Relapse to methamphetamine (Meth) use is often precipitated by exposure to drug-associated cues. Clinical studies suggest that cue-induced drug craving increases during early abstinence and remains elevated for extended time periods. An analogous phenomenon, termed 'incubation of drug craving' has been observed in rats trained to self-administer Meth. From an animal model-to-human translational perspective a limitation of rodent incubation studies is that the abstinence period preceding the relapse tests is experimenter-imposed (forced). In contrast, in humans, abstinence is often voluntary due the availability of alternative non-drug rewards. Based on these considerations, Dr. Caprioli recently developed a choice-based rat model of relapse after voluntary abstinence (1). The proposed model mimics human relapse after cessation of successful contingency management (CM) where the availability of monetary vouchers, given in exchange for 'clean' urine samples, maintains abstinence.
Notably, a recent clinical study, on the effectiveness of varying duration of a CM intervention in Meth addict, revealed that the number of participants who remained abstinence in a follow-up study increased as the exposure to CM increase.
Based on the above, the major objective of this proposal is to study over time similarity and differences of the synaptic alterations between the incubated Meth craving after forced and voluntary abstinence in rats. The central hypothesis, is that: both incubation after forced and voluntary abstinence-related plasticity in the medium spiny neurons (MSNs) of the nucleus accumbens (NAc) begins with decreased mGluR1 function enabling changes in AMPARs transmission, which promote Meth craving. However, a prolonged CM-based voluntary abstinence result in an attenuated cue-induced Meth seeking (as suggested by the human findings) and CP-AMPAR relative to the forced abstinence group.
This proposal is innovative, in our opinion, on several counts: (i) The incubation model provides a unique approach that specifically focuses on relapse during forced and voluntary abstinence, both of which occur in humans. Traditionally relapse studies have been conducted with reinstatement models that rely on extinction training (11). These models are not well suited to understand the plasticity that maintains drug craving because extinction training itself induces plasticity in the reward circuitry. Moreover, drug addicts do not undergo extinction training as part of their treatment. (ii) At present, to the best of our knowledge, there are only 6 papers available on the incubation of Meth craving after forced abstinence, focusing primarily on behavioral pharmacology, neural circuitry and epigenetics; our focus on synaptic transmission is relatively unique and is one of the aspects of our research that will open up novel future directions in the therapeutic setting. (iii) Showing that incubation and CP-AMPAR adaptations are less persistent in the voluntary abstinence relative to the forced abstinence condition will represent the first neurobiological correlate underlying the therapeutic efficacy of CM, currently the only effective treatment for many Meth addicts. In turn this will facilitate the discovery of new molecular targets relevant for treatment and therapy.
References:
(1) Caprioli D, Venniro M, Zeric T, Li X, Adhikary S, Madangopal R, et al (2015). Effect of the novel positive allosteric modulator of metabotropic glutamate receptor 2 AZD8529 on incubation of methamphetamine craving after prolonged voluntary abstinence in a rat model. Biological Psychiatry 78(7): 463-473.
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(5) Wang G, Shi J, Chen N, Xu L, Li J, Li P, et al (2013). Effects of Length of Abstinence on Decision-Making and Craving in Methamphetamine Abusers. PLoS ONE 8(7): e68791-e68791.
(6) Wolf ME (2016). Synaptic mechanisms underlying persistent cocaine craving. Nature reviews Neuroscience 17(6): 351-365.
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(8) Roll JM, Chudzynski J, Cameron JM, Howell DN, McPherson S (2013). Duration effects in contingency management treatment of methamphetamine disorders. Addictive behaviors 38(9): 2455-2462.
(9) Scheyer AF, Loweth JA, Christian DT, Uejima J, Rabei R, Le T, et al (2016). AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving. Biological Psychiatry.
(10) Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng L-J, Shaham Y, et al (2008). Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454(7200): 118-121.
(11) Venniro M, Caprioli D, Shaham Y (2016). Animal models of drug relapse and craving: From drug priming-induced reinstatement to incubation of craving after voluntary abstinence. Progress in brain research 224: 25-52.