Cholecystokinin-Mediated Neuromodulation of Anxiety and Schizophrenia: A “Dimmer-Switch” Hypothesis

Abstract

: Cholecystokin (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 have CCK agonists 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.

Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders

“… In humans, GWAS has found an association of CCK in pathways with increased neurofibrillary tangles and TREM2 protein levels, both previously associated with Alzheimer disease and related tauopathies. Despite mixed success as a direct therapeutic aid to ameliorate anxiety and symptoms of schizophrenia via CCK receptor antagonists, CCK knockout mice have increased prepulse inhibition, a key biomarker of the sensory overload characteristic of psychosis, and NPY mouse models of schizophrenia show increased anxiety traits and abnormal susceptibility to induced seizures. …”

Infra-Low Frequency Neurofeedback rapidly ameliorates schizophrenia symptoms: A case report of the first session

“…The answer as to why neurofeedback benefits such a great variety of different brain dysfunctions may be found in mechanisms similar to the one suggesting that cholecystokinin regulates dopaminergic (as well as GABAergic and glutaminergic) activity through a corticolimbic and a mesolimbic dimmer-switch process (Ballaz and Bourin, 2021a , b ; Ballaz et al, 2021 ).…”

“…In our opinion, certain two neurophysiological models for the etiology of schizophrenic symptoms that relate to one classical neurotransmitter, which is γ-aminobutyric acid (GABA) (Roberts, 1972 , 1976 ), and one neuropeptide/neuromodulator which is cholecystokinin-CCK (Hockfelt et al, 1980a , b ), although about 40 years old, when combined with very recent relevant research (Whissell et al, 2015 , 2019 ; Ballaz and Bourin, 2021a , b ; Ballaz et al, 2021 ; Ochoa-de la Paz et al, 2021 ), prove their contribution to understanding schizophrenia. The two models are not in conflict but complement each other Nestoros, 1980a .…”

“…Firstly, the increase of extreme stress causes the hyperactivity of dopaminergic (Brisch et al, 2014 ) and the hypoactivity in GABAergic neurotransmission (Nuss, 2015 ). Diazepam is known to reduce dopamine release in nucleus accumbens (Gomez et al, 2017 ) and potentiates the inhibitory action of GABA (Haefely, 1978 ; Haefely et al, 1978a , b ; Costa and Guidotti, 1979 ; Nestoros and Nistri, 1979 ; Nestoros, 1980b , c , 1982 , 1997a , b ); while cholecystokinin regulates dopaminergic (as well as GABAergic and glutaminergic) activity through a corticolimbic and a mesolimbic dimmer-switch process (Ballaz and Bourin, 2021a , b ; Ballaz et al, 2021 ). The inhibitory action of γ-aminobutyric acid (GABA) is mediated predominantly by interneurons (Kelsom and Lu, 2013 ).…”

CCK regulates osteogenic differentiation through TNFα/NF-κB in peri-implantitis

“…7 CCK is also the most abundant brain neuropeptide and participates in related behavioral functions such as memory, cognition, and reward through interactions with the opioid and dopaminergic components of the limbic system. 8 However, its involvement in peri-implantitis has not been elucidated.…”