygen probe or by global measurements of arterio-jugular difference performed with retrograde jugular vein catheter. Our main objective was to compare the two methods of detection and assess whether combining biomarkers from both procedures could improve outcome prediction, which has never been studied before. METHODS: This study included 400 sets of paired arterial and jugular venous samples and 3138 brain microdialyzates obtained from 18 poor-grade aSAH patients. Using Glasgow outcome scale (GOS), neurochemical data from unfavorable (GOS 1-3) and favorable (GOS 4-5) outcome groups were compared. RESULTS: The lactate/pyruvate ratio was found as the most sensitive marker for predicting unfavorable outcome (90%), although not specific. In contrast, hypoxic lactate events and those of metabolic ratio (MR) < 3.44, most frequently observed in the unfavorable outcome group than in the favorable one (13.9 vs 0.9% and 33.3 vs 3.75% respectively), were shown to be more specific biomarkers (86%) to predict unfavorable outcome, but less sensitive ( < 70%). The combination of these three biomarkers improved the accuracy of outcome prediction (sensitivity 90% and specificity 71%). DISCUSSION: Both retrograde jugular venous catheterization (RJVC) and cMD contribute to monitor poor-grade aSAH patients. In this preliminary study, we show that these two techniques are complementary and their combination increases the accuracy of outcome prediction.

Ultra high performance liquid chromatography as a tool for the discovery and the analysis of biomarkers of diseases: a review.

The development and use of UHPLC-based methods for the identification, validation and analysis of biomarkers for diseases is reviewed. The currents trends in types of stationary phases and modes of detection are discussed. Afterwards, examples are provided on the use of UHPLC-MS for finding novel biomarkers in samples from in vitro or in vivo animal models of human diseases, as well as in biofluid samples (mainly urine and plasma) obtained from patients. Molecular profiling and targeted analysis are considered, providing an overview of recent experimental or clinical works carried out using UHPLC analysis of compounds from various chemical classes, such as low molecular weight metabolites, hormones, lipids, peptides and proteins.

Outcome of poor-grade subarachnoid hemorrhage as determined by biomarkers of glucose cerebral metabolism.

PURPOSE: The aim of this study was to determine if the measurement of blood biomarkers of glucose cerebral metabolism, performed with retrograde jugular catheter, could predict the outcome of poor-grade aneurysmal subarachnoid hemorrhage (aSAH) patients. METHODS: This study was conducted in 68 poor-grade aSAH patients. A total of 4,024 blood samples obtained from jugular and radial catheters were analyzed for glucose, lactate, and oxygen content every 8 h for 10 ± 0.5 days. Metabolic ratio (MR) and lactate-oxygen index (LOI) were obtained by ratios using arterio-jugular differences. Functional outcome was evaluated at 12 months with the Glasgow Outcome Scale. RESULTS: Outcome was unfavorable in 40 patients. In this group of patients, the MR was significantly lower (p < 0.0001) and the LOI was significantly higher (p = 0.0001) than in the group with favorable outcome. The MR cutoff value, below which the patients are likely to have an unfavorable outcome, was determined to be 3.35. More interestingly, the data obtained in this study demonstrated that the patients achieving an unfavorable outcome were distinguished from those with a favorable outcome by having at least three events of MR inferior to 3.35 (sensitivity = 90 %, specificity = 82.1 %). Moreover, in patients who developed cerebral vasospasm, we observed a significant decrease in the MR. CONCLUSION: Our data provide additional support to the view that the MR is a reliable marker for predicting the outcome of poor-grade aSAH patients. Prospective studies are needed to confirm its value in multimodal monitoring.

Analytical validation of microdialysis analyzer for monitoring glucose, lactate and pyruvate in cerebral microdialysates.

BACKGROUND: Cerebral microdialysis is a valuable tool for neurochemical monitoring of acute brain injury. We performed an independent analytical validation of glucose, lactate and pyruvate methods on the new ISCUS(flex) new analyzer developed by CMA Microdialysis. METHODS: Evaluation of analytical parameters included limit of detection, limit of quantification, linearity, intra- and inter-assay imprecision expressed as the coefficient of variation (CV), recovery, inter-sample and inter-reagent contamination, drug and bilirubin interferences, sample stability, method comparison. RESULTS: Linearity ranges were 0.1-25 mmol/L, 0.2-12 mmol/L and 19-1500 µmol/L for glucose, lactate and pyruvate respectively. For critical threshold, intra- and inter-assay CVs were 3.1/4.5% for glucose (1 mmol/L), 3.5/4% for lactate (4 mmol/L) and 3.3/4.3% for pyruvate (100 µmol/L). Inter-assay CVs for lactate/pyruvate (LPR) and lactate/glucose (LGR) ratios were 5.9% and 6.0% respectively. For glucose, lactate, pyruvate, LPR and LGR, the reference change values (RCV) were 20%, 26%, 20%, 27% and 28% respectively. Practically, variations below 27% between two successive LPR values could not be interpreted as significant. CONCLUSION: These data prove that ISCUS(flex) has the qualities required for clinical application in neuro-intensive care. Correct clinical interpretation of data need the implementation of a strict quality control program and strong cooperation between clinicians and biologists.

In-capillary derivatization and capillary electrophoresis separation of amino acid neurotransmitters from brain microdialysis samples.

A new in-capillary derivatization method with naphtalene-2,3-dicarboxyaldehyde (NDA)/CN(-) has been developed for capillary electrophoresis with laser-induced fluorescence detection of brain microdialysate amino acids. Samples are sandwiched between two plugs of reagent mixture at the capillary inlet and subsequently separated. Highest derivatization yields are obtained by using a reagent to sample plug length ratio equal to 4, performing a first electrophoretic mixing followed by a zero potential amplification step before applying the separation voltage and using a NaCN to NDA concentration ratio equal to 1. This new single-step methodology allows the analysis of amino acid neurotransmitters in rat brain microdialysis samples.

Highly sensitive assay for the measurement of serotonin in microdialysates using capillary high-performance liquid chromatography with electrochemical detection.

A highly sensitive isocratic capillary high-performance liquid chromatographic (HPLC) method with electrochemical detection (ED) for the simultaneous measurement of serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in microdialysates has been developed using a 0.5 mm i.d. capillary column and a 11-nL detection cell. This method, validated on both pharmacological and analytical bases, can be performed using injection volumes as low as 1 microL. The limits of detection were 5.6 x 10(-11)mol/L and 3.0 x 10(-9)mol/L for 5-HT and 5-HIAA. Several applications of the present method are given on microdialysates from rodent brain and human spinal cord.

Dopaminergic transmission in STOP null mice.

Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.

Blockade of beta-adrenergic receptors prevents amphetamine-induced behavioural sensitization in rats: a putative role of the bed nucleus of the stria terminalis.

Recent findings have given evidence a role for noradrenergic transmission in the mechanisms underlying behavioural sensitization to psychostimulants. This work was undertaken to investigate the possible role of beta-adrenergic receptors in amphetamine-induced behavioural sensitization in rats. Rats were sensitized by a single administration of amphetamine (1 mg/kg s.c.) and challenged with the same dose 7 d later. The beta(1) /beta(2) -adrenergic receptor antagonists timolol (10 mg/kg i.p.) and nadolol (10 mg/kg i.p.), which respectively cross or do not readily cross the blood-brain barrier, were injected prior to the first or second amphetamine administration. Timolol, but not nadolol, prevented the initiation of behavioural sensitization without interfering with the expression of the sensitized response or the acute locomotor response to amphetamine. Since we found amphetamine-induced fos-activated cells closely associated with dopamine beta-hydroxylase immunoreactive varicosities in the bed nucleus of the stria terminalis (BNST), we investigated the effect of a bilateral micro-injection of timolol into this nucleus. Similarly to systemic administration, intra-BNST timolol (2.5 microg/side) prevented the development of behavioural sensitization. These results suggest that central beta-adrenergic receptors could specifically modulate early neuronal changes leading to the development of behavioural sensitization to psychostimulants, and that the BNST could be an important part of the brain circuitry involved in these long-term neuroadaptations.

Analysis of serotonin in brain microdialysates using capillary electrophoresis and native laser-induced fluorescence detection.

Serotonin or 5-hydroxytryptamine (5-HT) is a major neurotransmitter in the central nervous system. In this work, a method for analyzing 5-HT in brain microdialysis samples using a commercially available capillary electrophoresis (CE) system has been developed. A pH-mediated in-capillary preconcentration of samples was performed, and after separation by capillary zone electrophoresis, native fluorescence of 5-HT was detected by a 266 nm solid-state laser. The separation conditions for the analysis of 5-HT in standard solutions and microdialysates have been optimized, and this method has been validated on both pharmacological and analytical bases. Separation of 5-HT was performed using a 80 mmol/L citrate buffer, pH 2.5, containing 20 mmol/L hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and +30 kV voltage. The detection limit was 2.5 x 10(-10) mol/L. This method allows the in vivo brain monitoring of 5-HT using a simple, accurate CE measurement in underivatized microdialysis samples.

Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain.

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT(1A) receptor antagonist WAY-100,635 (20-100 microg/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA(3) pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT(1A) receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED(50)=58 and 254 mug/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 microg/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 microg/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT(1A) autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.

Endogenous neurotensin in the ventral tegmental area contributes to amphetamine behavioral sensitization.

Studies showing psychostimulant-like effects of exogenous neurotensin (NT) infused into the ventral tegmental area (VTA) prompted us to examine the role in the VTA of the endogenous NT in behavioral sensitization to amphetamine. Rats were sensitized to amphetamine by means of a subcutaneous amphetamine (1 mg/kg) injection, and the same dose was injected 7 days later to evaluate the expression of sensitization. The highly selective NT-receptor antagonist SR 142948A was injected into the VTA prior to the first and/or second amphetamine administration. SR 142948A (5 pmol/side) given before the first amphetamine exposure prevented the induction of behavioral sensitization, but did not alter the acute response to amphetamine. SR 142948A given with the second amphetamine administration did not affect the expression of behavioral sensitization. In contrast to administration into the VTA, intraperitoneal administration of SR 142948A (0.03, 0.1, or 0.3 mg/kg) had no detectable effect on the induction of amphetamine sensitization. These results suggest that activation of VTA NT receptors by endogenous NT may contribute to the neuroadaptations underlying behavioral sensitization to amphetamine.

High temporal resolution for in vivo monitoring of neurotransmitters in awake epileptic rats using brain microdialysis and capillary electrophoresis with laser-induced fluorescence detection.

A method for high temporal resolution monitoring of five neurotransmitters, dopamine (DA), noradrenaline (NA), gamma-aminobutyric acid (GABA), glutamate (Glu), l-aspartate (L-Asp), in freely-moving rats using microdialysis and capillary electrophoresis with laser-induced fluorescence detection (CE-LIFD) was developed. An on-line device, including microdialysis and derivatization with naphthalene-2,3-dicarboxaldehyde, mixes the dialysate with derivatization reagents directly in the collection tube, i.e. with no reactor. Thereafter, collected derivatized samples are analyzed off-line with an automated CE system coupled to a LIFD using a 442 nm excitation. The sampling time was limited by the minimal volume required for the analysis by the automated CE system used: neurotransmitters could be determined in 667 nl dialysates (940 nl after derivatization), i.e. in samples collected every 20 s with a flow rate of 2 microl/min. The detection limits at the dialysis probe were 3 x 10(-9), 1 x 10(-9), 1.9 x 10(-8), 4.2 x 10(-7), 2.1 x 10(-7) mol/l for DA, NA, GABA, Glu and L-Asp, respectively. The protocol was validated using in vitro/in vivo tests and the performances--repeatability, linearity, characteristics of the probes--were determined. Finally, the high temporal resolution allowed the simultaneous monitoring of these neurotransmitters in rats with genetic absence epilepsy and revealed, for the first time, increases in GABA concentrations concomitantly with the seizures, detected when our new microdialysis method was combined to electroencephalographic recordings.

Enhanced tail pinch-induced activation of catecholamine metabolism in the pericerulean area of RU 24722-treated rats.

Our study was devoted to determine in freely moving rats whether the increase in tissue concentration of tyrosine hydroxylase (TH) elicited by a single administration of RU 24722 could modify the catecholaminergic reactivity of neuronal processes present in the rostrolateral part of the pericerulean area (r-lPCA) in response to tail pinch. Catecholaminergic activity was monitored by measuring in vivo the concentration of dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) using microdialysis coupled to HPLC detection. In this study, the microdialysis probe was implanted at a sufficient distance from the lateral border of rostral nucleus locus ceruleus (LC) to avoid a large contribution of the noradrenergic cell bodies in the measurements performed. We first evidenced that DOPAC measured in the r-lPCA indicated the functional state of catecholaminergic metabolism in neuronal processes (dendrites and fibers) laying in this region. We also showed that the enhancement of TH protein concentration in the r-lPCA following RU 24722 treatment supported an increased in vivo catecholaminergic metabolism in this region. Furthermore, catecholaminergic metabolism response to tail pinch was potentiated in animals with greater TH tissue concentration. Thus, our study reveals that the modulation of both TH concentration and catecholaminergic metabolism in the r-lPCA may be critical in the functioning of cells and neuronal elements present in this region, notably in adaptive responses to noxious stimuli.

Simultaneous determination of vigabatrin and amino acid neurotransmitters in brain microdialysates by capillary electrophoresis with laser-induced fluorescence detection.

Capillary electrophoresis with laser-induced fluorescence detection (CE-LIFD) coupled to in vivo microdialysis sampling was used in order to monitor simultaneously a drug and several neurotransmitters in the brain extracellular fluid. Determination of the antiepileptic drug vigabatrin and the amino acid neurotransmitters glutamate (Glu), l-aspartate (l-Asp) and gamma-aminobutyric acid (GABA) was performed on low-concentration samples which were derivatized with naphthalene-2,3-dicarboxaldehyde (NDA) and separated using a pH 9.2 75 mM sodium borate running buffer containing 60 mM sodium dodecyl sulfate (SDS) and 5mM hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Glu, l-Asp and vigabatrin derivatized at a concentration of 1.0 x 10(-9) M, and GABA derivatized at a concentration of 5.0 x 10(-9) M, produced peaks with signal-to-noise ratios of 8:1, 8:1, 4:1 and 5:1, respectively. The nature of the neurotransmitter peaks found in rat brain microdialysates was confirmed by both electrophoretic and pharmacological validations. This method was used for monitoring vigabatrin and amino acid neurotransmitters in microdialysates from the rat striatum during intracerebral infusion of the drug and revealed rapid vigabatrin-induced changes in GABA and Glu levels. This original application of CE-LIFD coupled to microdialysis represents a powerful tool for pharmacokinetic/pharmacodynamic investigations.

Capillary electrophoresis combined with microdialysis in the human spinal cord: a new tool for monitoring rapid peroperative changes in amino acid neurotransmitters within the dorsal horn.

A method originally developed for the separation of the three neurotransmitters gamma-aminobutyric acid (GABA), glutamate (Glu) and L-aspartate (L-Asp) in microdialysis samples from rat brain (Sauvinet et al., Electrophoresis 2003, 24, 3187-3196) was applied to human spinal dialysates obtained during peroperative microdialysis from patients undergoing surgery against chronic pain. Molecules were tagged on their primary amine function with the fluorogene agent, naphthalene-2,3-dicarboxaldehyde (NDA), and, after separation by capillary electrophoresis (CE, 75 mmol/L borate buffer, pH 9.2, containing 70 mmol/L sodium dodecyl sulfate and 10 mmol/L hydroxypropyl-beta-cyclodextrin, + 25 kV voltage), were detected by laser-induced fluorescence detection (LIFD) using a 442 nm helium-cadmium laser. The complete method, including microdialysis sampling and analysis by CE-LIFD, has been validated for the analysis of human spinal microdialysates. The analytical detection limits were 1, 3.7 and 17 nmol/L for GABA, Glu and L-Asp respectively. This method allows an accurate measurement of the three amino acid neurotransmitters during an in vivo monitoring performed as rapidly as every minute in the human spinal dorsal horn. In addition, the effect of a brief peroperative electrical stimulation of the dorsal rootlets was investigated. The results obtained illustrate the advantages of combining microdialysis with CE-LIFD for studying neurotransmitters with such a high sampling rate.

Assessment of jugular blood oxygen and lactate indices for detection of cerebral ischemia and prognosis.

Levels of jugular blood oxygen saturation (SjvO2) and lactate have been proposed as indicators of cerebral ischemia and prognosis. However, sensitivity and specificity of these markers remain unknown. We retrospectively analyzed records of a series of 43 comatose patients at risk for cerebral ischemia, mainly after head injuries or subarachnoidal hemorrhage. Their SjvO2, jugulo-arterial lactate difference (VADLactate), and lactate-oxygen index (LOI) were determined every 8 hours. An increase in VADLactate and LOI was found, indicative of ischemia on CT scan, with threshold values of 0.30 mmol/L and 0.15, respectively. Sensitivity and specificity were 100% and 64%, respectively, for the VADLactate threshold, and 90% and 55%, respectively, for the LOI threshold. Regarding prediction of a poor outcome, only an increase in VADLactate had a predictive value with a sensitivity of 100% and specificity of 67%. No threshold value with sufficient sensitivity and specificity was found for SjvO2, as indicator of either ischemia or outcome. During progression to brain death, VADLactate and LOI reached abnormal levels earlier than cerebral perfusion pressure or SjvO2. They reacted markedly to focal ischemia due to vasospasm. Hyperlactacidemia rendered VADLactate and LOI uninterpretable by causing a brain lactate influx. Present data, if confirmed by a prospective study, would justify inclusion of intermittent VADLactate and LOI determinations in the multimodal cerebral monitoring.

In-vivo modulation of central 5-hydroxytryptamine (5-HT1A) receptor-mediated responses by the cholinergic system.

The aim of the present study was to investigate a putative modulation of rat 5-HT system by the muscarinic receptor antagonist atropine using in-vivo electrophysiological and behavioural techniques. In the dorsal raphe nucleus, administration of atropine (1 mg/kg i.v.) prevented the suppressant effect of the selective serotonin reuptake inhibitor paroxetine (0.5 mg/kg i.v.) on the spontaneous firing activity of 5-HT neurons, suggesting that atropine could induce an attenuation of somatodendritic 5-HT1A autoreceptors responsiveness. The 5-HT1A receptor agonist 8-OH-DPAT decreased both immobility in the forced swim test and the body core temperature. Pre-treatment with atropine (5 and 10 mg/kg i.p.) enhanced antidepressant-like effect of 8-OH-DPAT (1 mg/kg s.c.) and reduced 8-OH-DPAT (0.1 mg/kg s.c.)-induced hypothermia. In conclusion, the present study reports a functional role of muscarinic receptors in the modulation of pre- and post-synaptic 5-HT1A receptors mediated responses.