In the past 20 years, with the development of China’s economy, the production and per capita consumption of alcohol have increased significantly, and various hazards caused by alcohol consumption and the hospitalization rate of alcohol dependence have also increased. Alcohol dependence is not only a medical problem, but also a social problem, which is the third most harmful to human beings after cardiovascular diseases and tumors. Alcohol dependence is a recurrent encephalopathy, and its central pathogenesis is still unclear, involving the dysregulation of neurotransmitters such as adrenocorticotropin-releasing hormone (CRH), gamma amino butyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), opioid peptide, glutamate, and neuropeptide Y (NPY).
1.Overview of CRH
Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide that mainly regulates the stress response of the body p autonomic nervous system p endocrine response. as a stress hormone, CRH is mainly secreted by small cells in the paraventricular nucleus of the hypothalamus and regulates the stress response of the body through the hypothalamic-pituitary-adrenal axis (HPA). And as a peptide central neuromodulator, it acts on the central nervous system outside the hypothalamus and is involved in the regulation of a variety of neuroendocrine functions. Two types of CRH receptors have been cloned, namely CRH1 and CRH2 receptors.
Both are G protein-coupled receptors that couple GS proteins and activate this receptor to increase intracellular cAMP concentration .CRH1 receptors are distributed in the neocortex p anterior pituitary p basolateral amygdala p hippocampus p parabrachial nucleus and cerebellum, etc. CRH2 receptors are mainly distributed in subcortical structures such as lateral interventricular diaphragm p paraventricular nucleus of hypothalamus p choroid plexus, ventral parabrachial nucleus of hypothalamus, etc. Among them, CRH1 receptors are closely related to drug dependence, stress and anxiety. And CRH2 receptors are associated with appetite suppressant effects.
2. Effects of acute and chronic alcohol exposure on CRH system
Both acute or chronic alcohol exposure can affect the CRH system. Acute alcohol exposure can activate the HPA axis, for example, a single intraperitoneal injection of alcohol to rats can increase plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, while a pre-injection of CRH antiserum can inhibit the increase in plasma ACTH and corticosterone caused by alcohol injection, which indicates that the activation of HPA axis function by intraperitoneal alcohol injection is mediated by CRH. Chronic alcohol exposure, such as: plasma corticosterone levels were elevated in SD rats given 5% alcohol liquid chow for four weeks compared to controls, but after three weeks of abstinence, plasma corticosterone levels were significantly lower compared to controls, suggesting impairment of HPA axis function.
A similar conclusion was reached in another study, in which plasma corticosterone levels were significantly lower in rats consuming alcohol-containing liquid chow compared to controls within 1 day-3 weeks of abstinence. Central CRH function may also be altered for a prolonged period of time after alcohol withdrawal. For example, 10-12 hours after acute withdrawal, extracellular CRH in the central amygdala increased by about 500%, while another experiment showed that CRH in the amygdala, prefrontal cortex, and hippocampal cytoplasm of rats decreased significantly during 1-3 weeks of withdrawal, while CRH increased significantly after six weeks of withdrawal.
The elevated extracellular CRH in the central amygdala during acute withdrawal suggests that acute alcohol withdrawal as a stressor contributed to increased CRH release, whereas the decreased intracellular CRH content suggests excessive intracellular CRH release in these brain regions. A significant increase in CRH after six weeks suggests a prolonged dysfunction of central CRH after alcohol withdrawal. Since the amygdala plays an important role in regulating the body’s stress and emotional response, an increase in CRH in the amygdala indicates that the body is hypersensitive to stress after prolonged withdrawal. Clinical studies also suggest that HPA function is suppressed in alcohol abusers.
3. CRH and acute and chronic alcohol relapse after withdrawal
Both acute and chronic alcohol exposure can cause dysfunction of the central CRH system and the HPA axis. Conversely, the impaired central CRH system and HPA axis are also one of the central neural mechanisms in the pathogenesis of alcohol dependence, especially post-withdrawal anxiety is closely related to relapse.
CRH is closely related to alcohol dependence relapse. For example, the central CRH system mediates the electroshock-induced relapse behavior in alcohol-dependent rats. It was found that the induction of alcohol-dependent rats using foot electroconvulsive shock after performing bilateral adrenalectomy had no effect on their relapse behavior with or without exogenous corticosterone supplementation. In a stress-induced relapse model of alcohol dependence in rats, CRH mRNA expression was found to be elevated in the nucleus accumbens and central amygdala, but not in the paraventricular nucleus of the hypothalamus, suggesting that the CRH system in the nucleus accumbens and central amygdala mediates relapse.
CRH-mediated electroshock-induced relapse was also associated with the nucleus accumbens, as microinjection of the non-selective CRH receptor blocker d-Phe-CRH into the nucleus accumbens inhibited electroshock-induced relapse behavior in rats. The investigators suggest that this is related to the fact that CRH inhibits neurons in the nucleus accumbens, thereby inhibiting 5-HT release as a possible mechanism of stress-induced relapse, and that CRH receptor blockers play a de-inhibitory role.
Further studies showed that c-fos in brain regions associated with the septal nucleus projection was examined during microinjection of the non-selective CRH receptor blocker d-Phe-CRH, and only c-fos mRNA in the central amygdala was found to be significantly reduced, suggesting that it is also associated with inhibition of central amygdala activity.
Negative emotions such as anxiety after alcohol withdrawal are very closely related to relapse. In contrast, dysregulation of central CRH is an important mechanism of post-withdrawal anxiety. As already described above, CRH release from nuclei closely related to stressful emotions, such as the central amygdala and the bed nucleus of the terminal striatum, was significantly increased after acute withdrawal and returned to normal after alcohol intake. It was also found that the anxiety level of rats increased after acute withdrawal from alcohol, and CRH blockers could reduce the anxiety level of rats.
For example, the time spent in the open arm of the high-table maze was significantly shorter in alcohol-dependent rats after acute withdrawal, while the time spent in the open arm was significantly longer after intracerebral injection of CRH receptor blockers. Meanwhile, intracerebral injection of the non-selective CRH receptor antagonist D-Phe-CRH (12-41) significantly attenuated the post-withdrawal self-administration behavior in alcohol-dependent rats, but had no effect on non-alcohol-exposed history rats.The above studies suggest that acute withdrawal from alcohol activates CRH neurons in the central amygdala and the nucleus accumbens, increases CRH release, and mediates negative emotions such as post-withdrawal anxiety and thus increase drinking and relapse behavior.
4. Therapeutic implications of affecting the CRH system
Inhibiting the function of the CRH system can inhibit drinking behavior and reduce relapse. However, there are other experimental results that seem to contradict this conclusion. For example, microinjection of CRH in the lateral ventricle dose-dependently inhibited drinking in rats [20] seems to suggest that CRH inhibits drinking behavior in rats, but this may be due to an anorexic response similar to that after acute stress after CRH injection. This is because although alcohol consumption decreased in P rats during restraint stress, alcohol consumption increased in P rats compared to controls within 5 days after stress.
In NP rats, alcohol consumption did not change significantly during and after restraint stress, but increased significantly after 15-35 days compared to control rats, because CRH-deficient mice drank twice as much alcohol as normal mice during free choice of alcohol and water, probably due to a compensatory increase in urocortin1 expression in CRH-deficient mice, which is a member of the CRH family member, may also play a role in mediating stress. However, these theories cannot explain some phenomena, such as the lower expression levels of CRH in hypothalamus, amygdala, and cortex in high-alcohol selective rats compared to normal rats [23]. It can be seen that the mechanism of CRH effect on drinking behavior is complex, not simply promoting or inhibiting drinking behavior, and its mechanism needs to be further investigated.
5. Summary
Alcohol can impair the function of the CRH system, causing adaptive changes and imbalancing the relationship between the two. At the same time, animal experimental studies have also demonstrated that CRH can also affect the drinking behavior of rodents. Thus, CRH, as a factor regulating the stress response of the body, has an important role in the pathophysiological mechanism of alcohol dependence, especially in the withdrawal and relapse of alcohol dependence. Because the dysregulation of CRH and NPY is closely related to post-abstinence anxiety, and anxiety is closely related to relapse; therefore, CRH can be an attractive target for anti-relapse of alcohol dependence.