Mindfulness-Oriented Recovery Enhancement remediates anhedonia in chronic opioid use by enhancing neurophysiological responses during savoring of natural rewards

Background Neuropsychopharmacologic effects of long-term opioid therapy (LTOT) in the context of chronic pain may result in subjective anhedonia coupled with decreased attention to natural rewards. Yet, there are no known efficacious treatments for anhedonia and reward deficits associated with chronic opioid use. Mindfulness-Oriented Recovery Enhancement (MORE), a novel behavioral intervention combining training in mindfulness with savoring of natural rewards, may hold promise for treating anhedonia in LTOT. Methods Veterans receiving LTOT (N = 63) for chronic pain were randomized to 8 weeks of MORE or a supportive group (SG) psychotherapy control. Before and after the 8-week treatment groups, we assessed the effects of MORE on the late positive potential (LPP) of the electroencephalogram and skin conductance level (SCL) during viewing and up-regulating responses (i.e. savoring) to natural reward cues. We then examined whether these neurophysiological effects were associated with reductions in subjective anhedonia by 4-month follow-up. Results Patients treated with MORE demonstrated significantly increased LPP and SCL to natural reward cues and greater decreases in subjective anhedonia relative to those in the SG. The effect of MORE on reducing anhedonia was statistically mediated by increases in LPP response during savoring. Conclusions MORE enhances motivated attention to natural reward cues among chronic pain patients on LTOT, as evidenced by increased electrocortical and sympathetic nervous system responses. Given neurophysiological evidence of clinical target engagement, MORE may be an efficacious treatment for anhedonia among chronic opioid users, people with chronic pain, and those at risk for opioid use disorder.

Differential Aspects of Natural and Morphine Reward-Related Behaviors in Conditioned Place Preference Paradigm

Natural rewards are essential for animal survival. On the other hand, drug-seeking behaviours can be maladaptive and endanger survival. The present study was conducted to enhance our understanding of how animals respond to food and morphine as natural and drug rewards, respectively, in a conditioned place preference (CPP) paradigm. We designed a protocol to induce food-CPP and compare it as a natural reward with morphine-CPP in rats. The protocol for reward induction in all groups (foods and morphine) consisted of three phases: pre-test, conditioning, and post-test. In morphine groups, we injected morphine as a reward (5 mg/kg, s.c.), and for inducing natural-reward, we used two different protocols, by one of the rats were deprived of food for 24h. In the other method, rats were restricted for food for 14 days. During the conditioning period, animals received daily chow, biscuit, or popcorn as a reward inducer. Results revealed that CPP did not induce in food-deprived rats. A combination of food restriction (as a facilitator) and a biscuit or popcorn induced reward using CPP. In contrast, food deprivation did not facilitate food-CPP in response to regular food. Interestingly the CPP score of the group which received biscuit during a 7-day conditioning period was more than that of the morphine group. In conclusion, food restriction could be a better protocol than food deprivation to facilitate food reward.

Disrupting D2-NMDA receptor heteromerization blocks the rewarding effects of cocaine but preserves natural reward processing

Addictive drugs increase dopamine in the nucleus accumbens (NAc), where it persistently shapes excitatory glutamate transmission and hijacks natural reward processing. Herein, we provide evidence, from mice to human, that an underlying mechanism relies on drug-evoked heteromerization of glutamate NMDA receptors (NMDAR) with dopamine receptor 1 (D1R) or 2 (D2R). Using temporally-controlled inhibition of D1R-NMDAR heteromerization, we unraveled their selective implication in early developmental phases of cocaine-mediated synaptic, morphological and behavioral responses. In contrast, preventing D2R-NMDAR heteromerization blocked the persistence of these adaptations. Importantly, interfering with these heteromers spared natural reward processing. Strikingly, we established that D2R-NMDAR complexes exist in human samples and showed that, despite a decreased D2R protein expression in the NAc, psychostimulant-addicts display a higher proportion of D2R forming heteromers with NMDAR. These findings contribute to a better understanding of molecular mechanisms underlying addiction and uncover D2R-NMDAR heteromers as targets with potential therapeutic value.

Involvement of cAMP-Dependent Protein Kinase in the Nucleus Accumbens in Cocaine Versus Social Interaction Reward

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.