Regulatory Role of PFC Corticotropin-Releasing Factor System in Stress-Associated Depression Disorders: A Systematic Review.

Stress has a substantial role in formation of psychiatric disorders especially depression. Meanwhile, impairment of the prefrontal cortex (PFC) is connected to the executive and cognitive deficits induced by the stress. Given the involvement of the corticotropin-releasing factor (CRF) in stress-related processes and knowing the fact that PFC hosts a lot of CRF receptors and CRF neurotransmissions, it can worth to look at the CRF as a potential treatment for the regulation of depression disorders induced by stress within PFC region. Here, for the first time we aimed to systematically review the effectiveness of intra-PFC CRF system in the modulation of depression dysfunction caused by the stress in clinical and preclinical models/studies. Qualified researches were combined utilizing a comprehensive search of six databases including Scopus, Pubmed, Web of Science, Sciencedirect, APA PsycNet, and Embase in April 2021 and were evaluated through proper methodological quality assessment tools. Results indicate that PFC has a remarkable role in the modulation for stress-induced depression and intra-PFC CRF receptors agonist and antagonist are very considerable for regulating these types of impairments. Specifically, elevation of both CRF immunoreactivity and gene expression were observed in human studies. In the animal studies, mostly immunoreactivity or excitatory/inhibitory currents of CRF within the PFC regulated depression dysfunction. In conclusion, reviewed studies show a positive attitude toward the CRF system in regulation of the stress-induced depression; however, obviously further investigations are required to get closer to the best treatment. Prefrontal cortex corticotropin-releasing factor system regulates stress-induced depression. CRFR1, Corticotropin-releasing factor receptor of type1; PFC, Prefrontal cortex; Minus (-) and Plus (+) signs, dysregulation and upregulation, respectively.

Corticotropin-releasing factor receptor 1 in infralimbic cortex modulates social stress-altered decision-making.

Chronic stress could lead to a bias in behavioral strategies toward habits. However, it remains unclear which neuronal system modulates stress-induced behavioral abnormality during decision making. The corticotropin-releasing factor (CRF) system in the medial prefrontal cortex (mPFC), which has been implicated in governing strategy choice, is involved in the response to stress. The present study aimed to clarify whether altered function in cortical CRF receptors is linked to abnormal behaviors after chronic stress. In results, mice subjected to a 10-day social defeat preferred to use a habitual strategy. The infralimbic cortex (IL), but not the prelimbic cortex (PL) or anterior cingulate cortex (ACC), showed higher cFos expression in stress-subjected mice than in control mice, which may be associated with habitual behavior choice. Furthermore, CRF receptor 1 (CRFR1) agonist and antagonist infusion in IL during behavioral training mimicked and rescued stress-caused behavioral change in the decision-making assessment, respectively. An electrophysiological approach showed that the frequencies of both spontaneous IPSC and spontaneous EPSC, but not their amplitude, increased after stress and were modulated by CRFR1 agents. Further recordings revealed that an increased ratio of excitation to inhibition (E/I ratio) of IL by stress was rescued under conditions with CRFR1 antagonist. Collectively, these data indicate that CRFR1 plays a critical role in stress-permitted or enhanced glutamatergic and GABAergic presynaptic transmission in direct or indirect ways, as well as the modulation for E/I ratio in the IL. Thus, CRFR1 in the mPFC may be a proper target for treating cases of chronic stress-altered behavior.

Endocannabinoids and addiction memory: Relevance to methamphetamine/morphine abuse.

AIM: This review aims to summarise the role of endocannabinoid system (ECS), incluing cannabinoid receptors and their endogenous lipid ligands in the modulation of methamphetamine (METH)/morphine-induced memory impairments. METHODS: Here, we utilized the results from researches which have investigated regulatory role of ECS (including cannabinoid receptor agonists and antagonists) on METH/morphine-induced memory impairments. RESULTS: Among the neurotransmitters, glutamate and dopamine seem to play a critical role in association with the ECS to heal the drug-induced memory damages. Also, the amygdala, hippocampus, and prefrontal cortex are three important brain regions that participate in both drug addiction and memory task processes, and endocannabinoid neurotransmission have been investigated. CONCLUSION: ECS can be regarded as a treatment for the side effects of METH and morphine, and their memory-impairing effects.

Intra-hippocampal administration of orexin receptor antagonists dose-dependently attenuates reinstatement of morphine seeking behavior in extinguished rats.

It has been shown that the hippocampus plays an essential role in the regulation of reward and memory as indicated by the conditioned place preference (CPP) paradigm. Morphine-induced CPP is a common method to consider motivational properties of morphine in animals. Recently, this model has been used in many laboratories to investigate neuronal mechanisms underlying reinstatement of morphine seeking induced by drug re-exposure. Our previous studies indicate that the hippocampus especially CA1 region is involved in reinstatement of drug-seeking behaviors. Also, several studies have shown that orexin attenuates key functional and behavioral effects of its co-transmitter dynorphin. The present study evaluates the role of orexinergic receptors within the CA1 region of the hippocampus in the reinstatement of morphine-induced CPP. Therefore, after the extinction period, the different doses (SB 334867; 0.3, 3, and 30 nM/0.5 µl DMSO) of either orexin-1 or -2 receptor antagonists were bilaterally microinjected into the CA1, 15 min before receiving an effective priming dose of morphine (1 mg/kg). The results revealed that administration of both SB 334867 and TCS OX2 29 prior to injection of the priming dose of morphine significantly reduced the reinstatement of morphine-induced CPP without altering the animal's locomotor activity. Also, the 50% effective dose value of SB 334867 on the reinstatement of morphine seeking behavior was close three times more than that in TCS OX2 29 treatment group. Therefore, the consequences suggested that both orexin receptors in the CA1 play a considerable role in the reinstatement of morphine-induced CPP.

Role of intra-accumbal orexin receptors in the acquisition of morphine-induced conditioned place preference in the rats.

Orexin receptor shave essential role in the induction of reward-related behaviors to several drugs of abuse. In the present study, we investigated the effects of bilateral administration of SB334867, as an orexin-1 receptor antagonist, and TCS OX2 29, as an orexin-2 receptor antagonist, into the nucleus accumbens (NAc) on the acquisition of morphine-induced conditioned place preference (CPP) in the rats. Adult male Wistar rats (n=80; 220-250g) were entered in a CPP paradigm. Bilateral microinjections of different doses of SB334867 (1, 3, 10 and 30nM) or TCS OX2 29 (3, 10, 30 and 100nM) into the NAc (0.5µl/side) were done 5min before subcutaneous injection of morphine (5mg/kg) during 3-dayconditioning (acquisition) phase. The CPP scores and locomotor activity of animals were recorded by video tracking system and Ethovision software. The results demonstrated that intra-NAc microinjection of 3, 10 and 30nM solutions of SB334867 markedly decreased the acquisition of morphine-induced CPP in a dose-dependent manner. Intra-accumbal injection of 10, 30 and 100nM solutions of TCS OX2 29 significantly attenuated the acquisition of morphine CPP as well. In addition, contribution of orexin-1 receptors to development of morphine reward-related behaviors was more than orexin-2 receptors. Our results suggest that both orexin-1 and -2 receptors in the NAc are involved in the development of morphine-induced CPP. It seems that orexin-1 receptors in this region are more effective in development of drug seeking behaviors in the rats.