Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

Abstract

Addiction prioritizes drug use over innate needs by hijacking brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining FOS-Seq, CRISPR-perturbations, and snRNA-seq, we identify Rheb as a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses. Retrograde circuit mapping pinpoints orbitofrontal cortex which, upon activation, mirrors drug effects on innate needs. These findings deconstruct the dynamic, molecular, and circuit basis of a common reward circuit, wherein drug value is scaled to promote drug-seeking over other, normative goals.

Generalized cue reactivity in dopamine neurons after opioids

“…It is possible that the non-specific dopamine enhancement we observe here could promote behavioral activation which is sculpted to promote drug-seeking by causal information supplied by structures implicated in model-based learning, such as the orbitofrontal cortex. A recent report has suggested a similar role for the orbitofrontal cortex in promoting drug addiction by interfering with natural reward consumption (Tan, Browne et al 2024). Alternatively, it is also possible that behavioral selectivity is dictated by regulation of dopamine release distally at axon terminals, which may be regulated independently from somatic firing (Mohebi, Collins et al 2023).…”

Cellular and molecular basis of leptin resistance

“…Thus, new therapies that enhance endogenous leptin sensitivity via cell-typespecific inhibition of mTOR activity may provide an important therapeutic modality on its own or as an adjunct to incretin therapies or bariatric surgery. Recent advances in developing brainspecific rapalogues provide a possible means to selectively reduce mTOR activity specifically in brain and thus represent a potential means for treating of brain diseases associated with mTOR hyperactivity [92][93][94][95] . Alternatively, the development of means for cell specific delivery of rapamycin or identifying cell-type-specific mTOR components in POMC neurons could provide new avenues for treating obesity or maintaining weight loss 96 .…”

Breaking the Chains: Advances in Substance Addiction Research through Single-Cell Sequencing, Epigenetics, and Epitranscriptomic

“…These clusters exhibited known markers associated with two main types of MSNs: dopamine receptor D1-positive (Drd1-MSNs) and dopamine receptor D2-positive (Drd2-MSNs) [58]. The same neuronal substrate that allows drugs of abuse to access Drd1 and Drd2 MSNs in NAc has been confirmed to augment and corrupt a shared pathway that normally serves physiological needs [59]. Nevertheless, the investigation of genetically mediated variations in susceptibility to addiction-like behaviors was restricted by the use of inbred rodent strains.…”