Introduction:
Cholecystokinin ( CCK) is strongly linked to many mental health issues. It is a neuropeptide or a neurotransmitter that acts on the regions of the brain. It was identified in the gut first. Later it was found abundantly in the brain. The concentration of its presence in the brain regions indicates its role in many psychiatric-related disorders. CCK is linked to anxiety, panic disorders, schizophrenia, and addictions.
What Is Cholecystokinin?
Cholecystokinin ( CCK) is a neuropeptide and neurotransmitter present abundantly in the brain. Its highest concentration is in the brain's cortical and limbic regions and the basal ganglion. Two types of CCK receptors are present in the brain and gastrointestinal tissue. They are CCKA ( CCK1) and CCKB ( CCK2).
CCKA are the receptors present in the gastrointestinal tract. These receptors regulate the secretion of enzymes from the pancreas and help empty the gallbladder. These are also found in brain regions like the nucleus tractus solitaries, and hypothalamus, where the highest densities of structures are present. CCKB are the receptors widely distributed in the regions of the highest densities of the structures in the cerebral cortex, basal ganglia, nucleus accumbens, and forebrain limbic structures.
Both receptors belong to the guanine nucleotide-binding protein ( G-protein)- linked receptor superfamily containing seven transmembrane domains. At CCK receptors, its signal transduction is mediated through Gq-protein-related activation of phospholipase C and the formation of inositol 1,4,5, triphosphate (IP3), and 1,2-diacylglycerol ( DAG). Cloning of CCKA and CCKB in recent years has shown that mRNA for these two receptors is distributed in the same tissues.
There exist many receptors for CCK. Hence CCKA and CCKB receptor antagonists have been developed. These receptor antagonists belong to different chemical groups. Studies have shown that these antagonists and agonists play a role in psychiatric disorders. CCK agonists have shown anxiogenic action in animal models. CCKB receptors are responsible for anxiogenic actions.
In animal models, CCKB antagonists have demonstrated the ability to counteract the effects of CCKB agonists. However, CCK antagonists' explicit antagonism of anxiogenic actions in humans must be better defined. When an experiment was performed on a mouse model, CCKB antagonists have shown to reduce depression, whereas, in humans, it is yet to be done.
One of the chemical alterations in schizophrenia is a reduction in CCK levels in the cerebral cortex. But the actions of agonists or antagonists have not shown any results in schizophrenia. Hence, increasing the concentration levels of CCK in the brain may be more appropriate for treating schizophrenia.
In mammals, one of the brain regions called the amygdala, has a role in fear and anxiety. Abundant CCK neurons and CCKB receptors are found in the centromedial amygdaloid nuclei. It was found that CCK8 and CCK4 are responsible for anxiety and panic attacks.
What Is the Bioactivity of Cholecystokinin-4?
The bioactivity of CCK4 includes,
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The biological activation of carboxy amidated tetrapeptide of CCK is identified as a gastric acid regulatory hormone called gastrin.
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Studies have identified that active sites or receptors be C-terminal tetrapeptide amide.
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Studies have revealed that many different CCK has the same common tetrapeptide.
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In other studies, it was found that the insulinogenic effect was associated with tetrapeptides containing CCK.
What Is the Role of Cholecystokinin-4 on Panicogenic Activity?
The panicogenic activity of CCK-4 includes,
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Studies of CCK-4 have shown that these target CCKB receptors and create anxiety with the help of other neurotransmitter systems.
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One of the studies found that the CCKB receptor is more sensitive to CCK-4, especially among individuals with panic disorders.
What Are the Forms of Cholecystokinin Present in the Brain?
In the brain, more abundantly present is the CCK-8, and next comes the CCK-5.
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CCK-5 may get degraded to CCK-4.
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CCK-4 has panicogenic action.
If CCK4 is exogenously given, it may be responsible for panic attacks.
CCK Concentration in Plasma: The concentration of CCK is low in mammalian plasma. CCK-33, 58, 22,8 are the forms of CCK found in plasma. Among these predominant forms of CCK is CCK-33.
Association of CCK Receptor With Genes: Studies have found that the CCKA receptor is not associated with polymorphism of gene, and the CCKB receptor is found to be associated with polymorphism of gene.
What Is the Role of CCKB Receptors in Panic Disorder Therapy?
First, it was known that CCKB receptors try to bind with CCK4 and cause panic attacks. Hence it was understood that CCKB antagonists could treat panic disorders. Studies have been done on a few CCKB antagonists like L-365,260, and these reduced the panic attacks caused due to CCK4. It was found that this effect was possible only when the L-365,260 was administered just before the injection of CCK4. Another antagonist CI-988 showed a weak effect on panic attacks caused due to CCK-4 in healthy individuals but failed in individuals affected with panic disorder. A recent study on rats with anxiety showed that CCKB receptor antagonist LY-225,910 reduced anxiety levels among rats. This effect is yet to be demonstrated in humans.
A study has revealed that systemic administration of CCK-4 may cause respiratory and cardiovascular alterations in humans. It is also found that the administration of CCK2 receptor antagonist can counteract this effect and attenuates these changes from occurring or reduces the differences in cardiovascular and respiratory changes.
It is also found that the use of CCKB antagonists, along with the reduction of anxiety, may also reduce the memory of that particular individual. Hence further studies need to be conducted to overcome such complications.
Conclusion:
CCK peptides and receptors are present abundantly in the brain. Its actions in inducing panic attacks were known. Hence studies were conducted to overcome anxiety and panic disorders ( psychiatric disorders) using CCK receptor antagonists. Thus it becomes essential to know about CCK, its types, its role in anxiety and panic disorder, and its use in treating psychiatric disorders. Knowing helps an individual to seek help from a healthcare professional early. Early diagnosis leads to effective treatment. This, in turn, helps in achieving good quality of life.
