Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol

Abstract

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, i9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these 4 drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies, and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse.

Cocaine Seeking During Initial Abstinence Is Driven by Noradrenergic and Serotonergic Signaling in Hippocampus in a Sex-Dependent Manner

“…(d) Depiction of DH areas where Fos was counted, representative image from Bregma − 3.14 (Paxinos and Watson, 2006). cocaine-naive subjects (Becker et al, 2016) such that increased Fos during ED1 may reflect a return to baseline Fos levels. Regardless, our findings that Fos levels correlate with ED1 responding in many regions indicate that such activation may play an important role in ED1 drug seeking.…”

Ketamine blocks morphine-induced conditioned place preference and anxiety-like behaviors in mice

“…Repeated exposure to morphine increases levels of anxiety both in humans and in animal models of substance use disorders (Gold et al, 1978;1979;Becker et al, 2017). Additionally, it is posited that relapse to opioids in abstinent patients is caused by negative affective states driving negative reinforcement (Solomon and Corbit, 1978;Koob and Le Moal, 2008;Evans and Cahill, 2016).…”

“…Morphine possesses anxiolytic-like properties during initial exposure (Koks et al, 1999;Sasaki et al, 2002;Shin et al, 2003). However, during opioid abstinence, symptoms of anxiety (Gold et al, 1978;1979;Li et al, 2009;Shi et al, 2009) or anxiety-like behaviors are observed (Cabral et al, 2009;Becker et al, 2017). Here, we show that 24 h following repeated morphine injections (once a day for 5 days), mice display anxiety-like behaviors in the elevated plus maze (Fig.…”

Neuroinflammation—a co-occurring phenomenon linking chronic pain and opioid dependence

“…Similarly, opioid dependent patients have a high incidence of depression. Indeed, opioid use in the absence of pain has been shown to induce a protracted abstinence syndrome [25,26], and can increase the likelihood of major depressive episodes [27]. There is also recent evidence that long-term prescription opioid use is associated with both new onset and recurrence of depression [28], as well as enhances the risk of developing treatment resistant depression [29 • ].…”