Cannabidiol Attenuates Methamphetamine-Induced Autophagy in Primary Rat Neurons via the 5-HT1A/AC/cAMP/PKA/CREB Signaling Pathway

Methamphetamine (METH) induces neurotoxicity via excessive and incomplete autophagy, although the underlying mechanisms remain unclear. This study investigated cannabidiol (CBD)’s protective effect and the role of the 5-Hydroxytryptamine 1A receptor (5-HT1A)/adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway in primary hippocampal neurons. METH (2 mM, 24 h) reduced neuronal viability, downregulated 5-HT1A, activated the AC/cAMP/PKA/CREB pathway, and simultaneously upregulated autophagy-related proteins (Beclin-1, Microtubule-associated protein 1 light chain 3 [LC3], and Sequestosome 1 [p62]) and overall autophagic flux, indicating impaired lysosomal degradation during autophagy. CBD (1–10 μM) reversed METH-induced autophagy, restored viability, and normalized pathway protein expression. 5-HT1A agonist eptapirone synergized with CBD to inhibit autophagy, while the antagonist WAY-100635 abolished CBD’s effects. These findings demonstrate that CBD, acting as an allosteric modulator of 5-HT1A, alleviates METH-induced neuroautophagy by restoring 5-HT1A activity and suppressing excessive AC/cAMP/PKA/CREB activation, highlighting its potential as a therapeutic agent for METH-related neurotoxicity.