Good news! Better prospects of achieving good riddance of addiction!
"... researchers ... have uncovered a mechanism in the brain that allows cocaine and morphine to take over natural reward processing systems. ... these findings shed new light on the neural underpinnings of drug addiction and could offer new mechanistic insights to inform basic research, clinical practice, and potential therapeutic solutions. ...
They discovered a largely overlapping population of cells that respond to both addictive drugs and natural rewards, and demonstrated that repeated exposure to the drugs progressively disrupts the cells' ability to function normally, resulting in behavior being directed toward drug-seeking and away from natural rewards. ...
Moreover, the research team identified a well-established intracellular signaling pathway—mTORC1—that facilitates the disruption of natural reward processing by the drugs. As part of that discovery, investigators found a gene (Rheb) that encodes an activator of the mTORC1 pathway that may mediate this relationship, potentially providing a novel therapeutic target for future discovery in a field of medicine that currently offers few effective treatments. ..."
From the editor's summary and abstract:
"Editor’s summary
Innate brain functions that normally process natural rewards are corrupted by drugs of abuse. However, the underlying physiological and molecular mechanisms linking these functions are still unclear. Tan et al. compared the response of key reward circuits activated by hunger and thirst with the response to morphine and cocaine in the same animals ... They found that the protein RHEB (Ras homolog enriched in brain), a signaling partner of mammalian target of rapamycin, is a crucial molecular substrate that enables drugs to gain access to neurons that process natural reward. This molecular mechanism is engaged in dissociable ensembles of neurons of a brain region called the nucleus accumbens. These neuronal ensembles are at the center of the addictive effects of these drugs, where conflict between drug-taking and the homeostatic regulation of hunger and thirst takes place. ...
Structured Abstract
INTRODUCTION
Drugs of abuse produce pleasurable feelings and reinforce consummatory behavior directed toward their acquisition. These same properties are characteristic of natural rewards that satisfy innate needs, such as food or water. Decades of research has shown that brain systems processing natural rewards are also impacted by drugs of abuse at the physiological, circuit, cellular, and molecular levels. These findings raise the hypothesis that drugs of abuse cause addiction by “hijacking” a common reward pathway, ultimately promoting drug intake while curbing other healthy goals. However, the specific neural substrates for such a shared reward pathway remain unidentified.
RATIONALE
Identification of a neural substrate that processes multiple classes of rewards necessitates multimodal analysis of neurobiological functions. This includes pinpointing central nodes that respond to reward exposure, examining specific cell types within this brain node that encode distinct rewarding experiences within the same individual, and identifying molecular effectors that mediate cellular and physiological adaptations. For this purpose, we employ a combination of approaches including whole-brain neuronal activity mapping, in vivo two-photon longitudinal calcium imaging at single-neuron resolution, and single-cell sequencing after in vivo CRISPR perturbation of a candidate gene. These multifaceted approaches enable the exploration of multiple components that comprise a common reward pathway and allow us to study how repeated drug exposure “hijacks” innate needs through this shared conduit.
RESULTS
Using whole-brain FOS mapping combined with chemogenetic inhibition approaches, we identify the nucleus accumbens (NAc) as a central hub necessary for both cocaine and morphine to disrupt natural reward (food and water) consumption. In vivo longitudinal tracking of individual dopaminoceptive neuron activity in the NAc in awake, behaving mice revealed overlapping ensemble responses across drugs of abuse and natural rewards, with drugs producing greater levels of activation. Repeated exposure to drugs of abuse augmented cell type–specific neural dynamics indicative of an escalation of drug responses, and subsequently disorganized natural reward processing in the NAc after drug withdrawal. We then developed a “FOS-Seq” approach to correlate brain-wide FOS patterns with brain-wide in situ gene expression data. We identified Rheb, a gene encoding a small GTPase that activates the mTOR pathway, as being correlated with FOS induction by chronic exposure to either cocaine or morphine. By integrating in vivo CRISPR perturbation of Rheb with single-nucleus RNA sequencing in the NAc, we demonstrated an essential role of Rheb in regulating signal transduction pathways associated with drug action in dopaminoceptive cells, and in diminishing natural reward consumption after chronic exposure to drugs of abuse. Finally, functional mapping of NAc-projecting neurons from regions that are activated by drugs of abuse points to orbitofrontal cortex as a potential ascending node that curbs natural reward consumption as verified with chemogenetic activation.
CONCLUSION
We delineated a common reward pathway that enables drugs of abuse to interfere with the fulfillment of homeostatic needs for food or water. These findings provide mechanistic insights into the intensification of drug-directed behavior in substance use disorders."
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