In substance use disorder (SUD)/drug addiction, individuals often seek drug rewards at a large cost. Recent findings demonstrate that natural rewards may offer significant therapeutic potential against SUD. However, the mechanism by which natural rewards counteract SUD remains unclear. While incentive sensitization theory provides valuable insights, a comprehensive understanding is still lacking. In this review, we first summarize the evidence and potential neurobiological mechanisms that support the protective effect of natural rewards against SUD, such as palatable food, social interaction, physical exercise, and environmental enrichment. Then, we propose an updated incentive sensitization framework to explain how natural rewards resist SUD by modulating wanting and liking. This review contributes to our understanding of the interaction between natural rewards and drug rewards, potentially facilitating the development of novel therapeutic strategies for SUD.

Neuropathic pain (NP) is well-known to be complicated and challenging to manage. Organisms have been shown to initiate various intrinsic compensatory strategies to alleviate NP, which could be utilized to aid the development of therapeutic treatments. However, these mechanisms that alleviate NP have not been fully elucidated. Here we show that spinal glycine receptor α1 (GlyRα1) is a key element of an intrinsic compensatory mechanism to alleviate NP. This spinal GlyRα1-mediated compensatory mechanism is manifested in many ways, including enhanced inhibitory glycinergic transmission and increased GlyRα1 protein expression levels. We show such GlyRα1 upregulation is achieved via an intracellular calmodulin kinase II/IV (CaMKII/IV)-cAMP response element binding protein signaling pathway. We demonstrate that dehydroxylcannabidiol, a synthetic nonpsychoactive cannabinoid that specifically targets GlyRs, significantly potentiates spinal GlyR function, inhibits spared nerve injury–induced spinal neuronal hyperactivity, and ultimately abrogates the development of hyperalgesia. These results suggest that the compensatory upregulated spinal GlyRα1 is efficacious in alleviating NP. Thus, our study reveals a potential strategy for the clinical treatment of NP by utilizing this central compensatory mechanism.

Alzheimer's disease (AD) is a major neurodegenerative disorder that causes severe cognitive decline and poses a significant burden on global health systems. Despite extensive research, effective treatments to stop neurodegeneration or promote neuronal regeneration in AD remain elusive. Psychoactive substances as modulators of neurophysiological functions, have received increased attention in research. The main psychoactive agents, such as central nervous system depressants and stimulants, cannabinoids, psychedelics, opioids and ketamine, are being explored for their abilities to enhance learning and cognitive performance and potential neurorestorative functions. In this paper, we review the molecular mechanisms and therapeutic potential of psychoactive substances in AD, in the aim to guide future research directions.