Sex Differences between CRF1 Receptor Deficient Mice following Naloxone-Precipitated Morphine Withdrawal in a Conditioned Place Aversion Paradigm: Implication of HPA Axis

Abstract

BackgroundExtinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R) and the different response of male and female mice in the expression and extinction of the aversive memory.Methodology/Principal FindingWe used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10–60 mg/kg). Negative state associated with naloxone (1 mg/kg s.c.)-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. No sex differences for CPA expression were found in wild-type (n = 29) or CRF1R knockout (KO) mice (n = 29). However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH) levels observed in wild-type (n = 11) mice after CPA expression, were attenuated in CRF1R KO mice (n = 10). In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished.Conclusion/SignificanceThese results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished.

Conditioned aversive memory associated with morphine withdrawal increases brain‐derived neurotrophic factor in dentate gyrus and basolateral amygdala

“…However, CP‐154 526 interrupts naloxone‐induced CPA in morphine‐treated animals suggesting that the consolidation process of opioid‐withdrawn associated aversion could be linked to CRF1 receptor activation. These results are in agreement with previous studies performed in CFR1 knockout mice . In addition, CP‐154 526 administration abolished the acquisition of morphine‐conditioned place preference (CPP) .…”

“…According to previous studies, present results showed that naloxone administration to mice dependent on morphine evoked an increased in body weight loss (0.79 ± 0.04 g) compared with the control group receiving saline instead morphine (0.12 ± 0.06 g; t 14 = 8.369, P < .0001; Student's t test. The body weight loss was accompanied by other withdrawal signs such as ptosis, teeth chattering, tremor, piloerection, lacrimation, rinorrhea, spontaneuous jumping, wet‐dog shakes, salivation, and diarrhea …”

Multifunctional opioid receptor agonism and antagonism by a novel macrocyclic tetrapeptide prevents reinstatement of morphine‐seeking behaviour

“…Further work is needed to investigate efficacy against multiple types of nociception (e.g., in models of neuropathic pain, which were not evaluated here) and in a battery of additional models of addiction (such as rodent self‐administration). The ameliorating effects on reinstatement demonstrated here were time‐dependent, but were not evaluated in the context of important factors such as opioid withdrawal and the prolonged dysphoria over time that is associated with reinstatement to morphine‐seeking behaviour (Garcia‐Carmona, Baroja‐Mazo, Milanes, & Laorden, 2015). Further studies evaluating the effects of cyclo [Pro‐Sar‐Phe‐ d ‐Phe] treatment in drug‐responding animals still actively seeking drugs are also important, although beyond the scope of this initial evaluation.…”

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

“…The neural mechanisms that underlie the sexually dimorphic prevalence of these disorders are unclear. Cells that produce corticotropin‐releasing factor (CRF), and those that express the primary receptor for CRF, the G S ‐coupled cognate receptor, CRF receptor 1 (CRFR1), represent intriguing cell phenotypes that might regulate these sex differences, given their known role in regulating anxiety, depression, and stress hormone secretion (Chrousos, ; Da Silva et al, ; Garcia‐Carmona, Baroja‐Mazo, Milanes, & Laorden, ; Holly et al, ; Schussler et al, ).…”