Title:Cholecystokinin-Mediated Neuromodulation of Anxiety and Schizophrenia: A “Dimmer-Switch” Hypothesis
Volume: 19
Issue: 7
Author(s): Santiago J. Ballaz*Michel Bourin
Affiliation:
- School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San Jose s/n, San Miguel de Urcuquí,Ecuador
Keywords:
Anxiety, cholecystokinin, dopamine, gamma-aminobutyric acid, glutamic acid, schizophrenia.
Abstract: Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant
behavioral functions like memory, cognition, and reward through its interactions with the opioid
and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors,
CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2
receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK
expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation
by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither
CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown
neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory
role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons
that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the
excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability
of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on
how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate
levels of CCK release in the basal striatum may control the interplay between cognition and reward
circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/
inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between
corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.
