476. Cryptotanshinone, a natural compound, and its metabolite ameliorate addictive properties of nitrous oxide via modulating D1 receptor and TrkB Pathway in the nucleus accumbens
International Journal of Neuropsychopharmacology September 9, 2026 DOI: 10.1093/ijnp/pyag040.077 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal and in vitro study Peer reviewed |
|---|---|
| Population | Mice (N2O-induced conditioned place preference model) and PC12 cells |
| Interventions | Cryptotanshinone (CTS) Tanshinone IIA (TAN IIA) SKF 81297 7 8-DHF |
| Duration | CTS administration via gavage for 4 days |
| Key points | Cryptotanshinone and its metabolite Tanshinone IIA attenuated N2O-induced conditioned place preference and reduced D1R/TrkB pathway signaling and neuronal hyperactivity markers in the nucleus accumbens of mice, and suppressed D1R/TrkB agonist effects in PC12 cells. The authors propose these compounds promote extinction of N2O reward and may have potential for treating substance use disorders. |
Abstract
Abstract Background While nitrous oxide (N2O) abuse has been a growing international public health issue, there is a dearth of effective intervention strategies. Our previous study has demonstrasted that addictive properties of N2O are associated with its regulation of D1 receptor and BDNF pathway in the ventral tegmental area-nucleus accumbens. Aims & Objectives This study aimed to investigate the potential of Cryptotanshinone (CTS), a natural compound from Salvia miltiorrhiza (Danshen), and its metabolite Tanshinone IIA (TAN IIA) in alleviating N2O-induced conditioned place preference (CPP) and modulating dopamine D1 receptor (D1R) and TrkB pathway in the nucleus accumbens.
Method: In vivo experiment, a CPP mouse model was established via N2O exposure, followed by CTS administration via gavage for 4 days. In vitro experiment, PC12 cells were exposed to the D1R agonist SKF 81297 and TrkB agonist 7,8-DHF, with subsequent CTS or TAN IIA treatment.
Results: In animal model, N2O exposure significantly increased CPP scores, upregulated the expression of proteins associated with the D1R and TrkB pathways (such as p-CREB and p-CaMKII) and increased the number of p-CaMKII and p-CREB-positive cells in the nucleus accumbens (NAc). These effects were attenuated by CTS treatment. N2O exposure increased the colocalization of c-fos with choline acetyltransferase (ChAT) and glutamate decarboxylase-67 (GAD-67), while CTS treatment significantly decreased the number of ChAT/c-fos positive neurons. Molecular docking indicated no significant difference in binding affinity between CTS/TAN IIA and D1R/TrkB. In PC12 cell line, stimulation with the D1R and TrkB agonists increased the pathway protein expression, Ca2+ activity, and the density of c-fos, all of which were notably suppressed by CTS and TAN IIA. Discussion & Conclusions CTS and TAN IIA effectively reversed behavioral and molecular markers of N2O reward, potentially via downstream regulation of the D1R and TrkB pathways. This action mitigates NAc neuronal hyperactivity, supporting N2O extinction. Our findings demonstrate that CTS and TAN IIA promote the extinction of N2O-induced CPP by functionally inhibiting the D1R and TrkB pathways, highlighting their potential for treating substance use disorders.