Suppression of Conditioned Fear by Administration of CCKB Receptor Antisense Oligodeoxynucleotide into the Lateral Ventricle

Tsutsumi, Takashi; Akiyoshi, Jotaro; Hikichi, Takatoshi; Kiyota, Akio; Kohno, Yutaka; Katsuragi, Satomi; Yamamoto, Yoshiyuki; Isogawa, Koichi; Nagayama, Haruo

doi:10.1055/s-2001-18030

Cited by 19 publications

(9 citation statements)

References 38 publications

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“…These results suggest that their anxious phenotype is associated with a high CCKergic tone operating via CCK-2 receptors. As expected from the above, the intracerebroventricular administration of CCK-2 receptor [109] and pre-pro-CCK [110] antisense oligonucleotides decreases anxiety in the Elevated Plus-Maze and conditioned fear in rats.…”

Section: Molecular Biological Approachessupporting

confidence: 51%

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

Mora

Jacobsen²,

Crespo-Ramírez

et al. 2008

Neurochem Res

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The amygdala plays a key role in anxiety. Information from the environment reaches the amygdaloid basolateral nucleus and after its processing is relayed to the amygdaloid central nucleus where a proper anxiogenic response is implemented. Experimental evidence indicates that in this information transfer a GABAergic interface controls the trafficking of impulses between the two nuclei. Recent work indicates that interneuronal communication can take place by classical synaptic transmission (wiring transmission) and by volume transmission in which the neurotransmitter diffuses and flows through the extracellular space from its site of release and binds to extrasynaptic receptors at various distances from the source. Based on evidence from our laboratory the concept is introduced that neurotransmitters in the amygdala can modulate anxiety involving changes in fear learning and memories by effects on receptor mosaics in the fear circuits through wiring and volume transmission modes of communication.

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Section: Molecular Biological Approachessupporting

confidence: 51%

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

Mora

Jacobsen²,

Crespo-Ramírez

et al. 2008

Neurochem Res

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“…These findings indicate that a CCKergic tone may dynamically associate with stressors to cause anxiety, and that the expression of anxiety may be dynamically regulated by CCKergic tone. Other evidence suggesting a role of CCKergic tone in the pathogenesis of anxiety includes: (i) knockout of the CCKR-2 or the use of the CCKR-2 antisense oligo in animals produces anxiolytic effects (50,51), and (ii) varying fear responses among different animal strains can be attributed to different expression levels of CCKR-2 (52, 53). Our results further support these findings to indicate an important role of the CCKergic tone in anxiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Chen

Nakajima

Meacham

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic ''tone,'' which is largely determined by the expression level of the CCKR-2. Using the tTA͞tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular͞ neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity.behaviors ͉ transgenic mouse

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“…CCK-B antisense significantly suppressed the expression of conditioned fear, without affecting motor behavior. Autoradiography showed decreased binding in rats infused with CCK-B antisense [68]. …”

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y

Bowers

Choi

Ressler

2012

Physiology & Behavior

141

103

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The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the μ opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the amygdala to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation.

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Suppression of Conditioned Fear by Administration of CCKB Receptor Antisense Oligodeoxynucleotide into the Lateral Ventricle

Cited by 19 publications

References 38 publications

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse

Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y

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