title: The effects of midazolam and D-cycloserine on the release of glutamate and GABA in the basolateral amygdala of low and high anxiety rats during extinction trial of a conditioned fear test.
abstract: In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15 mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75 mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders.
authors.affiliation: Department of Neurochemistry, Institute of Psychiatry and Neurology, 02-957 Warsaw, 9 Sobieskiego Street, Poland. mlehner@ipin.edu.pl
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Lehner
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wisłowska-Stanek
authors.forename: Ewa
authors.initials: E
authors.lastname: Taracha
authors.forename: Piotr
authors.initials: P
authors.lastname: Maciejak
authors.forename: Janusz
authors.initials: J
authors.lastname: Szyndler
authors.forename: Anna
authors.initials: A
authors.lastname: Skórzewska
authors.forename: Danuta
authors.initials: D
authors.lastname: Turzyńska
authors.forename: Alicja
authors.initials: A
authors.lastname: Sobolewska
authors.forename: Adam
authors.initials: A
authors.lastname: Hamed
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bidziński
authors.forename: Adam
authors.initials: A
authors.lastname: Płaźnik
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001008:Anxiety Disorders / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003523:Cycloserine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D018709:Statistics, Nonparametric; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
chemical_list: D058785:GABA-A Receptor Agonists; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003523:Cycloserine; D008874:Midazolam