Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice

Abstract

Aim: Histamine plays an important role in morphine addiction and memory-dependent behavior. However, little is known about the effect of histamine on the impairment of memory after morphine withdrawal. This study was designed to investigate the effect of histamine on memory impairment induced by morphine withdrawal in histidine decarboxylase knockout (HDC-KO) and wild-type (WT) mice. Methods: WT and HDC-KO mice were given subcutaneous morphine or saline twice daily for 5 consecutive days. The mice received a cued or contextual fear conditioning session 7 days after the last injection. During subsequent days, mice received 4 cued or contextual extinction sessions (one session per day). Western blot was used to assess extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala and hippocampus. Results: Morphine withdrawal did not affect the acquisition of cued or contextual fear responses. It impaired cued but not contextual fear extinction. The acquisition of cued and contextual fear responses was accelerated in HDC-KO mice. Histamine deficiency aggravated the impairment of cued fear extinction induced by morphine withdrawal, whereas histamine (icv, 5 µg/mouse) reversed this effect. Morphine withdrawal decreased ERK phosphorylation in the amygdala after cued fear extinction, especially in HDC-KO mice. Conclusion: These results suggest that morphine withdrawal specifically impairs cued fear extinction and histamine ameliorates this impairment. Its action might be mediated by the modulation of ERK phosphorylation in the amygdala. Histamine should be explored for possible roles in the prevention or treatment of morphine abuse and relapse.

Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear

“…Consistent with their overall experience of stress being comparable to that of controls, we have previously shown them to exhibit normal anxiety-like behavior in the open field and elevated plus maze (19). Unimpaired fear memory has previously been documented in these animals – in fact, enhanced cued and contextual fear conditioning have been reported in these animals previously (34, 35). We do not see such an enhancement of fear learning in our animals.…”

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

“…Withdrawal jumping induced by naloxone (Gong et al, 2010b) or by discontinuation of chronic morphine administration (Gong et al, 2010a) was reduced in Hdc −/− mice, compared to wild-type. On the other hand, the morphine withdrawal-induced impairment of extinction of cued fear conditioning was more pronounced in Hdc −/− mice than in wild-type animals, and i.c.v.…”

“…On the other hand, the morphine withdrawal-induced impairment of extinction of cued fear conditioning was more pronounced in Hdc −/− mice than in wild-type animals, and i.c.v. injection of histamine reversed this Hdc −/− phenotype (Gong et al, 2010a).…”

“…Fear memory in the passive avoidance test (light-dark chamber) (Acevedo et al, 2006a,b) and in a test of cued and contextual fear conditioning (Liu et al, 2007;Gong et al, 2010a) was improved in Hdc −/− mice, indicating that histamine may inhibit fear memory consolidation. This was confirmed by the observation that i.c.v.…”

Drug addiction: a curable mental disorder?

“…As mentioned above, the comorbidity of addiction and other mental disorders are common in patients with substance-use disorder. Drug use-and withdrawal-induced emotional alterations may interact with or facilitate the occurrence of other mental disorders, which in turn promote drug use and relapse [59,60].…”