MDMA enhances acute prosocial behaviors in Octopus bimaculoides, an otherwise asocial and solitary species.

Octopuses treated with MDMA spent significantly more time in the social proximity zone near a novel conspecific compared to saline controls, and exhibited extensive tactile exploration of the social object.

The serotonin transporter (SERT/SLC6A4) from O. bimaculoides has a conserved MDMA binding site in the transmembrane domain.

Phylogenetic analysis confirms that the octopus SERT (encoded by OCBIM_22008529mg / Slc6A4) is orthologous to human SLC6A4.

The SERT transmembrane domain binding pocket for MDMA shows conservation of key residues across vertebrate and invertebrate species separated by >500 million years of evolution.

MDMA binds SERT and reverses its transport direction, increasing extracellular serotonin levels, which underlies the prosocial behavioral effects.

A three-chambered social approach task was used to quantify social behavior changes, demonstrating that MDMA-induced prosocial behavior in octopus parallels effects seen in humans and rodents.

MDMA-treated octopuses exhibited extensive ventral surface tactile exploration of the social stimulus, a behavior not seen in saline controls.

Human and octopus lineages are separated by over 500 million years of evolution and show divergent anatomical patterns of brain organization, yet serotonergic social behavior circuits are conserved.

First genome sequence of O. bimaculoides (2.7 Gb, ~33,000 protein-coding genes), providing the gene models including OCBIM_22008529mg.

Extensive mRNA editing in neural genes and massive expansions in protocadherins and C2H2 zinc-finger transcription factors.

Serotonin (5-HT) modulates short- and long-term synaptic plasticity in the octopus vertical lobe, a brain region essential for learning and memory.

The octopus vertical lobe contains serotonergic innervation, confirming serotonin as a functional neurotransmitter/neuromodulator in the cephalopod nervous system.

SSRIs (fluoxetine) and SNRIs (venlafaxine) alter burying/camouflage behavior in juvenile cuttlefish at environmentally relevant concentrations, demonstrating that serotonergic disruption broadly affects innate behavior in cephalopods

40 SLC6 family genes identified in the chordate invertebrate Ciona savignyi, demonstrating extensive gene expansion in this family across invertebrate lineages

SLC6A4 subfamily (monoamine/serotonin transporters) is phylogenetically distinct from amino acid transporter and GABA transporter subfamilies within SLC6

Cross-species chimera studies between human and Drosophila SERT mapped structural determinants of transport specificity and pharmacological sensitivity