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PubMed2005

Effect of noradrenergic system on the anxiolytic-like effect of DOI (5-HT2A/2C agonists) in the four-plate test.

RATIONALE: Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors demonstrated an anxiolytic-like effect in the four-plate test (FPT). (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; a 5-HT2A receptor agonist) also possessed strong anxiolytic-like effect in the same test. A 5-HT2A mechanism seems to be implicated in the mechanism of action of both antidepressants and DOI in this test. On the other hand, the alpha-adrenergic ligands have also demonstrated an activity in other models of anxiety. A previous study demonstrated that the alpha2-adrenoceptor agonists abolished the anxiolytic-like effect of antidepressants. OBJECTIVES: The aim of the present study was to evaluate the role of noradrenergic system on the regulation of 5-HT2 receptors implicated in the DOI anxiolytic-like activity in the FPT. METHODS: First, the effect of noradrenergic and serotonergic lesions on DOI anxiolytic-like activity was studied in the FPT. Second, the effect of co-administration of alpha-adrenoceptor ligands and DOI was evaluated in the same test. RESULTS: The noradrenergic and serotonergic lesions had no effect on DOI (1 mg/kg) anti-punishment activity in the FPT. Adrafinil 0.25 and 4 mg/kg (an alpha1-adrenoceptor agonist), prazosin 0.5 and 2 mg/kg (an alpha1-adrenoceptor antagonist) and idazoxan 1 and 4 mg/kg (an alpha2-adrenoceptor antagonist) did not modify the activity of DOI. Clonidine 0.06 mg/kg, guanabenz 0.125 and 0.5 mg/kg (two alpha2-adrenoceptor agonists) and guanfacine 0.06 and 0.125 mg/kg (a specific alpha2A-adrenoceptor agonist) completely abolished DOI-induced increase in punished passages. CONCLUSION: These results indicate that the DOI seems to act on the 5-HT2 receptors post-synaptically located. The effect of DOI is regulated by the alpha2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed2005

Some facilitatory effects of lorazepam on dynamic visual binding.

RATIONALE: The benzodiazepine lorazepam enhances the potential for inhibitory gamma-aminobutyric acid (GABAA) synapses in the cortex to stabilize postsynaptic, excitatory activity by synchronizing discharge rates at frequencies of around 40 Hz. Treatment with lorazepam also affects contour integration processes, suggesting that GABAA-mediated synchronization plays a role in visuospatial organization. This conclusion is supported by other physiological studies that link visual feature integration with neuronal synchronization. OBJECTIVES: One experiment was conducted to assess variations in dynamic figural priming as a result of lorazepam administration. METHODS: Observers were presented a modified version of a figural priming paradigm designed to investigate the effects of dynamic synchronization on visual feature integration. The priming paradigm consisted of premask crosses presented in a square arrangement within the same phase of a multiphase premask matrix oscillating at 40 Hz. Observers responded to a subsequently presented target square. The modification consisted of line elements presented at various distances relative to the unspecified extension of the lines making up the premask crosses. It was expected that priming effects would be enhanced for lines terminating close to the unspecified extension but only following administration of lorazepam. RESULTS: As anticipated, priming was enhanced substantially when the premask crosses flickered around static lines that terminated adjacent to the unspecified extension between the premask crosses. This effect was maximal following treatment with lorazepam. CONCLUSIONS: This finding supports the idea that GABAA-enhanced inhibitory synchronization mediates continuity coding during early visual processing.

Adult↗
PubMed2005

Effects of kava-kava extract on the sleep-wake cycle in sleep-disturbed rats.

RATIONALE: Kava-kava extract may be useful as an herbal medicine for treatment of insomnia and anxiety. OBJECTIVES: The present study was undertaken to investigate the effects of kava-kava extract on the sleep-wake cycle in comparison with that of flunitrazepam using sleep-disturbed rats. METHODS: Electrodes for measurement of electroencephalogram (EEG) and electromyogram (EMG) were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-rapid eye movement (non-REM) and REM sleep were measured from 09:00 to 15:00. RESULTS: A significant shortening of the sleep latency in sleep-disturbed rats was observed following the administration of kava-kava extract at a dose of 300 mg/kg, while no effects were observed on the total waking and non-REM sleep time. On the other hand, flunitrazepam showed a significant shortening in sleep latency, decrease in total waking time and increase in total non-REM sleep time. Although the effects of flunitrazepam were antagonized by the benzodiazepine receptor antagonist flumazenil, the effect of kava-kava extract was not antagonized by flumazenil. Kava-kava extract showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with flunitrazepam. Flumazenil caused no significant effect on the changes in delta activity induced by both kava-kava extract and flunitrazepam. CONCLUSIONS: Kava-kava extract is an herbal medicine having not only hypnotic effects, but also sleep quality-enhancement effects.

Animals↗
PubMed2005

Acute effects of alprazolam on risky decision making in humans.

RATIONALE: GABA-A receptor ligands, including benzodiapines, may induce disinhibitory effects that increase the probability of risky decision making. To date, few laboratory studies have examined the acute, dose-related effects of benzodiazepines on human risk-taking behavior. Recent data indicate that in the United States alprazolam is the benzodiazepine most frequently misused for recreational purposes. OBJECTIVES: The present study was designed to demonstrate a dose-response relationship between acute alprazolam administration and human risk taking. Furthermore, this investigation sought to examine: (1) the behavioral mechanisms that may be involved in changes in the probability of risky decision making related to alprazolam administration and (2) risk seeking-related personality variables that may predict drug effects on risk taking. METHODS: Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.5, 1.0, and 2.0 mg alprazolam in a within-subject repeated-measures design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, trial-by-trial response probabilities, and personality correlates related to drug effects at the 2.0-mg dose. RESULTS: Alprazolam administration produced dose-related changes in subjective effects, response rates, and, most importantly, dose-dependently increased selection of the risky response option. The 2.0-mg dose increased the probability of making consecutive risky responses following a gain on the risky response option. Increases at 2.0 mg were related to a combination of personality scales that included high venturesomeness and novelty seeking and low harm avoidance. CONCLUSIONS: Alprazolam administration produced increases in human risk taking under laboratory conditions. In union with previous studies, the observed shift in trial-by-trial response probabilities suggests that sensitivity to consequences (e.g., oversensitivity to recent rewards) may be an important mechanism in the psychopharmacology of risky decision making. Additionally, risk-seeking personality traits may be predictive of acute drug effects on risk-taking behavior.

Administration, Oral↗
PubMed2006

Midazolam does not inhibit association formation, just its storage and strengthening.

RATIONALE: Although there have been many studies examining the effects of benzodiazepines on memory performance, their effects on working memory are equivocal and little is known about whether they affect the efficacy of practice of already learned material. OBJECTIVES: The objectives in two experiments were to examine (a) whether midazolam impairs performance on a working memory task designed to minimize mnemonic strategies such as rehearsal or chunking of information to be recalled and (b) the effect of midazolam on repeated practice of paired associates that were learned before drug administration. MATERIALS AND METHODS: Both experiments involved subcutaneous administration of 0.03 mg of saline or midazolam per kilogram of bodyweight in within-subject, placebo-controlled designs, involving 23 subjects in (a) and 31 in (b). RESULTS: The drug had no effect on the ability to recall the digits in serial order even though the encoding task prevented the digits from being rehearsed or maintained in an articulatory buffer. Paired associates that were learned before the injection showed a benefit of subsequent practice under saline but not under midazolam. CONCLUSIONS: The results suggest that (a) midazolam does not affect the formation of new associations in short-term memory provided that the presentation rate is not too fast to form these associations when sedated, despite the evidence that the drug blocks long-term memory (LTM) retention of associations; and (b) the potential for over-learning with practice of learned associations in LTM is adversely affected by midazolam such that repeated exposures do not strengthen new learning.

Adult↗
PubMed2006

Dose effects of triazolam on brain activity during episodic memory encoding: a PET study.

RATIONALE: Although it is well established that acute benzodiazepine administration impairs episodic memory encoding, little is known about the neuroanatomical substrates of this effect. OBJECTIVE: The objective was to examine the acute dose effects of the benzodiazepine hypnotic triazolam on brain activity during episodic memory encoding. METHODS: After oral capsule administration (placebo, 0.1, 0.2, and 0.4 mg/70 kg triazolam), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H2O during performance of semantic categorization and orthographic categorization tasks in a double-blind, within-subject design in 12 healthy volunteers. The rCBF associated with episodic memory encoding was measured by subtracting the rCBF during orthographic categorization from that during semantic categorization and by examining correlations between brain activity during encoding and subsequent recognition memory performance. RESULTS: Results in the placebo condition replicated those of nonpharmacological encoding studies, including activation in left ventrolateral prefrontal cortex. Correlations between brain activity and subsequent memory performance additionally showed medial temporal activation. Triazolam produced dose-related impairment in memory performance and dose-related deactivation in encoding-associated areas including right prefrontal cortex, left parahippocampal gyrus, and left anterior cingulate cortex. CONCLUSIONS: Results are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes thought to be controlled by the medial temporal lobe. In addition to elucidating the brain mechanisms underlying these benzodiazepine-induced behavioral deficits, results of this study also help validate hypotheses generated in nonpharmacological neuroimaging studies regarding the processes controlled by these brain regions.

Adult↗
PubMed2006

Vulnerability of long-term neurotoxicity of chlorpyrifos: effect on schedule-induced polydipsia and a delay discounting task.

INTRODUCTION: Chlorpyrifos (CPF) is a common organophosphate (OP) insecticide that has been widely used in extensive agriculture as a pesticide. The primary mechanism of acute toxic action of OPs is inhibition of acetylcholinesterase (AChE). However, targets other than AChE have been proposed to contribute to the acute lethal action and side effects of short- or long-term exposure to these compounds. Bekkedal et al. (Sci Total Environ 274:119-123;2001) showed that chronic administration of the OP trimethylolpropane phosphate (TMPP) reduces the number of schedule-induced polydipsia (SIP) sessions necessary to induce asymptotic drinking level. MATERIALS AND METHODS: In the present work, rats were injected with 250 mg/kg CPF and 6 months later, its effect on schedule-induced polydipsia was evaluated. In addition, after stable levels of SIP, a pharmacological study was carried out to determine the implication of other systems in the long-term effects of OPs. Finally, these animals were evaluated in a delay discounting task, as a measure of impulsivity. RESULTS: Results indicate that the CPF group gives more licks to obtain the same amount of water than control rats (VHC). Moreover, the administration of diazepam produces an increased water intake in the CPF without any observable effect in VHC rats. Data of the delay discounting task show that CPF rats prefer an immediate reward and show a major impulsive choice. DISCUSSION: Taken together, our data confirm and extend the long-term behavioral effects of subcutaneous administration of CPF and point to a role for other systems that, besides AChE inhibition, contribute to the long-term neurotoxicity of CPF.

Acetylcholinesterase↗
PubMed2006

Neutral and emotional episodic memory: global impairment after lorazepam or scopolamine.

RATIONALE: Benzodiazepines and anticholinergic drugs have repeatedly been shown to impair episodic memory for emotionally neutral material in humans. However, their effect on memory for emotionally laden stimuli has been relatively neglected. OBJECTIVE: We sought to investigate the effects of the benzodiazepine, lorazepam, and the anticholinergic, scopolamine, on incidental episodic memory for neutral and emotional components of a narrative memory task in humans. MATERIALS AND METHODS: A double-blind, placebo-controlled independent group design was used with 48 healthy volunteers to examine the effects of these drugs on emotional and neutral episodic memory. RESULTS: As expected, the emotional memory advantage was retained for recall and recognition memory under placebo conditions. However, lorazepam and scopolamine produced anterograde recognition memory impairments on both the neutral and emotional components of the narrative, although floor effects were obtained for recall memory. Furthermore, compared with placebo, recognition memory for both central (gist) and peripheral (detail) aspects of neutral and emotional elements of the narrative was poorer after either drug. CONCLUSIONS: Benzodiazepine-induced GABAergic enhancement or scopolamine-induced cholinergic hypofunction results in a loss of the enhancing effect of emotional arousal on memory. Furthermore, lorazepam- and scopolamine-induced memory impairment for both gist (which is amygdala dependent) and detail raises the possibility that their effects on emotional memory do not depend only on the amygdala. We discuss the results with reference to potential clinical/forensic implications of processing emotional memories under conditions of globally impaired episodic memory.

Adolescent↗
PubMed2000

Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat.

RATIONALE: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. OBJECTIVES: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). METHODS: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. RESULTS: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. CONCLUSIONS: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ suggesting a role for it in anxiety.

Animals↗
PubMed2000

Socio-psychological stress-induced antinociception in diabetic mice.

RATIONALE: Although it is well established that different forms of stress produce a pronounced antinociception, the effect of diabetes on psychological stress-induced antinociception is not yet clear. OBJECTIVES: The effect of diabetes on psychological stress-induced antinociceptive effect was assessed in mice. METHODS: Animals were rendered diabetic by an injection of streptozotocin (200 mg/kg, i.v.). Mice were exposed to psychological stress in the compartment of a communication box. The antinociceptive response was evaluated by the tail-flick test, using radiant heat as a stimulus, which was performed before stress (pre-stress latency) and 0, 30 and 60 min after stress. RESULTS: Exposure to socio-psychological stress for 5, 10 and 15 min produced duration-dependent antinociception in diabetic mice. However, in non-diabetic mice, no appreciable antinociception was found even in the case of socio-psychological stress for 15 min. Pretreatment with diazepam (0.3 mg/kg, i.p.) significantly attenuated socio-psychological stress-induced antinociception in diabetic mice (vehicle: 62.9 +/- 5.5%, n = 10; diazepam: 22 +/- 1%, n = 10). Furthermore, pretreatment with flumazenil (1 mg/kg, i.v.), a benzodiazepine receptor antagonist, also significantly reduced socio-psychological stress-induced antinociception in diabetic mice (vehicle: 77.9 +/- 5.0%, n = 10; flumazenil: 5.8 +/- 1.2%, n = 10). In contrast, pretreatment with methyl beta-carboline-3-carboxylate (beta-CCM, 2 mg/kg, i.v.), a benzodiazepine receptor inverse agonist, significantly enhanced socio-psychological stress-induced antinociception in non-diabetic mice (vehicle: 4.9 +/- 0.6%, n = 10; beta-CCM: 61.5 +/- 5.9%, n = 10), but not in diabetic mice (vehicle: 50.7 +/- 4.5%, n = 10; beta-CCM: 64.4 +/- 7.2%, n = 10). CONCLUSIONS: These results indicate that emotional stress can readily induce antinociception in diabetic mice. Furthermore, this enhanced emotional stress-induced antinociception might be attributable to an increase in the production and/or release of endogenous ligands for benzodiazepine receptors, such as diazepam binding inhibitor, which act as inverse benzodiazepine receptor agonists.

Animals↗
PubMed2001

Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study.

RATIONALE: Benzodiazepines have dependency-producing properties, and the majority of patients who are prescribed benzodiazepines and are treated for benzodiazepine dependency are women. Inability to cope with withdrawal symptoms may lead to continued consumption of benzodiazepines, often with the development of tolerance and dose escalation as a consequence. OBJECTIVE: In the present study we analyzed gender-related differences in reactions to placebo injections in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil among patients previously treated for benzodiazepine dependency and healthy controls. METHODS: Ten patients and ten controls (five males and five females in each group) received two placebo injections (separated by 15 min) on two separate occasions (1-13 weeks apart). The patients had been benzodiazepine free for 47 (4-266) weeks on the first occasion. Subjective ratings of symptoms, thought to be important during/after withdrawal of benzodiazepines, were made before and after each injection, as well as registrations of blood pressure and heart rate. RESULTS: An overall difference existed between previously benzodiazepine-dependent subjects and healthy controls, with patients scoring higher on negative and somatic aggregates and lower on a positive aggregate. A four-way interaction (group x gender x occasion x time) was found for negative and somatic aggregates, which could mainly be explained by the reactions of female patients. Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure. There was no significant response to placebo among male patients or for controls (males or females) for ratings of any variable. CONCLUSIONS: The results suggest that there might be gender-specific differences in reactions to placebo injections, with female patients being more affected. Arguments for and against explanatory factors such as expectation, provider factors, habituation, regression toward the mean, and reduction of anxiety are presented.

Adult↗
PubMed2001

Acute dose-effects of scopolamine on false recognition.

RATIONALE: Recently, there has been increased research interest in the phenomenon of false recognition, in which participants claim to recognize words that had not been presented during an initial study phase but that are associatively related to presented words. Acute administration of the benzodiazepine hypnotic triazolam has been shown to decrease false recognition rates. However, no false recognition studies have examined the effects of scopolamine, an anticholinergic drug that might produce a different profile of memory-impairing effects than the benzodiazepines due to its distinct neurochemical profile. OBJECTIVE: This study was designed to examine the acute dose-effects of scopolamine on false recognition. METHODS: The effects of subcutaneously administered scopolamine (0.3 and 0.6 mg/70 kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated-measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: Scopolamine produced dose-related reductions in both true and false recognition rates, and induced a more conservative response bias relative to placebo for recollection-based ("remember") responses to studied words. CONCLUSIONS: While scopolamine's effects on false recognition are similar to those observed previously with triazolam, its effects on response bias may differ from those of triazolam.

Adult↗
PubMed2001

Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands.

RATIONALE: Pineal and Harderian gland melatonin production as well as plasma melatonin levels were investigated in male Wistar rats (12 weeks old) after administration of diazepam, a benzodiazepine widely used as anxiolytic. OBJECTIVE: The present study investigates the effects of a chronic administration of diazepam on pineal and Harderian gland melatonin contents. METHODS: Diazepam was administered subcutaneously, for 21 days, at a dosage of 3 mg/kg body weight per day, 1 h before the onset of darkness. RESULTS: Diazepam clearly affected pineal melatonin biosynthesis and plasma melatonin levels. Diazepam reduced the pineal melatonin content (by a factor of 2) and the activity of N-acetyltransferase (NAT) (by a factor of 3.5), as well as plasma melatonin levels (by a factor of 1.5), but had no effects on pineal hydroxyindole-O-methyltransferase activity. By contrast to the pineal gland, diazepam failed to affect the Harderian gland melatonin content. CONCLUSIONS: Our results suggest that the inhibition of melatonin production induced by diazepam in vivo may be due to a direct action of this benzodiazepine on the pineal gland, through its action on NAT, the key enzyme of melatonin synthesis, and that the control of melatonin production in the Harderian glands may be different from that observed in the pineal gland.

Acetylserotonin O-Methyltransferase↗
PubMed2001

Subchronic effects of the GABA-agonist lorazepam and the 5-HT2A/2C antagonist ritanserin on driving performance, slow wave sleep and daytime sleepiness in healthy volunteers.

RATIONALE: Lorazepam, a benzodiazepine anxiolytic, may increase daytime sleepiness and impair psychomotor performance, which is hazardous for patients engaging in daily activities such as car driving. Given current prescription practice, information on the repeated dose effects is required. The 5-HT2A/2C antagonist ritanserin was originally developed as a safer alternative to the benzodiazepines, yet having limited clinical efficacy. 5HT2A/2C receptors have been implicated in regulating slow-wave sleep but little is known about their role in human performance. OBJECTIVE: The present study investigated the subchronic effects of the benzodiazepine anxiolytic lorazepam and the 5-HT2A/2C antagonist ritanserin on actual driving performance, objective and subjective sleepiness, and nocturnal slow wave sleep. METHODS: Eighteen healthy volunteers were treated twice daily for 7 days with ritanserin 5 mg, lorazepam 1.5 mg or placebo. Treatments were administered according to a double-blind, cross-over design. Tests were performed on day 7 of each treatment week. Sleep EEG was recorded during the preceding night. RESULTS: Lorazepam had a pronounced impairing effect on lateral position control and induced daytime sleepiness, while having no effect on other parameters. In contrast, ritanserin did not impair driving performance or affect objectively measured daytime sleepiness, while subjects reported to feel more alert during daytime. Moreover, consistent with its effects on 5-HT2 receptors, ritanserin increased the amount of nocturnal slow wave sleep. There were no relationships between changes in slow wave sleep and performance parameters. CONCLUSIONS: Lorazepam administered for 7 consecutive days may be hazardous for patients who engage in driving activities. Antagonism of 5-HT2A/2C receptors, as accomplished by ritanserin, increases slow wave sleep and is devoid of effects on objective sleepiness and driving behaviour. Whether this extends to other cognitive and psychomotor domains remains to be established.

Adult↗
PubMed1996

GABAergic influences on plus-maze behaviour in mice.

Manipulations of GABA function have been found to produce highly variable effects in animal models of anxiety. In the present series, an ethological version of the murine elevated plus-maze was used to examine in detail the behavioural profiles of diazepam (1.5 mg/kg; positive control) and a range of GABA-related compounds: valproic acid (100-400 mg/kg), No-711 (1.25-10.0 mg/kg), muscimol (0.5-3.0 mg/kg), (+)bicuculline (4.0-8.0 mg/kg), picrotoxin (0.25-2.0 mg/kg), R(+)baclofen (0.375-3.0 mg/kg) and CGP 35348 (25-200 mg/kg). On both conventional and ethological indices, results confirmed the anxiolytic profile of diazepam under present test conditions, and revealed substantially similar effects for the GABA-T inhibitor, valproic acid (100-400 mg/kg), and the GABAA receptor agonist, muscimol (2 mg/kg). The GABA reuptake inhibitor, No-711, produced weak anxiolytic-like effects at low doses (1.25-2.5 mg/kg) but disrupted behaviour at the highest dose tested (10 mg/ kg). Although the GABAA receptor antagonists, (+)bicuculline and picrotoxin, produced changes indicative of anxiety enhancement, concomitant behavioural suppression was evident at high doses (8 mg/kg and 1-2 mg/kg, respectively). Further studies suggested that the effects observed with bicuculline may be mediated by an active metabolite, such as bicucine. In contrast to the effects of valproic acid and direct GABAA receptor manipulations, the GABAB receptor agonist, R(+) baclofen, non-specifically disrupted behaviour at the highest dose tested (3 mg/kg) while the GABAB receptor antagonist, CGP 35348, was inactive over the dose range studied. Although present data confirm the sensitivity of the plus-maze to agents which modify GABAA receptor function, further studies will be required in order more fully to characterize this relationship.

Animals↗
PubMed1997

Enhancement by flumazenil of dopamine release in the nucleus accumbens of rats repeatedly exposed to diazepam or imidazenil.

The effect of long-term treatment (three times daily for 3 weeks) with a behaviorally relevant dose of the benzodiazepine receptor partial agonist imidazenil (0.5 mg/kg, IP) on basal dopamine release in the nucleus accumbens of freely moving rats was compared with that of diazepam (3 mg/kg, IP), a benzodiazepine receptor full agonist. Challenge doses of imidazenil and diazepam decreased the extracellular dopamine concentration in the nucleus accumbens by approximately the same extent in animals repeatedly exposed to vehicle or to the respective drug. Moreover, the abrupt discontinuation of long-term treatment with diazepam or imidazenil failed to affect basal dopamine release in this brain area during the first 5 days of withdrawal. In contrast, administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens 6 h after withdrawal of diazepam or imidazenil, respectively. Flumazenil induced a similar but smaller effect (50% increase) 5 days after diazepam withdrawal but had no effect 5 days after discontinuation of imidazenil treatment. The results support an involvement of the mesoaccumbens dopaminergic neurons in the withdrawal syndrome precipitated by flumazenil and allow further differentiation of benzodiazepine receptor partial and full agonists with respect to dependence liability of dopaminergic neurons in the nucleus accumbens.

Animals↗
PubMed1997

Flumazenil blockade of anxiety following ethanol withdrawal in rats.

In previous research, the drug flumazenil has been categorized both as a pure benzodiazepine antagonist and as a benzodiazepine partial agonist. The following studies used an elevated plus maze to test whether flumazenil would exert any antianxiety action in rats. While chlordiazepoxide (3.0 mg/kg), ethanol (0.75 g/kg), and the atypical benzodiazepine zolpidem (1.0 mg/kg) all significantly increased time spent on the open arms and percent open arm entries, flumazenil (1-10 mg/kg) alone did not produce any anxiolytic effects on the maze. Withdrawal from chronic ethanol treatment led to a decrease in open arm time and percent open arm entries. Flumazenil (3.0 mg/kg) blocked these changes, suggesting that the effects of flumaxenil are at least partially dependent upon the levels of stress or anxiety in the subjects. An anxiolytic action of flumazenil was not seen following the central administration of the neuropeptide corticotropin-releasing factor (CRF), which reduced open arm time on the elevated plus maze. These results support the hypothesis that the mechanism of action for flumazenil effects on the anxiety observed during ethanol withdrawal involves antagonism of an endogenous benzodiazepine inverse agonist, rather than activity as a partial agonist or blockade of CRF-mediated effects.

Animals↗
PubMed1997

Effects of lorazepam administration on striatal dopamine D2 receptor binding characteristics in man--a positron emission tomography study.

Lorazepam is a widely used benzodiazepine class anxiolytic drug. It is known to enhance GABAergic neurotransmission in the brain, but the actions of benzodiazepines on other neurotransmitter systems are largely unknown. We studied the effects of 1 week's administration with lorazepam (2 mg daily, PO) or placebo on striatal D2 dopamine receptors in four healthy male volunteers using a double-blind randomized cross-over design. D2 receptor density and affinity as well as binding potential (Bmax/Kd) were measured with [11C]-raclopride and positron emission tomography. Although the individual responses varied, lorazepam did not significantly affect D2 receptor binding characteristics, nor did the average effect sizes exceed test-retest variability of the method. In conclusion, the results suggest that striatal D2 dopamine receptor characteristics are not affected by the clinically relevant lorazepam treatment regimen used.

Adult↗