The availability of efficacious pharmacotherapies for the treatment of cocaine use disorders remains a significant unmet societal need. Cocaine exerts its psychoactive effects primarily by inhibiting presynaptic reuptake of monoamine neurotransmitters, including serotonin (5-HT). There are at least 14 different 5-HT receptor subtypes in the brain, and prior studies have shown that the 5-HT7 receptor subtype plays a role in learning and memory, neural plasticity, impulsivity, alcohol intake, and some behavioral responses to psychostimulants. In this study, we sought to determine the effects of the selective 5-HT7 antagonist SB-656104A on cocaine self-administration under conditions of increasing behavioral demand using the progressive ratio paradigm. Male rats were trained to self-administer cocaine at a dose of 0.75 mg/kg/infusion. Following acquisition and stabilization of operant responding on a fixed-ratio schedule and subsequent transition to and stabilization under progressive ratio conditions, animals were treated with vehicle or one of three doses of SB-656104A (3, 10, or 20 mg/kg) prior to additional progressive ratio sessions. None of the doses of SB-656104A had any effect on breakpoints for cocaine intake or time to reach breakpoint. These data indicate that blockade of 5-HT7 receptors with SB-656104A does not alter cocaine intake under conditions of increased behavioral demand. Nonetheless, further studies with other 5-HT7 ligands should be pursued.
Rodarte et al. (2026) studied this question.