Brainstem mediates diazepam enhancement of palatability and feeding: microinjections into fourth ventricle versus lateral ventricle

The hypothesis that benzodiazepine-induced hyperphagia is due to a specific enhancement of the palatability of foods has been supported by previous ‘taste reactivity’ studies of affective (hedonic and aversive) reactions to taste palatability. Diazepam and chlordiazepoxide enhance hedonic reactions of rats (rhythmic tongue protrusions, etc.) to sweet tastes in a receptor-specific fashion. A role for brainstem circuits has been indicated by a previous demonstration of the persistence of the taste reactivity enhancement by diazepam after midbrain decerebration. The present study examined whether benzodiazepine brainstem receptors are the chief substrates for palatability enhancement even in intact brains. We compared the effectiveness of benzodiazepine microinjections to elicit feeding and enhance hedonic reactions when delivered into either the lateral ventricle (forebrain) or the fourth ventricle (brainstem) of rats. The results show diazepam is reliably more effective at eliciting feeding and enhancing positive hedonic reactions to oral sucrose when microinjections are made in the fourth ventricle than in the lateral ventricle. We conclude that brainstem neural systems containing benzodiazepine-GABA receptors are likely to be the chief substrates for benzodiazepine-induced palatability enhancement.     

Mechanisms underlying the antidopaminergic effect of clonazepam and melatonin in striatum

Intrastriatal injection of the GABA_A antagonist, bicuculline, caused about a 75% decrease in the inhibitory effect of the central-type benzodiazepine (BZ) agonist, clonazepam or the indoleamine hormone, melatonin, on apomorphine-induced rotation in a 6-hydroxydopamine model of dopaminergic supersensitivity. Pretreatment with the peripheral-type BZ antagonist, PK 11195 (intrastriatally or intraperitoneally), also attenuated the antidopaminergic effect of these drugs but with much less potency than bicuculline. However, the combination of both bicuculline and PK 11195, injected directly into the striatum, completely blocked the antidopaminergic action of clonazepam or melatonin. These results indicate that the antidopaminergic action of clonazepam and melatonin in the striatum involves two distinct mechanisms: (1) a predominant GABAergic activation via the BZ/GABA_A receptor complex, and (2) a secondary mechanism linked to a PK 11195- sensitive BZ receptor pathway. Recent studies indicate that PK 11195 blocks BZ-induced inhibition of the adenylyl cyclase-cyclic AMP pathway in the striatum. Since cyclic AMP has been implicated in the rotational behaviour of 6-hydroxydopamine-lesioned animals, it is possible that the antidopaminergic action of clonazepam and melatonin also involves suppression of this second messenger. All rights reserved.     

Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory

The effects of diazepam and lorazepam on explicit memory and perceptual priming were studied 50, 130 and 300 min after drug administration. Sixty healthy volunteers were randomly assigned to one of five parallel groups (placebo, diazepam 0.2 or 0.3 mg/kg, lorazepam 0.026 or 0.038 mg/kg). The corresponding doses of benzodiazepines exerted a similar negative effect on explicit performance. Lorazepam markedly impaired priming performance, whereas the effect of diazepam was intermediate between that of placebo and that of lorazepam 0.038 mg/kg. The impairment was maximal at the theoretical peak plasma concentration. Contamination by explicit memory could account for the decrease in priming performance observed in the diazepam groups.     

Intoxicating effects of lorazepam and barbital in rat lines selected for differential sensitivity to ethanol

The motor impairing effects and plasma concentrations of barbital and lorazepam were studied in the alcohol tolerant (AT) and alcohol non-tolerant (ANT) rat lines developed for low and high sensitivity to motor impairment from ethanol. The mixed (M) line, from which the AT and ANT rats were derived, was also included in the study. Like ethanol, barbital and lorazepam impaired the performance of the ANT rats more than that of the AT rats. The motor performance of the M rats was relatively more impaired after barbital than after lorazepam administration at the same dose used in the AT and ANT rats. At the two latter time points (2.5 and 3.5 h) the sensitive ANT rats had significantly higher serum barbital concentrations than the AT rats. The serum barbital concentrations of the AT and ANT rats did not differ, however, at the two first time points (0.5 and 1.5 h) of the tilting plane tests, although the ANT rats were significantly more intoxicated. The concentrations of lorazepam in plasma do not explain the differential motor impairment either, since the sensitive ANT rats had lower plasma concentrations than the insensitive AT rats. The results, thus, suggest that the selection involved in the development of the AT and ANT lines has not been specific for ethanol. The results also support the idea that ethanol, barbiturates and benzodiazepines have some modes of action in common.     

Dixyrazine premedication for cataract surgery. A comparison with diazepam

Peroral dixyrazine (15–30 mg, n = 50) and diazepam (4–10 mg, n = 50) were used as premedicants for geriatric patients having cataract surgery under regional block. Compared to the diazepam patients, a larger number of the dixyrazine medicated patients appeared anxious, and there was a statistically significant difference between the groups, when summing up changes in anxiety throughout the study period. The dixyrazine patients needed more frequent supplementation with intravenous sedative drugs, compared with their diazepam counterparts. Peroral dixyrazine is an applicable choice for calm patients, when only slight sedation, or avoidance of somnolence are required.     

Differences in enhancing effects of zolpidem and benzodiazepine drugs on recurrent inhibition in rat hippocampal slices

It has been reported that the clinical and electroencephalographic profiles of zolpidem, a non-benzodiazepine drug which binds preferentially to the ω₁ benzodiazepine recognition sites located within the GABA_A receptor complex, are different from those of benzodiazepine drugs, which bind non-selectively to the ω₁ and ω₂ sites. In order to clarify the electrophysiological mechanism underlying the unique profile of zolpidem, the present study compared the enhancing effects of zolpidem and two benzodiazepine drugs, triazolam and diazepam, on recurrent inhibition. This inhibition was expressed as suppression of the orthodromically induced population spikes by the preceding antidromic stimulation of the alveus in the CA1 region of rat hippocampal slices. The rank order of potency for enhancing recurrent inhibition was triazolam > diazepam > zolpidem. From the present results and previously reported findings that zolpidem has a lower affinity for the ω₂ sites than diazepam while both have the same affinity for the ω₁ sites, we concluded that the hippocampal recurrent inhibition appears to be enhanced mainly by activation of the ω₂ sites, but not by that of the ω₁ sites. Furthermore, the lower potency of zolpidem for enhancing recurrent inhibition may underlie its unique profile in terms of its clinical and electroencephalographic effects. Received: 1 November 1996/Final version: 22 January 1997     

Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography (PET)

NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared ⁷⁶Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [¹¹C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [⁷⁶Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [⁷⁶Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage. Received 19 April and in revised form 10 June 1997     

Trial of an intervention to reduce chronic benzodiazepine use among residents of aged-care accommodation

Abstract Background: Many residents of aged-care accommodation are chronic users of benzodiazepines. This pattern of use contradicts current guidelines and may adversely affect residents. It was hypothesised that a lasting reduction in benzodiazepine use could be achieved through a programme which involved prescribers, residents and caregivers in the change process. Aim: To demonstrate that an intervention which involved education and relaxation training for patients, and education of prescribers and caregivers, could reduce levels of chronic benzodiazepine use among residents of an aged-care facility. Methods: Two aged-care facilities from metropolitan Adelaide were chosen; one received the intervention, the other was a no-intervention comparison. Pre-test, post-test and follow-up interviews were conducted with 60 residents: 27 from the intervention setting and 33 from the comparison setting. Residents at the intervention setting were provided with relaxation skills training, and their medical practitioners and caregivers were provided with information about alternative strategies for managing sleep disturbance. Outcome measures were: the proportion of residents using benzodiazepines, total medication use, cognitive performance, emotional responsiveness, subjective health and sleep ratings and an index of well-being. Results: The proportion of participants in the intervention condition who used benzodiazepines declined significantly (from 70% to 35%); the reduction was maintained over the subsequent three months. No adverse consequences were associated with cessation of benzodiazepine use; there was improvement in emotional responsiveness among those who ceased benzodiazepine use. This structured intervention strategy is a useful approach for reducing levels of chronic benzodiazepine use among residents of aged-care accommodation.     

Abuse liability of flunitrazepam among methadone-maintained patients

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4 mg caused euphoria-related effects as measured by increases in ARCI-MBG and “high” scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential. Received: 13 February 1998/Final version: 1 May 1998     

Specific modulation of social memory in rats by cholinomimetic and nootropic drugs,by benzodiazepine inverse agonists,but not by psychostimulants

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. In this study the effect of various psychotropic drugs on this investigatory behaviour was examined. The procedure was as follows: an unfamiliar juvenile rat was placed in the home cage of an adult rat for 5 min. The time spent by the adult rat in investigating the juvenile was recorded. The adult rat was then immediately treated with vehicle or test compounds, and was again exposed for 5 min to the same juvenile 2 h later. At this time point vehicle-treated rats no longer recognized the juvenile rat, i.e. the time of investigation was similar to that observed during the first presentation. Arecoline (1 and 3 mg/kg IP), physostigmine (0.05 and 0.1 mg/kg SC), RS86 (0.5 mg/IP) and nicotine (0.125 and 0.5 mg/kg IP) reduced in a dose-dependent fashion the time spent in investigating the juvenile during the second exposure. This result cannot be attributed to nonspecific effects, since it was not observed when a different juvenile was used for the second exposure. The effect of arecoline was reversed by scopolamine, but not by methylscopolamine. Aniracetam reduced investigatory behaviour at the dose of 50 mg/kg IP. FG 7142 (5 mg/kg IP) and -CCM (0.4 mg/kg IP) were also active and their effect was reversed by Ro 15-1788. dl-Amphetamine (0.5 and 1 mg/kg IP), nomifensine (1.25–10 mg/kg IP) and strychnine (0.25 and 0.5 mg/kg IP) were ineffective or reduced this behaviour unspecifically. Social recognition may therefore represent a useful and simple test to detect compounds which enhance short-term, olfactory, memory and to assess in the same animals the specificity of this activity.