How might cannabinoids influence sexual behavior?

Marijuana and hashish are widespread drugs of abuse that contain Δ9-tetrahydrocannabinol (THC), a bioactive ingredient best known for its psychotropic effects. Remarkably, THC also produces multiple nonpsychotropic effects: for example, analgesia, hypotension, modulation of bronchospasm, and reduction of inflammation (1–6). That THC also influences sexual behavior was clearly demonstrated for the first time in the early 1980s; yet the precise molecular mechanism of this effect has remained unsolved. In this issue of PNAS, Mani et al. (7) revisit these seminal experiments. They identify the molecular target by which THC affects sexual behavior, and unveil a remarkable operative cross talk mechanism between THC and the progesterone and dopamine signaling pathways, which were already known to play a central role in reproductive behavior. The chemical synthesis of THC was first described in 1964 (8). In the following years, researchers used synthetic THC to study its diverse biological effects. Whether these effects occurred through receptors or simply by changing plasma membrane fluidity was unknown. One early hypothesis, which has now been abandoned, was that THC could directly bind to the estrogen receptor, thus competing for the sequence of events initiated by estrogen (9, 10). Although controversial, this hypothesis had the advantage of stimulating research to ascertain a link between cannabinoids and sexual behavior. An important step forward in understanding the biological effects of cannabinoids was made in 1988 when Howlett and colleagues (11) used a high-affinity radioactive cannabinoid ligand, [3H]CP-55,940, to demonstrate the existence of a specific cannabinoid binding site in cell membranes of rat brain. This discovery was shortly followed by the molecular cloning and sequencing of the cannabinoid CB1 and CB2 receptors (12, 13). Both receptors …