Brainstem areas activated by diazepam withdrawal as measured by Fos-protein immunoreactivity in rats.
In the 1970s, chronic treatment with benzodiazepines was supposed not to cause dependence. However, by the end of the decade several reports showed that the interruption of a prolonged treatment with diazepam leads to a withdrawal syndrome characterized, among other symptoms, by an exaggerated level of anxiety. In laboratory animals, signs that oscillate from irritability to extreme fear-like behaviors and convulsions have also been reported. In recent years many studies have attempted to disclose the neural substrates responsible for the benzodiazepines withdrawal. However, they have focused on telencephalic structures such as the prefrontal cortex, nucleus accumbens and amygdala. In this study, we examined the Fos immunoreactivity in brain structures known to be implicated in the neural substrates of aversion in rats under spontaneous diazepam-withdrawal. We found that the same group of structures that originally modulate the defensive responses evoked by fear stimuli, including the dorso-medial hypothalamus, the superior and inferior colliculus and the dorsal periaqueductal gray, were most labeled following diazepam withdrawal. It is suggested that an enhanced neural activation of neural substrates of fear in the midbrain tectum may underlie the aversive state elicited in diazepam-withdrawn rats.
Fontanesi
Lucas Baptista
LB
Instituto de Neurociências & Comportamento-INeC, Campus USP, Ribeirão Preto, 14040-901 SP, Brazil.
Ferreira
Renata
R
Cabral
Alicia
A
Castilho
Vanessa Moreno
VM
Brandão
Marcus Lira
ML
Nobre
Manoel Jorge
MJ
D000704:Analysis of Variance; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000502:physiology; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D003336:Tectum Mesencephali / Q000187:drug effects / Q000378:metabolism
D002492:Central Nervous System Depressants; D016760:Proto-Oncogene Proteins c-fos; D003975:Diazepam