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PubMed2004

Venlafaxine in children and adolescents with attention deficit hyperactivity disorder.

The primary purpose of this study was to describe tolerability and efficacy of venlafaxine in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). A 6-week open trial of venlafaxine was conducted in 13 children and adolescents (mean age 9.9 +/- 2.5 years) with ADHD, and without comorbid depression. Venlafaxine was initiated at a dose of 18.75 mg/day and flexibly titrated to 56.25 mg/day. The Conners parent scale and Clinical Global Improvement (CGI) severity item were performed at baseline and at the end of the 6-week trial. All subjects completed the trial. Mean final dose of venlafaxine was 40.3 +/- 7.0. Venlafaxine was significantly effective in reducing the total score of the Conners parent scale from baseline to endpoint (P < 0.002, Z =-3.113) and the CGI severity item (P < 0.05). Transient side-effects such as somnolence (n = 2), stomachache (n = 2), and headache (n = 1) disappeared after second week of treatment. Also three subjects complained of sedation after raising the dose to 56.5 mg/day, therefore the dose was reduced to the previous level. These preliminary data suggest that venlafaxine may be an effective medication in the treatment of some children and adolescents with ADHD. Future double-blind controlled trials should be undertaken.

Adolescent↗
PubMed2006

Comparison of venlafaxine extended release versus paroxetine for treatment of patients with generalized anxiety disorder.

This trial was to evaluate the efficacy and tolerability of venlafaxine extended release (XR) and paroxetine for treatment of patients with generalized anxiety disorder (GAD). Sixty patients who met DSM-IV criteria for GAD were randomly assigned to either venlafaxine XR or paroxetine for 8 weeks. Efficacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression-Severity of Illness (CGI-S) scale at the baseline, week 1, week 4, and week 8. The side-effects were collected with reported adverse events and laboratory tests throughout the study period. Repeated measures analysis of variance (ANOVA) on the HAM-A and CGI-S scores showed a significant decrease over time in both treatment groups without significant group difference or time x group interaction effect. There were no serious adverse events in both groups. This open trial demonstrated that either venlafaxine XR or paroxetine would be effective and tolerable for the treatment of patients with GAD. Double blind, placebo-controlled head-to-head comparison studies are needed to draw a definite conclusion.

Adult↗
PubMed2003

Single olfactory sensory neurons simultaneously integrate the components of an odour mixture.

Most odours are complex mixtures. However, the capacities of olfactory sensory neurons (OSNs) to process complex odour stimuli have never been explored in air-breathing vertebrates. To face this issue, the present study compares the electrical responses of single OSNs to two odour molecules, delivered singly and mixed together, in rats in vivo. This work is the first aimed at demonstrating that single OSNs simultaneously integrate several chemical signals and which, furthermore, attempts to describe such processes for the whole concentration range over which single OSNs can work. The results stress that complex interactions occur between components in odour mixtures and that OSN responses to such mixtures are not simply predictable from the responses to their components. Three types of interactions are described. They are termed suppression, hypoadditivity and synergy, in accord with psychophysical terminology. This allows us to draw links between peripheral odour reception and central odour coding. Indeed, events occurring in single OSNs may account for the dominating or even the masking effects of odour molecules in complex mixtures, i.e. for the prevailing action of a minor component in the final qualitative perception of a mixture. We conclude that our observations with binary mixtures anticipate the complexity of processes which may rise at the level of a single OSN in physiological conditions. Following this hypothesis, a natural odour would induce a multi-chemical integration at the level of single OSNs which may result in refining their individual odour-coding properties, leading them to play a crucial role in the final performance of the olfactory system.

Action Potentials↗
PubMed1998

Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells.

1. CB-1 cannabinoid receptors are strongly expressed in the molecular layer of the cerebellar cortex. We have analysed, in patch-clamped Purkinje cells (PCs) in rat cerebellar slices, the effect of the selective CB-1 agonists WIN55,212-2 and CP55,940 and of the selective CB-1 antagonist SR141716-A on excitatory synaptic transmission and synaptic plasticity. 2. Bath application of both agonists markedly depressed parallel fibre (PF) EPSCs. This effect was reversed by SR141716-A. In contrast, responses of PCs to ionophoretic application of glutamate were not affected by WIN55, 212-2. 3. The coefficient of variation and the paired-pulse facilitation of these PF-mediated EPSCs increased in the presence of WIN55,212-2. 4. WIN55,212-2 decreased the frequency of miniature EPSCs and of asynchronous synaptic events evoked in the presence of strontium in the bath, but did not affect their amplitude. 5. WIN55, 212-2 did not change the excitability of PFs. 6. WIN55,212-2 impaired long-term depression induced by pairing protocols in PCs. This effect was antagonized by SR141716-A. The same impairment of LTD was produced by 2-chloroadenosine, a compound that decreases the probability of release of glutamate at PF-PC synapses. 7. The present study demonstrates that cannabinoids inhibit synaptic transmission at PF-PC synapses by decreasing the probability of release of glutamate, and thereby impair LTD. These two effects might represent a plausible cellular mechanism underlying cerebellar dysfunction caused by cannabinoids.

Animals↗
PubMed2001

Signal transduction of cannabinoid CB1 receptors in a smooth muscle cell line.

1. The effects of cannabinoid (CB) receptor stimulation on membrane currents in single cells from the Syrian hamster vas deferens cell line DDT1MF-2 were investigated using the whole cell patch clamp technique. 2. The CB receptor agonist CP55,940 evoked a concentration-dependent transient outward current. The selective CB1 receptor ligand SR141716 (1 microM), but not the selective CB2 receptor ligand SR144528 (1 microM), inhibited the outward current. Pertussis toxin (100 ng ml-1 for 20 h) completely abolished the outward current. 3. Western blotting with an antibody against the rat (r)CB1 receptor showed a band characteristic for the CB1 receptor around 63 kDa in DDT1MF-2 cells. 4. The reversal potential for the outward current measured using a voltage ramp protocol was -84 +/- 5 mV. The current was inhibited by the Ca2+-dependent K+ channel blockers iberiotoxin (10 nM) and charybdotoxin (10 nM). 5. Removal of Ca2+ from the bathing solution, or the addition of 0.1 mM Cd2+ completely abolished the outward current evoked by 10 microM CP55,940. 6. The sarcoplasmic Ca2+ pump inhibitor thapsigargin reduced the outward current evoked by 10 microM CP55,940 in a concentration-dependent manner. 7. The mitogen-activating protein kinase (MAP kinase) inhibitor PD98059, but not the phospholipase C inhibitor U73122, inhibited the outward current evoked by 10 microM CP55,940. 8. The adenylyl cyclase inhibitor SQ22,536 (100 microM) and 8-Br-cyclic AMP (10 microM) significantly reduced the outward current evoked by 10 microM CP55,940. 9. Our data suggest that CB1 receptor stimulation in DDT1MF-2 cells leads to activation of a large conductance Ca2+-dependent K+ channel through a Gi/Go protein-mediated rise in [Ca2+]i, for which both inhibition of adenylyl cyclase and activation of MAP kinase are required. In addition, the cannabinoid-induced increase in [Ca2+]i is likely to arise from capacitive Ca2+ entry.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Response properties of isolated mouse olfactory receptor cells.

Response properties of isolated mouse olfactory receptor cells were investigated using the suction pipette technique. Cells were exposed to the odour cineole or to solutions of modified ionic content by rapidly changing the solution superfusing the cilia. All experiments were performed at 37 degrees C. Mouse olfactory receptor cells displayed a steep dependence of action potential frequency on stimulus concentration, a 3-fold increase in stimulus concentration often saturating the firing frequency at 200-300 Hz. The receptor current increased more gradually with increasing cineole concentration and did not saturate within the 100-fold range of cineole concentrations applied. When stimulated for 30 s with a low odour concentration, cells responded with sporadic spike firing. Higher concentrations led to the generation of a large receptor current at the onset of stimulation which returned to baseline levels within a few seconds, accompanied during its rising phase by a short burst of action potentials. Thereafter an oscillating response pattern was observed during the remainder of the stimulus, consisting of repetitive increases in receptor current of around 1 s duration accompanied by short bursts of action potentials. Olfactory adaptation was studied by comparing the responses to two closely spaced odour stimuli. The response to the second odour stimulus recovered to 80% of its original magnitude when the cell was superfused with Ringer solution during the 5 s interval between odour exposures. In contrast, exposure to a choline-substituted low Na+ solution between odour stimuli had two effects. First, the receptor current response to the first odour stimulus did not terminate as quickly as in the presence of Na+, suggesting the presence of a Na+ -Ca2+ exchanger. Second, the response to the second stimulus only recovered to 55% of its original magnitude, demonstrating the involvement of Na+-Ca2+ exchange in the recovery of sensitivity in mouse olfactory receptor cells following stimulation.

Action Potentials↗
PubMed1992

Ca(2+)-dependent release from rat brain of cannabinoid receptor binding activity.

As a result of the identification, pharmacological characterization, and localization of the cannabinoid receptor in the CNS, the existence of an endogenous ligand for this receptor can be hypothesized. Following the premise that such a substance could have the properties of a neuromodulator being stored in intracellular vesicles, we tested the ability of increased intracellular Ca2+ levels to stimulate release. We demonstrate here that the Ca2+ ionophore A23187 can induce release of cannabinoid-like binding activity in the presence but not in the absence of Ca2+. The effect of A23187 was maximal at 1.2 microM, consistent with vesicular release. It was necessary to increase the concentration of extracellular free Ca2+ to greater than 60 nM to evoke release. The released cannabinoid-like binding activity displaced [3H]CP-55940 binding to cannabinoid receptors in rat synaptosomal membranes in a concentration-dependent manner. This is the first report of a substance present endogenously in brain that can be released in a Ca(2+)-dependent manner and that binds to the cannabinoid receptor.

Animals↗
PubMed2004

The response of synaptophysin and microtubule-associated protein 1 to restraint stress in rat hippocampus and its modulation by venlafaxine.

As part of our continuing study of neural plasticity in rat hippocampus, we examined two structural proteins involved in neuronal plasticity, synaptophysin (SYP) and microtubule-associated protein 1 (MAP1) for their response to repeated restraint stress and modulation of such response by the antidepressant drug venlafaxine. This drug has the pharmacological action of inhibiting the reuptake of serotonin and norepinephrine in nerve terminals. We subjected the rats to restraint stress for 4 h per day for three days, and then injected the animals intraperitoneally (i.p.) with vehicle or 5 mg/kg/day of venlafaxine for various time periods. In all, eight groups of 10 rats each were used. The expression of these two proteins in hippocampal tissue of the rats was examined by means of western blot and immunohistochemical staining techniques. We found that restraint stress decreased the expression of SYP in the rat hippocampus by 50% (p < 0.01), and increased the expression of MAP1 by 60% (p < 0.01). SYP returned to the pre-stress levels in three weeks and MAP1 in two weeks. In animals treated with venlafaxine post-stress, SYP returned to pre-stress levels after 2 weeks and MAP1 after 1 week. These findings enhance our understanding of the compromise of the hippocampus by stressful assaults, and may be relevant to the action of venlafaxine in the treatment of patients with major depression, a mental disease thought to be related to the mal-adaptation of subjects to environmental stressors.

Animals↗
PubMed2005

Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects.

We investigated the role of the Ras/extracellular-regulated kinase (ERK) pathway in the development of tolerance to Delta(9)-tetrahydrocannabinol (THC)-induced reduction in spontaneous locomotor activity by a genetic (Ras-specific guanine nucleotide exchange factor (Ras-GRF1) knock-out mice) and pharmacological approach. Pre-treatment of wild-type mice with SL327 (50 mg/kg i.p.), a specific inhibitor of mitogen-activated protein kinase kinase (MEK), the upstream kinase of ERK, fully prevented the development of tolerance to THC-induced hypolocomotion. We investigated the impact of the inhibition of ERK activation on the biological processes involved in cannabinoid tolerance (receptor down-regulation and desensitization), by autoradiographic cannabinoid CB1 receptor and cannabinoid-stimulated [(35)S]GTPgammaS binding studies in subchronically treated mice (THC, 10 mg/kg s.c., twice a day for 5 days). In the caudate putamen and cerebellum of Ras-GRF1 knock-out mice and SL327 pre-treated wild-type mice, CB1 receptor down-regulation and desensitization did not occur, suggesting that ERK activation might account for CB1 receptor plasticity involved in the development of tolerance to THC hypolocomotor effect. In contrast, the hippocampus and prefrontal cortex showed CB1 receptor adaptations regardless of the genetic or pharmacological inhibition of the ERK pathway, suggesting regional variability in the cellular events underlying the altered CB1 receptor function. These findings suggest that at least in the caudate putamen and cerebellum, the Ras/ERK pathway is essential for triggering the alteration in CB1 receptor function responsible for tolerance to THC-induced hypomotility.

Aminoacetonitrile↗
PubMed2004

Effects of venlafaxine on ethanol withdrawal syndrome in rats.

The present study was designed to investigate the effects of venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), on ethanol withdrawal syndrome in rats. Adult male Wistar rats (187-319 g) were used for the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair-fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Venlafaxine (5, 10, 20 and 40 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behaviour and wet dog shakes were recorded or rated. A second series of injections was given at the 6th hour after the first one, and rats were then tested for audiogenic seizures. Venlafaxine produced some inhibitory effects on locomotor hyperactivity, stereotypic behaviours and wet dog shakes. However, a two-way anova of the data did not indicate any significant effect. It reduced the incidence of the audiogenic seizures at the 6th hour of ethanol withdrawal. Venlafaxine (20 mg/kg) also prolonged the latency of the seizures significantly. Our results suggest that acute venlafaxine treatment has limited beneficial effects on ethanol withdrawal syndrome in rats.

Analysis of Variance↗
PubMed1984

The effects of 3,5,5-trimethylcyclohexanol on hepatic cholesterol synthesis, bile flow and biliary lipid secretion in the rat.

The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat. In both acute and long-term dosing experiments TMC significantly inhibited hepatic S-3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. TMC was a potent choleretic, with detectable effects on bile flow at low doses, which also reduced coupling of cholesterol secretion to bile salt secretion. Single large doses tended to lower biliary cholesterol output and caused significant reduction in cholesterol saturation index after biliary diversion for 1 h. TMC and its widely prescribed ester cyclandelate, which is rapidly degraded to TMC after ingestion, should be investigated further as potential cholelitholytic treatments in man.

Animals↗
PubMed1992

Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism.

Cannabinoid receptor ligands irreversibly inhibited peak voltage-activated Ca currents (44%) in NG108-15 cells; this inhibition was Pertussis toxin-sensitive. Inhibition was largely due to a reduction in the omega-conotoxin sensitive portion of high-voltage activated (HVA) current, although there was also a significant decrease in low-voltage activated current (56%) and in the nifedipine-sensitive portion of HVA current (41%).

Analgesics↗
PubMed1993

Cross-tolerance between delta-9-tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212-2 and anandamide.

1. Mice pretreated intraperitoneally for 2 days with delta-9-tetrahydrocannabinol (delta-9-THC) at a dose of 20 mg kg-1 day-1 and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta-9-THC. This pretreatment also induced tolerance to the hypothermic effects of the cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212-2 (4.9 fold), but not to the hypothermic effect of the putative endogenous cannabinoid, anandamide. 2. Vasa deferentia removed from mice pretreated intraperitoneally with delta-9-THC twice at a dose of 20 mg kg-1 day-1 were less sensitive to its inhibitory effect on electrically-evoked contractions than vasa deferentia obtained from control animals. The cannabinoid pretreatment induced a 30 fold parallel rightward shift in the lower part of the concentration-response curve of delta-9-THC and a marked reduction in the maximal inhibitory effect of the drug. It also induced tolerance to the inhibitory effects on the twitch response of CP 55,940 (8.7 fold), WIN 55,212-2 (9.6 fold) and anandamide (12.3 fold). 3. The results confirm that cannabinoid tolerance can be rapid in onset and support the hypothesis that it is mainly pharmacodynamic in nature. The finding that in vivo pretreatment with delta-9-THC can produce tolerance not only to its own inhibitory effect on the vas deferens but also to that of three other cannabimimetic agents, suggests that this tissue would be suitable as an experimental model for investigating the mechanisms responsible for cannabinoid tolerance. 4. Further experiments are required to establish why tolerance to anandamide-induced hypothermia was not produced by a pretreatment with delta-9-THC that did induce tolerance to the hypothermic effects of delta-9-THC, CP 55,940 and WIN 55,212-2 and to the inhibitory effects of delta-9-THC,CP 55,940, WIN 55,212-2 and anandamide on the twitch response of the vas deferens.

Amides↗
PubMed1996

Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine.

1. CP 50,556, CP 55,940, nabilone, CP 56,667, delta 9 -tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.46, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [3H]-CP 55,940 from cannabinoid binding sites. 2. Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50 = 1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens. 3. SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 microM) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine. 4. Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2. 5. Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 microM SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940. 6. These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine. 7. THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor. 8. At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.

Acetylcholine↗