Benzodiazepines increase preprocholecystokinin messenger RNA levels in rat brain

Rattray, Marcus; Singhvi, Sanjay; Wu, Pei‐Ying; Andrews, Nick; File, Sandra E.

doi:10.1016/0922-4106(93)90129-w

Cited by 18 publications

(7 citation statements)

References 10 publications

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“…light-dark box reduced CCK mRNA values relative to mice not exposed to the apparatus irrespective of odor treatment. In other investigations, rat cerebral cortex CCK mRNA levels were increased after a single injection of the anxiolytic agent diazepam (Rattray et al 1993). In contrast, CCK mRNA was elevated in the VTA of mice exposed to butyric acid but not following TMT exposure relative to saline treated mice.…”

Section: Mesocorticolimbic Cck Mrna Expression Following Odor Exposurmentioning

confidence: 72%

Odor-Induced Variation in Anxiety-Like Behavior in Mice is Associated with Discrete and Differential Effects on Mesocorticolimbic Cholecystokinin mRNA Expression

Hebb

Zacharko

Domínguez

et al. 2002

Neuropsychopharmacology

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The present investigation assessed alterations in mesocorticolimbic cholecystokinin (CCK) mRNA following novel predator and non-predator odor exposure and light-dark testing in CD-1 mice. In brief, acute exposure of CD-1 mice to the predator odor, 2,5-dihydro-2, 4,5-trimethylthiazoline (TMT; the major component of the anal gland secretions of the red fox), or the control odor, butyric acid (BA), suppressed rearing behavior during odor presentation, subsequently induced anxiety in the light dark test, and was associated with increased mesocorticolimbic CCK mRNA relative to saline treated mice. Only mice exposed to TMT displayed elevated freezing behaviors during odor treatment. In the light-dark test, mice exposed to either BA or TMT took longer to reenter the light section of the apparatus and spent less cumulative time in the light relative to mice exposed to saline. The decreased time spent in the light as well as light dark transitions were exaggerated among mice exposed to fox odor. Odor presentation was associated with increased CCK mRNA in mesocorticolimbic sites. Butyric acid was associated with enhanced CCK gene expression in the VTA, while both BA and TMT were associated with increased medial prefrontal cortex (mPFC) CCK mRNA levels. Increased CCK mRNA within the VTA and mPFC was evident among mice despite testing in the light-dark box. In contrast, basolateral nucleus of the amygdala (BLA) CCK mRNA was enhanced following odor exposure among mice in the light dark test relative only to saline treated mice which demonstrated a natural decrease in BLA CCK mRNA following the light dark test. The differential pattern of CCK mRNA associated with discrete psychogenic stressor manipulations and the provocation of anxiety-like behavior associated with such experiences is discussed.

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Section: Mesocorticolimbic Cck Mrna Expression Following Odor Exposurmentioning

confidence: 72%

Odor-Induced Variation in Anxiety-Like Behavior in Mice is Associated with Discrete and Differential Effects on Mesocorticolimbic Cholecystokinin mRNA Expression

Hebb

Zacharko

Domínguez

et al. 2002

Neuropsychopharmacology

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“…Additionally, behavioral studies showed that CCK-4-induced anxiety is antagonized by benzodiazepines (Harro et al, 1993). Moreover, Rattray et al (1993) showed that GABA seems to affect the expression of the CCK-gene in that CCK mRNA is increased both after a single benzodiazepine injection and after benzodiazepine withdrawal (Rattray et al, 1993). Furthermore, it has been shown in rat studies that GABA and benzodiazepines attenuated CCK release, whereas GABA A -receptor antagonists such as bicuculline led to an increase in CCK release (Yaksh et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

Effects of Alprazolam on Cholecystokinin-Tetrapeptide-Induced Panic and Hypothalamic–Pituitary–Adrenal-Axis Activity: A Placebo-Controlled Study

Zwanzger

Eser

Aicher

et al. 2002

Neuropsychopharmacol

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Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 mg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.

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“…Further evidence will be necessary in order to scrutinize the underlying reasons of the complex pathology of benzodiazepine dependence and withdrawal. Also the investigation of a possible involvement of further neurotransmitters may offer new clues (Rattray et al, 1993) Rat cortical cell culture/Diazepam Increase in CCK mRNA after a single injection and after diazepam withdrawal, but not during chronic diazepam treatment (Bradwejn and de Montigny, 1984) Rat hippocampal pyramidal neurones Inhibition of CCK-8 induced neuronal activation (Becker et al, 2001) Rats/Diazepam Inhibition of overflow with CCK-like material due to social stress Clinical Studies (Zwanzger et al, 2001) Humans/vigabatrin/CCK-4 Reduction of CCK-4 induced panic symptoms and significant attenuation of CCK induced ACTH and cortisol increase (Zwanzger et al, 2003a) Humans/tigabine/CCK-4 Reduction of CCK-4 induced panic symptoms (Zwanzger et al, 2003b) Humans/alprazolam/CCK-4 Reduction of CCK-4 induced panic symptoms and significant attenuation of CCK induced ACTH and cortisol increase (Rasmussen et al, 1993) Rats elucidating the underlying correlations. The findings demonstrated in this review demonstrate associations rather than causality.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with the hypothesis that enhanced CCK levels reflect increased anxiety and fear, CCK levels seem to be up regulated due to benzodiazepine withdrawal. Accordingly in rats cessation of diazepam treatment was associated with an increase in the number of CCK-8 receptors in the frontal cortex and the hippocampus (Harro et al, 1990) and with enhanced CCK mRNA expression in the cortical cortex (Rattray et al, 1993;Pratt and Brett, 1995). Accordingly CCK receptor antagonists have been reported to attenuate benzodiazepine withdrawal reactions (Rasmussen et al, 1993).…”

Section: Neuroendocrine Effects Due To Benzodiazepine Withdrawalmentioning

confidence: 99%

Neuroendocrine pathways in benzodiazepine dependence: new targets for research and therapy

Heberlein

Bleich

Kornhuber

et al. 2007

Human Psychopharmacology

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Benzodiazepines are known to modulate the activity of the hypothalamo-pituitary-adrenocortical (HPA) axis by antagonizing the effects of corticotropin-releasing factor (CRH). Besides regulating the HPA axis CRH evolves properties of a neurotransmitter in the limbic system that is closely involved in the delivery of the emotional consequences of the stress response. At a superordinated level Neuropeptide Y (NPY) and Cholecystokinin (CCK) affect the release of CRH and modulate thereby the intensity of the physiological stress response. Benzodiazepine treatment interferes not only with the release of CRH but also with the release of NPY and CCK. Alterations in the intracortical ratio of NPY, CCK and CRH are correlated with behavioural changes like increased respectively decreased anxiety and subsequent alterations in the activity of the HPA axis. Recent research offers the possibility that the alterations of plasma levels of these neuropeptides are not only a secondary phenomenon due to drug intake, but that low levels of those neuropeptides that modulate anxiety and fear can possibly explain addiction to substances that counterbalance these deficits. Depending on the available results possible implications of NPY and CCK on benzodiazepine addiction and withdrawal symptoms are reviewed, thereby providing topics for further research.

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Benzodiazepines increase preprocholecystokinin messenger RNA levels in rat brain

Cited by 18 publications

References 10 publications

Odor-Induced Variation in Anxiety-Like Behavior in Mice is Associated with Discrete and Differential Effects on Mesocorticolimbic Cholecystokinin mRNA Expression

Odor-Induced Variation in Anxiety-Like Behavior in Mice is Associated with Discrete and Differential Effects on Mesocorticolimbic Cholecystokinin mRNA Expression

Effects of Alprazolam on Cholecystokinin-Tetrapeptide-Induced Panic and Hypothalamic–Pituitary–Adrenal-Axis Activity: A Placebo-Controlled Study

Neuroendocrine pathways in benzodiazepine dependence: new targets for research and therapy

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