Increased cocaine self‐administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula

Serotonin (5‐HT) and the habenula (Hb) contribute to motivational and emotional states such as depression and drug abuse. The dorsal raphe nucleus, where 5‐HT neurons originate, and the Hb are anatomically and reciprocally interconnected. Evidence exists that 5‐HT influences Hb glutamatergic transmission. Using serotonin transporter knockout (SERT−/−) rats, which show depression‐like behavior and increased cocaine intake, we investigated the effect of SERT reduction on expression of genes involved in glutamate neurotransmission under both baseline conditions as well as after short‐access or long‐access cocaine (ShA and LgA, respectively) intake. In cocaine‐naïve animals, SERT removal led to reduced baseline Hb mRNA levels of critical determinants of glutamate transmission, such as SLC1A2, the main glutamate transporter and N‐methyl‐D‐aspartate (Grin1, Grin2A and Grin2B) as well as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (Gria1 and Gria2) receptor subunits, with no changes in the scaffolding protein Dlg4. In response to ShA and LgA cocaine intake, SLC1A2 and Grin1 mRNA levels decreased in SERT+/+ rats to levels equal of those of SERT−/− rats. Our data reveal that increased extracellular levels of 5‐HT modulate glutamate neurotransmission in the Hb, serving as critical neurobiological substrate for vulnerability to cocaine addiction. Serotonin transporter (SERT) knockout (KO) rats were tested for cocaine self‐administration and glutamate system components in the habenula. Compared to wild‐type (WT) control rats, SERT‐KO rats self‐administered higher amounts of cocaine. Naive SERT‐KO rats, known to have elevated levels of extracellular serotonin, exhibited lower levels of glial glutamate transporters and AMPA/NMDA receptor subunits. After cocaine self‐administration, these components reduced in WT rats to the level of KO rats, whereas in KO rats, a slight or no further decrease was observed.