Brainstem areas activated by diazepam withdrawal as measured by Fos-protein immunoreactivity in rats

Fontanesi, Lucas Baptista; Ferreira, Rafaela Scalco; Cabral, Alícia; Castilho, V.M.; Brandão, Marcus Lira; Nobre, Manoel Jorge

doi:10.1016/j.brainres.2007.07.007

Cited by 17 publications

(8 citation statements)

References 72 publications

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“…As it was observed that the chronic intraperitoneal injection of a placebo solution elicits, by itself, anxiety in rats tested in the EPM (Griebel et al, 1994), in this study we used the voluntary oral intake as the method of choice. In a previous study we have demonstrated that this method elicits low anxiety levels in rats treated chronically (Fontanesi et al, 2007). Our results showed higher levels of aversion in withdrawn rats when compared with controls, revealed by their increased levels of vocalizations.…”

Section: Discussionsupporting

confidence: 65%

“…It is possible that the same neurobiological substrates that are activated to promote anxiety-like behaviours induced by external aversive stimuli could be overactive during benzodiazepine withdrawal. In a recent study (Fontanesi et al, 2007) we showed high levels of neural activation in brainstem areas mainly involved in the modulation/expression of defensive behaviours in rats withdrawn from diazepam. Chemical or electrical stimulation of these same regions elicits a pattern of performance Finally, the fact that similar emotional negative states are attenuated by anxiolytic drugs seems to support the view that similar neurobiological substrates may be affected by both experiences, anxiety-like states elicited by fear stimuli and drug withdrawal.…”

Section: Discussionmentioning

confidence: 88%

“…The procedure used for diazepam oral intake has been described previously (Fontanesi et al, 2007). Briefly, the animals were submitted on a daily basis to 14 hours of water deprivation (19:00 to 9:00), followed by 10 hours of water ad libitum (9:00 to 19:00).…”

Section: Administration Of Diazepam By Oral Routementioning

confidence: 99%

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Analysis of the chronic intake of and withdrawal from diazepam on emotional reactivity and sensory information processing in rats

Ross

Castilho

Brandão

et al. 2008

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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It has been demonstrated that, on abrupt withdrawal, patients with chronic exposure can experience a number of symptoms indicative of a dependent state. In clinical patients, the earliest to arise and most persistent signal of withdrawal from chronic benzodiazepine (Bzp) treatment is anxiety. In laboratory animals, anxiety-like effects following abrupt interruption of chronic Bzp treatment can also be reproduced. In fact, signs that oscillate from irritability to extreme fear behaviours and seizures have been described already. As anxiety remains one of the most important symptoms of Bzp withdrawal, in this study we evaluated the anxiety levels of rats withdrawn from diazepam. Also studied were the effects on the motor performance and preattentive sensory gating process of rats under diazepam chronic treatment and upon 48-h withdrawal on three animal models of anxiety, the elevated plus-maze (EPM), ultrasonic vocalizations (USV) and startle + prepulse inhibition tests. Data obtained showed an anxiolytic-and anxiogenic-like profile of the chronic intake of and withdrawal from diazepam regimen in the EPM test, 22-KHz USV and startle reflex.Diazepam chronic effects or its withdrawal were ineffective in promoting any alteration in the prepulse inhibition (PPI). However, an increase of PPI was achieved in both sucrose and diazepam pretreated rats on 48-h withdrawal, suggesting a procedural rather than a specific effect of withdrawal on sensory gating processes. It is also possible that the prepulse can function as a conditioned stimulus to informing the delivery of an aversive event, as the auditory startling-eliciting stimulus. All these findings are indicative of a sensitization of the neural substrates of aversion in diazepam withdrawn animals without concomitant changes on the processing of sensory information.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 88%

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Analysis of the chronic intake of and withdrawal from diazepam on emotional reactivity and sensory information processing in rats

Ross

Castilho

Brandão

et al. 2008

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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show abstract

“…Abrupt withdrawal of a benzodiazepine (12, 24 or 48 h) following prolonged administration (7-21 days) has been shown to induce anxiety in rats or mice, measured in different animal models: plus-maze (Assie´et al, 1991;Bhattacharya et al, 1995;File and Hitchcott, 1991;Fontanesi et al, 2007;Martijena et al, 1996;Pokk and Zharkovsky, 1998;Wright et al, 1991), social interaction (Andrews and File, 1993;Andrews et al, 1997) or in both (Begg et al, 2005), and light-dark test (Souza Pinto et al, 2007). Withdrawal for 24 h from chronic diazepam treatment (21 days) has been related to increased 5-HT release in the hippocampus (Andrews and File, 1993;Andrews et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

2009

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The present work aimed to evaluate the effects of social separation for 14 days (chronic stress) and of withdrawal from a 14-day treatment with diazepam (acute stress) on the exploratory behaviour of male rats in the elevated plus-maze and on serotonin (5-hydroxytryptamine) turnover in different brain structures. Social separation had an anxiogenic effect, evidenced by fewer entries into, and less time spent on the open arms of the elevated plus-maze. Separation also selectively increased 5-hydroxytryptamine turnover in the hippocampus and median raphe nucleus. Diazepam withdrawal had a similar anxiogenic effect in grouped animals and increased 5-hydroxytryptamine turnover in the same brain structures. Chronic treatment with imipramine during the 14 days of separation prevented the behavioural and neurochemical changes caused by social separation. It is suggested that the increase in anxiety determined by both acute and chronic stress is mediated by the activation of the median raphe nucleus-hippocampal 5-hydroxytryptamine pathway.

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“…The HP, through its connections with structures such as the Amygdala or the medial Prefrontal Cortex, among others, is a brain structure implicated in contextual conditioning [35]. Furthermore, the anxiogenic effect promoted by DZ withdrawal was accompanied by signi icant Fos-positive immunoreactivity in telencephalic, diencephalic and mesencephalic areas related to anxiety and fear circuits in the brain [36], as well as to enhanced Locus Coeruleus and Dorsal Raphe Nucleus neuronal activity [16,37]. All these changes may contribute not only to the physical withdrawal symptoms involving autonomic function, but also to the increased HP plasticity that has been described to underlie DZ dependence and withdrawal [6,16,38].…”

Section: Discussionmentioning

confidence: 99%

Diazepam Withdrawal Expression is related to Hippocampal NOS-1 Upregulation

Pérez¹

2017

Arch Pharm Pharm Sci

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Background: Benzodiazepines are usually prescribed for anxiety and sleep disorders in a long-term fashion that may cause drug dependence. Discontinuation after prolonged administration may lead to withdrawal expression, being anxiety the most predominant sign. It has been described that a contextdependent associative learning process underlies diazepam dependence. Nitric oxide is a crucial player in learning and memory processes, hippocampal transmission, as well as in benzodiazepines withdrawal. Considering that previous results from our laboratory showed an increase in hippocampal functional plasticity only in diazepam dependent rats, the aim of the present investigation is to determine whether diazepam dependence could alter neuronal nitric oxide synthase enzyme (NOS-1) expression within the hippocampus, by using western blot. Results: chronic diazepam-treated animals that developed dependence showed increase in NOS-1 expression in dorsal, but not in ventral hippocampus, while no-dependent or control animals presented similar NOS-1 protein levels. Conclusion: withdrawal from long-term diazepam exposure could be associated to increased nitric oxide neurotransmission within dorsal hippocampus induced by NOS-1 over-expression. This mechanism could underlie the improved hippocampal synaptic transmission previously observed in diazepam withdrawn animals. Confi rmatory experiments need to be addressed to determine the mechanisms by which nitric oxide participates in benzodiazepines withdrawal in order fi nd new molecular targets to develop pharmacological tools to prevent the withdrawal syndrome.

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Brainstem areas activated by diazepam withdrawal as measured by Fos-protein immunoreactivity in rats

Cited by 17 publications

References 72 publications

Analysis of the chronic intake of and withdrawal from diazepam on emotional reactivity and sensory information processing in rats

Analysis of the chronic intake of and withdrawal from diazepam on emotional reactivity and sensory information processing in rats

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

Diazepam Withdrawal Expression is related to Hippocampal NOS-1 Upregulation

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