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PubMed2005

Role of nitric oxide in brain regions related to defensive reactions.

Nitric oxide synthase (NOS) positive neurons are located in most brain areas related to defensive reactions, including the dorsolateral periaqueductal grey (dlPAG). NOS inhibitors injected into this structure induce anxiolytic-like responses whereas NO donors promote flight reactions. Intra-dlPAG administration of carboxy-PTIO, a NO scavenger, or ODQ, a soluble guanylate cyclase inhibitor, produced anxiolytic-like effects on rats exposed to the elevated plus-maze (EPM). A double-staining experiment using NADPHd histochemistry and c-Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG, paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus. Cat exposure also increased activation of NOS neurons in the medial amygdala, dorsal pre-mammillary nucleus and bed nucleus of stria terminalis. Local infusion into the dlPAG of a glutamate NMDA-receptor antagonist (AP7) or a benzodiazepine agonist (midazolam) completely prevented the flight reactions induced by intra-dlPAG administration of SIN-1, a NO donor. The responses were also inhibited by the 5-HT2A/C agonist DOI but not by a 5-HT1A agonist. These results suggest a modulatory role for NO on brain areas related to defensive reactions, probably by interacting with glutamate, serotonin and/or GABA-mediated neurotransmission.

2-Amino-5-phosphonovalerate↗
PubMed2004

Spastic paretic hemifacial contracture (SPHC) in a patient with multiple sclerosis. A clinical, EMG and neuroimaging study.

We present the case of a 42-year-old woman with a 4-year history of definite multiple sclerosis (MS) and sustained contracture of the left hemiface with marked left deviation of the nose, deepened left nasolabial groove, narrowed palpebral fissure and weakness of the contracting muscles. Needle electromyography showed continuous resting activity of irregularly firing motor unit potentials (MUP) in the left orbicularis oculi (OO) and orbicularis oris, but not in the left frontalis. Simultaneous recording of maximal voluntary contraction of the OO on both sides showed marked preponderance on the right. Blink reflex findings were consistent with an injury in the pons, mainly in the vicinity of the left facial nucleus. A magnetic resonance imaging study showed multiple supra- and infra-tentorial white matter lesions, as well as multiple lesions at the level of the pons. Complete recovery was observed after 3 months. This condition has been described in cases of brainstem tumor as spastic paretic hemifacial contracture (SPHC). Up to now SPHC has not been explicitly associated with MS and, in this case, it could be arguably attributed to hyperexcitability of the facial neurons due to demyelination of the corticofacial fibers.

Adult↗
PubMed2004

Altered taste function in mice deficient in the 65-kDa isoform of glutamate decarboxylase.

The 65-kDa isoform of glutamate decarboxylase (GAD65) is considered to play an important role for GABA synthesis in the central nervous system. Using mice with targeted ablation of the GAD65 gene (GAD65(-/-) mice) we investigated a possible involvement of GABAergic neurotransmission in several taste functions. Preference/aversion responses to four basic tastes were not different between GAD65(-/-) and wild-type mice during a 48-h two-bottle choice test. GAD65(-/-) mice consumed less sucrose-quinine mixtures than did wild-type mice. The injection of midazolam (5 mg/kg), a benzodiazepine agonist, significantly increased the consumption of 100 mM sucrose in the wild-type mice. The same injection, however, failed to increase intake of the 100 mM sucrose in GAD65(-/-) mice. These results suggest that GAD65-generated GABA is not implicated in basic taste functions such as simple detection and discrimination. Rather, more complex processing of taste information including taste mixtures and palatability may be finely tuned by GAD65-mediated GABA synthesis.

Analysis of Variance↗
PubMed2006

Neuromodulatory effect of bromazepam on motor learning: an electroencephalographic approach.

To investigate the effects of bromazepam on motor performance and electroencephalographic activity (qEEG) in healthy subjects, during the process of learning a typewriting task, with a focused attention demand. A randomized double-blind model was used to allocate subjects in one of the following conditions: placebo (n=13), bromazepam 3 mg (n=13) or bromazepam 6 mg (n=13). Forty minutes after treatment administration, subjects were submitted to the motor task. EEG activity was recorded simultaneously. The analyzed variables were: number of errors and execution time, which were extracted from each block of the typewriting task, and mean relative power values in the beta band (13-35 Hz), extracted from the qEEG. A significantly lower number of typing errors was observed in both bromazepam conditions (Br 3 mg and Br 6 mg) when compared to the placebo. There was no difference between the two bromazepam conditions. For the execution time variable, a better performance was observed in the Br 3 mg condition, but with no statistical significance. The highest degree of cortical activation during the task was observed in Br 3 mg and Br 6 mg when compared to placebo. The medication's anxiolytic effect intensifies the attentional focus over predictable events occurring in reduced perceptual fields. The qEEG's accentuated response in pre-motor and primary motor areas suggests a greater effort directed to the most relevant aspects of the task. In short, the doses employed (3 and 6 mg) seem to enhance the learning of motor tasks that involve focused attention, such as typewriting.

Adult↗
PubMed2004

Local and remote functional connectivity of neocortex under the inhibition influence.

The current paper focuses on a relatively new and promising area of the study of EEG transformations during brain information processing based on the reduction of the signal to the discrete quasi-stationary segment sequences which may reflect individual brain microstates or discrete operations. In this framework, the complex brain functions require integration of several operations throughout the whole neocortex. However, the role of inhibitory brain systems in such processes is still unsettled. The effects of a single dose (30 microg/kg) of lorazepam on the operational activity of neuronal populations and on the temporal binding between them were examined in a double-blind randomized crossover placebo-controlled study with eight healthy volunteers. EEG measures at 20 channels were evaluated on two occasions: (1) eyes closed, (2) eyes open. In short, we conducted a two-by-two factorial study where one factor manipulated GABAergic neurotransmission (lorazepam vs. placebo), and the other factor was simply brain state (eyes closed vs. eyes opened). We were primarily interested in the main effect of lorazepam. In the present study, a connection between the mesoscopic level, described by the local functional processes (neuronal assemblies or populations) and the macroscopic level, described as a sequence of metastable brain states (remote functionally synchronized neuronal populations) was established. The role of inhibitory brain systems facilitated by lorazepam in the operational dynamics of neuronal populations and in the process of EEG structural synchrony (SS) (topological peculiarities) was addressed for the first time. It was shown that GABA signaling reorganized the dynamics of local neuronal populations and the remote functional connectivity between them.

Adult↗
PubMed2005

Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats.

The benzodiazepine diazepam impairs memory and long-term potentiation (LTP) in the hippocampus. Here, we investigate the effect of diazepam on LTP of C-fiber evoked field potentials in spinal dorsal horn, which is relevant to pathological pain. LTP of C-fiber evoked field potentials was recorded in the superficial layers of spinal dorsal horn in urethane-anesthetized Sprague--Dawley rats. Diazepam was applied locally at the recording spinal segments before and after LTP induction by tetanic stimulation. We found (1) Diazepam completely blocked LTP induction. (2) Diazepam and midazolam reversed spinal LTP, when applied at 30 min after LTP induction and depressed but could not reverse spinal LTP, when applied at 3 h after LTP induction. (3) Pretreatment with benzodiazepine receptor antagonist flumazenil or GABA(A) receptor antagonist bicuculline completely blocked the inhibitory effects of diazepam on spinal LTP. In contrast, when the inhibitory effect of diazepam was fully established, neither of these antagonists was capable of reversing the inhibition by diazepam. (4) Spinal application of the GABA(A) receptor agonist 3-amino-1-propanesulfonic acid (3-APSA) at a dose of 50 microg, produced a transient inhibition of spinal LTP. These results suggest that diazepam might prevent and depress spinal plastic change produced by noxious stimulation via activation of the GABA(A) -benzodiazepine receptor complex.

Animals↗
PubMed2006

Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent.

Literature data have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II/III mGluRs show anxiolytic-like properties in preclinical studies. However data reporting anxiolytic-like action of group III mGlu receptor antagonists were also published. In the present paper we investigated the anxiolytic-like activity of the group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). To examine its anxiolytic-like effects, the basolateral amygdala was chosen as an injection site, as this brain region is involved in the regulation of anxiety-related behavior. To detect anxiolytic-like activity, the Vogel conflict-drinking test in rats was used. Intra-amygdalar injections of CPPG exhibited dose-dependent, potent anxiolytic-like action at a dose of 75 nmol, which was blocked by a concomitant administration of the group III mGlu receptor agonist CI (S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) at a dose of 7.5 nmol. The benzodiazepine receptor antagonist flumazenil (given intraperitoneally, 10 mg/kg) did not change the anxiolytic-like effect of CPPG, but that effect was abolished by the non-selective antagonist of 5-HT receptors metergoline and the antagonist of 5-HT2A/C receptors ritanserin (both given intraperitoneally at doses of 2 and 0.5 mg/kg, respectively). These findings suggest that the blockade of group III mGlu receptors in the amygdala is responsible for anxiolysis and that serotonergic, but not the benzodiazepine recognition site of the GABA-ergic system are involved in the anxiolytic-like response induced by group III mGlu antagonist.

Animals↗
PubMed2006

Benzodiazepine inhibits hypothalamic presympathetic neurons by potentiation of GABAergic synaptic input.

Presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus receive inputs from gamma-aminobutyric acid (GABA)-containing neurons, which regulate sympathetic outflow and cardiovascular function. Benzodiazepines can decrease blood pressure and sympathetic nerve activity when used for induction of anesthesia, but the sites and mechanisms of action are uncertain. In this study, we determined the effect of the benzodiazepine agonist diazepam on GABAergic inhibitory postsynaptic currents (IPSCs) and the firing activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons. RVLM-projecting PVN neurons were retrogradely labeled by fluorescent microspheres injected into the RVLM in rats. Whole-cell and cell-attached recordings were performed on labeled PVN neurons in the hypothalamic brain slice. Bath application of 1-10 microM diazepam significantly increased the decay time constants of the GABAergic miniature IPSCs and evoked IPSCs in a dose-dependent manner. Also, diazepam significantly increased the amplitude of evoked IPSCs but not of miniature IPSCs. Pretreatment with the benzodiazepine antagonist flumazenil completely blocked the diazepam-induced increases in the amplitude and decay time constants of the evoked IPSCs. Furthermore, diazepam significantly decreased the firing activity of PVN-RVLM neurons that responded with increased firing to the GABA(A) receptor antagonist bicuculline. In contrast, diazepam had no significant effect on the firing activity of bicuculline-unresponsive PVN-RVLM neurons. This study provides new information that the benzodiazepine suppresses the firing activity of PVN presympathetic neurons by potentiation of GABAergic inputs.

Action Potentials↗
PubMed2003

Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain.

Short-term exposure of adult rats to nitrous oxide (N2O), an inhalational anesthetic and NMDA (N-methyl-D-aspartate) antagonist, causes a reversible neurotoxic vacuole reaction in neurons of the posterior cingulate/retrosplenial cortex (PC/RSC) which resembles that caused by low doses of other NMDA antagonists. Since high doses or prolonged exposure to other NMDA antagonists can cause neurons to die, we assessed whether prolonged N2O exposure might also cause neuronal cell death. Adult female Sprague-Dawley rats were exposed to 150-vol% N2O (approximately EC50 for N2O anesthesia in rats) for various durations from 1 to 16 h. The time course for onset and disappearance of the reversible vacuole reaction was studied, as was the time course and dose requirement for triggering cell death. A maximum vacuole reaction was observed in PC/RSC neurons in brains examined immediately after 3 h of 150-vol% N2O exposure and the same magnitude of vacuole reaction was observed when brains were examined immediately after a longer period of N2O exposure. When N2O was terminated at 3 h and the rats were killed 1 h later, the vacuole reaction was markedly diminished and if the rats were killed 3 h later the vacuole reaction had completely disappeared. Prolonged exposure to 150-vol% N2O (for 8 h or more) caused neuronal cell death which was detectable by silver staining 32 h later. Concurrently administered GABAergic agents, diazepam (an i.v. anesthetic), or isoflurane (an inhalational anesthetic), prevented this cell death reaction. Our findings demonstrate that short-term exposure of adult rats to N2O causes injury to PC/RSC neurons that is rapidly reversible, and prolonged N2O exposure causes neuronal cell death. These neurotoxic effects, including the cell death reaction, can be prevented by coadministration of GABAmimetic anesthetic agents. Duration of NMDA receptor blockade appears to be an important determinant of whether neurons are reversibly injured or are driven to cell death by an NMDA antagonist drug.

Analysis of Variance↗
PubMed2005

Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions.

Stress increases plasma and brain concentrations of corticosteroids and neuroactive steroids. Cortisol is the most important stress hormone in the hypothalamic pituitary adrenocortical system. However, significant amounts of the mineralocorticoid deoxycorticosterone are also released during stress. Deoxycorticosterone undergoes biotransformation to allotetrahydrodeoxycorticosterone, a neuroactive steroid with anxiolytic and anticonvulsant properties. Our studies indicate that the anticonvulsant activity of deoxycorticosterone is mediated by its conversion to allotetrahydrodeoxycorticosterone, which is a potent positive allosteric modulator of GABA(A) receptors. Although the role of allotetrahydrodeoxycorticosterone within the brain is undefined, recent studies indicate that stress induces increases in allotetrahydrodeoxycorticosterone to levels that can activate GABA(A) receptors. These results might have significant implications for human stress-sensitive conditions such as epilepsy, panic disorder, post-traumatic stress disorder, and major depression. In epilepsy, a role for adrenal allotetrahydrodeoxycorticosterone in seizure susceptibility has been suggested. Recent preclinical studies indicate a role of neuroactive steroids in ethanol actions. Although these studies provide a better understanding of the role of allotetrahydrodeoxycorticosterone and related neuroactive steroids in acute stress, further studies are clearly warranted to ascertain the specific role of neuroactive steroids in the pathophysiology of chronic stress and related brain conditions.

Adrenal Cortex↗
PubMed2006

Midazolam disrupts fear memory reconsolidation.

The current research examines the influence of midazolam (MDZ) on memory reconsolidation using a contextual fear paradigm in rats, based on three context-shock training trials (0.7 mA, 3 s). First, we evaluate the effect of MDZ (1 mg/kg, i.p.) injected shortly after the training procedure. Second, we examined the influence of MDZ after a brief exposure (90 s) either in the training context (reactivation procedure) or in a neutral environment (no reactivation procedure) and one day later, freezing behavior was scored when rats were re-exposed to the training environment. Third, we investigate both the effect of MDZ administered at different times following reactivation on fear memory and the persistence of such effect 10 days after reactivation. Finally, we test whether the MDZ effect could be reverted by a single weak training trial (0.2 mA, 3 s) or by the presentation of the same unconditioned stimulus in the absence of the conditioned stimulus as a reminder which proves to induce significant freezing in rats not previously trained. Results show that MDZ interferes with the formation of a contextual fear memory only when administered after the reactivation procedure but not after the training procedure. This interference was effective up to 60 min after reactivation and not at a later time. No spontaneous recovery of freezing behavior was observed 11 days after MDZ injection which was not reverted by a weak training trial and by the unconditioned stimulus alone. All these data support the idea that stimulating GABA A receptor sites via MDZ selectively disrupts the reconsolidation process of a contextual fear memory.

Animals↗
PubMed2004

Flumazenil positron emission tomography and other ligands for functional imaging.

Most PET receptor studies in idiopathic generalized epilepsy conducted to date include only small numbers of patients and should be interpreted with caution. Differences between earlier and later studies can largely be explained by different inclusion criteria and improving methodology. The finding of some increase of GABAA receptor binding in IGE has a potential pathologic basis in microdysgenesis. Future studies aiming to elucidate the pathophysiology of IGEs may benefit from the use of subtype-specific opioid ligands, available now, and GABAB ligands, if and when they become available.

Brain↗
PubMed2007

Ganaxolone.

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. GNX is an allosteric modulator of GABA(A) receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. GNX has been shown to be well tolerated in adults and children. In early phase II studies, GNX has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures.

Animals↗
PubMed2003

GABAergic agents prevent alpha-melanocyte stimulating hormone induced anxiety and anorexia in rats.

Alpha-melanocyte stimulating hormone (alpha-MSH) is a hypothalamic peptide believed to play a tonic inhibitory role in feeding and energy homeostasis. Systemic administration of alpha-MSH is known to produce anorexia and anxiety. Since synaptic contacts between gamma-aminobutyric acid (GABA)ergic terminals and alpha-MSH neurons in the hypothalamus have been reported, the present work was undertaken to refine our knowledge on the role of GABAergic systems in anxiety and anorexia induced by intracerebroventricular (icv) administration of alpha-MSH in rats. The anxiety was assessed by elevated plus maze, and spontaneous food consumption was monitored during dark cycle. Prior administration of diazepam and muscimol that promote the function of GABA(A) receptors reversed the anxiogenic response and decreased food intake elicited by alpha-MSH. In contrast, bicuculline, the GABA(A) receptor antagonist, not only enhanced the effects of alpha-MSH but also prevented the influence of GABAergic drugs on alpha-MSH-induced anorexia and anxiety. These findings suggest that alpha-MSH-induced anxiety and anorexia are due to its negative influence on GABAergic system.

Animals↗
PubMed2004

Sedative and sleep-enhancing properties of linarin, a flavonoid-isolated from Valeriana officinalis.

We have recently reported the presence of the anxiolytic flavone 6-methylapigenin (MA) and of the sedative and sleep-enhancing flavanone glycoside 2S (-) hesperidin (HN) in Valeriana officinalis and Valeriana wallichii. MA, in turn, was able to potentiate the sleep-inducing properties of HN. The present paper reports the identification in V. officinalis of the flavone glycoside linarin (LN) and the discovery that it has, like HN, sedative and sleep-enhancing properties that are potentiated by simultaneous administration of valerenic acid (VA). These effects should be taken into account when considering the pharmacological actions of valeriana extracts.

Animals↗
PubMed2004

Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task.

Dehydroepiandrosterone (DHEA) exerts multiple effects in the rodent central nervous system (CNS), mediated through its nongenomic actions on several neurotransmitter systems, increasing neuronal excitability, modulating neuronal plasticity and presenting neuroprotective properties. It has been demonstrated that DHEA is a potent modulator of GABA(A), NMDA and Sigma receptors. In the present study, we investigated the effect of DHEA on (i) basal- and K(+)-stimulated l-[(3)H]glutamate release from synaptosomes (both in vitro and ex vivo), (ii) synaptosomal l-[(3)H]glutamate uptake (in vitro), and (iii) an inhibitory avoidance task (in vivo). The results indicated that DHEA in vitro increased glutamate release by 57%, and its intracerebroventricular infusion increased the basal-[(3)H]glutamate release by 15%. After 30 min of intraperitoneal administration, DHEA levels in the serum or CSF increased 33 and 21 times, respectively. Additionally, DHEA, intraperitoneally administrated 30 min before training, improved memory for inhibitory avoidance task. Concluding, DHEA could improve memory on an inhibitory avoidance task, perhaps due to its ability to physiologically strength the glutamatergic tonus by increasing glutamate release.

Animals↗
PubMed2004

Evidence that muscarinic receptors are involved in nicotine-facilitated spatial memory.

A delayed nonmatching-to-position task (DNMPT) in a water maze (nine trials per day, 10 days) was used to investigate the role of muscarinic acetylcholinergic receptor (mAChR) in nicotine-facilitated spatial memory in Wistar rats. The index of spatial memory was determined by the number of correct choices made in choice swim (CS) and the time taken to complete the swim in the correct CS. Diazepam (6 mg kg(-1) ip, daily) significantly impaired choice accuracy and increased the swim time for correct CS. In contrast, when nicotine (2 mg kg(-1) sc, twice daily) and diazepam were administered simultaneously in the last three sessions of training, the choice accuracies of CS were similar to controls and significantly higher than in the diazepam group. However, the swim times for correct CS were longer in the nicotine+diazepam group than in controls. Atropine (30 mg kg(-1) ip, daily) significantly decreased the choice accuracies of CS. The choice accuracies of CS swim times for correct CS in the atropine group did not differ significantly from those in the nicotine+atropine group, in which nicotine (2 mg kg(-1) sc, twice daily) and atropine were given simultaneously. These results show that nicotine improves memory performance when the functions of mAChRs are normal; when the mAChRs are blocked, nicotine does not enhance spatial memory. Therefore, mAChRs are involved in the spatial memory-enhancing effect of nicotine.

Animals↗
PubMed2007

A possible mechanism for anxiolytic and antidepressant effects of alpha- and beta-amyrin from Protium heptaphyllum (Aubl.) March.

In the present study, we examined the anxiolytic and antidepressant effects of the mixture of alpha- and beta-amyrin (AMY), pentacyclic triterpenes isolated from the stem bark resin of Protium heptaphyllum. These effects of AMY were demonstrated by the open-field, elevated-plus-maze, rota rod, forced swimming, and pentobarbital-induced sleeping time tests, in mice. In the open-field test, AMY at the doses of 10, 25 and 50 mg/kg, after intraperitoneal or oral administrations, significantly decreased the number of crossings, grooming, and rearing. All these effects were reversed by the pre-treatment with flumazenil (2.5 mg/kg, i.p.), similarly to those observed with diazepam used as a positive standard. In the elevated-plus-maze test, AMY increased the time of permanence and the number of entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed arms were decreased. All these effects were also completely reversed by flumazenil, an antagonist of benzodiazepine receptors. In the pentobarbital-induced sleeping time test, AMY at the same doses significantly increased the animals sleeping time duration. In the rota rod test, AMY did not alter motor coordination and, thus, was devoid of effects, as related to controls. Since AMY, at the doses of 10 and 25 mg/kg, showed a sedative effect in the open field test, lower doses (2.5 and 5.0 mg/kg) were used in the forced swimming test, producing a decrease in the immobility time, similarly to that of imipramine, the positive control. The effect of AMI was greater when it was administered 15 min after imipramine (10 mg/kg). However, the antidepressant AMY effects were not altered by the previous administration of paroxetine, a selective blocker of serotonin uptake. In addition, AMY effects in the forced swimming test were totally blocked by reserpine pretreatment, a drug known to induce depletion of biogenic amines. In conclusion, the present work evidenced sedative and anxiolytic effects of AMY that might involve an action on benzodiazepine-type receptors, and also an antidepressant effect where noradrenergic mechanisms will probably play a role.

Animals↗