An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine neuron inputs following prenatal cannabinoid exposure.

Serra V.; Brandalise F.; Miczán V.; Katona I.; Melis M. · bioRxiv : the preprint server for biology · 2026

**Background & Methods** This preclinical study utilized a rat model to investigate how prenatal exposure to Δ9-tetrahydrocannabinol (THC) affects endocannabinoid-mediated synaptic plasticity at dopamine neurons in the ventral tegmental area (VTA). The research examined synaptic transmission and receptor signaling mechanisms in male offspring following prenatal cannabinoid exposure (PCE). **Key Findings** • Prenatal THC exposure eliminated endocannabinoid-mediated synaptic plasticity at excitatory glutamatergic synapses on VTA dopamine neurons, accompanied by reorganization of presynaptic architecture that impaired type-1 cannabinoid receptor control over glutamate release. • PCE-exposed dopamine neurons exhibited a compensatory signaling switch from endocannabinoid to nitric oxide (NO)-dependent mechanisms, resulting in reciprocal forms of plasticity: NO-dependent long-term potentiation of GABAergic (inhibitory) synapses and long-term depression of glutamatergic (excitatory) synapses. • These PCE-induced metaplastic changes shifted the balance of excitatory-inhibitory control over dopamine neurons, potentially contributing to increased vulnerability to psychiatric disorders including psychosis and substance use disorders. **Dosage & Administration** Not reported. The study did not specify THC dosing regimens, exposure timing during pregnancy, or route of administration. **Safety & Adverse Effects** Not reported. The paper focuses on mechanistic neurobiological changes rather than acute or chronic safety outcomes in the animal model. **Evidence Quality** This is a preclinical animal study published as a preprint, limiting the current evidence level. Significant limitations include: (1) findings derive from a rat model and may not directly translate to humans; (2) study examined only male offspring, limiting generalizability to females; (3) as a preprint, the work has not undergone peer review; (4) no data on dose-response relationships or behavioral/functional outcomes are provided. While the mechanistic investigation of synaptic plasticity is novel and detailed, clinical relevance remains indirect. These findings require validation through peer review, replication studies, and eventual human research to establish clinical significance for understanding prenatal cannabis exposure-related psychiatric risk.

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