Chronic cannabinoid administration in vivo compromises extinction of fear memory

Abstract

Endocannabinoids are critically involved in the extinction of fear memory. Here we examined the effects of repeated cannabinoid administration on the extinction of fear memory in rats and on inhibitory synaptic transmission in medial prefrontal cortex (mPFC) slices. Rats were treated with the CB1 receptor agonist WIN55212-2 (WIN 10 mg/kg, i.p.) once per day for 7 d. On day 8, the rats were submitted to a standard fear conditioning procedure, and retention of memory was measured with potentiated startle paradigm. We found that (1) WIN-pretreated rats exhibited much less extinction to cue alone presentations; (2) the reduction of fear-potentiated startle normally seen when the CB1 receptor agonists were infused into the mPFC was absent in the WIN-pretreated rats; (3) WIN-induced inhibition of GABAergic transmission was significantly less in slices from the WIN-pretreated rats than that from the vehicle-pretreated control; (4) WIN failed to induce extracellular signal-regulated kinases (ERKs) phosphorylation in the WIN-pretreated rats; and (5) the level of CB1 receptor in the WIN-pretreated rats was lower than that of vehicle-pretreated rats. These results suggest that endocannabinoids within the mPFC play an important role in the extinction of conditioned fear. However, long-term marijuana use may limit its clinical efficacy for the treatment of anxiety disorders.

Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: A critical review of preclinical research

“…Some of the findings point to the risks of this method of intervention: high systemic doses were either ineffective or led to impairment of extinction (Chhatwal et al, 2005; Pamplona et al, 2006), and chronic administration not only impaired extinction in a drug free state but also blocked any enhancement that otherwise resulted from acute CB1 agonism (Lin, Mao, Chen, & Gean, 2008). …”

Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention

“…Recent evidence, however, suggests that activity in the medial prefrontal cortex (mPFC) is critical for cued fear learning, in addition to the amygdala (Quirk et al, 1995(Quirk et al, , 2003. As anatomical evidence demonstrates that CCK, CCKBR and Cnr1 localize to prefrontal cortex (Larsson and Rehfeld, 1979;Zarbin et al, 1983;Herkenham et al, 1990) and behavioral studies implicate prefrontal Cnr1 in fear (Laviolette and Grace, 2006;Lin et al, 2008Lin et al, , 2009Ganon-Elazar and Akirav, 2013;Kuhnert et al, 2013), similar immunofluorescence experiments should be performed in mPFC. In addition, site-specific behavioral experiments should be conducted in follow-up studies to determine whether the observed Cnr1-CCKBR interaction occurs in BLA.…”

M-Type Potassium Channels Modulate the Intrinsic Excitability of Infralimbic Neurons and Regulate Fear Expression and Extinction

“…It is also possible that endocannabinoids produced in IL during extinction (Lin et al, 2008(Lin et al, , 2009) may inhibit M-type K ϩ channels (Schweitzer, 2000;Kano et al, 2009). The inhibition of M-type K ϩ channels depolarizes the neurons and increases their membrane resistance to increase the probability that the IL neurons will fire spikes during the tone.…”