Membrane androgen receptors may mediate androgen reinforcement

Anabolic-androgenic steroid (AAS) abuse is widespread. Moreover, AAS are reinforcing, as shown by self-administration in rodents. However, the receptors that transduce the reinforcing effects of AAS are unclear. AAS may bind to classical nuclear androgen receptors (ARs) or membrane receptors. We used two approaches to examine the role of nuclear ARs in AAS self-administration. First, we tested androgen self-administration in rats with the testicular feminization mutation (Tfm), which interferes with androgen binding. If nuclear ARs are essential for AAS self-administration, Tfm males should not self-administer androgens. Tfm males and wild-type (WT) littermates self-administered the non-aromatizable androgen dihydrotestosterone (DHT) or vehicle intracerebroventricularly (ICV) at fixed-ratio (FR) schedules up to FR5. Both Tfm and WT rats acquired a preference for the active nose-poke during DHT self-administration (66.4+/-9.6 responses/4 h for Tfm and 79.2+/-11.5 for WT responses/4 h), and nose-pokes increased as the FR requirement increased. Preference scores were significantly lower in rats self-administering vehicle (42.3+/-5.3 responses/4 h for Tfm and 19.1+/-4.0 responses/4 h for WT). We also tested self-administration of DHT conjugated to bovine serum albumin (BSA) at C3 and C17, which is limited to actions at the cell surface. Hamsters were allowed to self-administer DHT, BSA and DHT-BSA conjugates for 15 days at FR1. The hamsters showed a significant preference for DHT (18.0+/-4.1 responses/4 h) or DHT-BSA conjugates (10.0+/-3.7 responses/4 h and 21.0+/-7.2 responses/4 h), but not for BSA (2.5+/-2.4 responses/4 h). Taken together, these data demonstrate that nuclear ARs are not required for androgen self-administration. Furthermore, androgen self-administration may be mediated by plasma membrane receptors.