Other groups have used different tools to modulate activity of the two MSNs in drug abuse models. Hikida et al. (2010) used AAV vectors to express tetracycline-repressive transcription factor (tTa) using the substance P (a D1+ MSN gene) or enkephalin (a D2+ MSN gene) promoters. These vectors were injected into the NAc of mice, in which tetanus toxin light chain (TN) – a bacterial toxin that cleaves the synaptic vesicle-associated protein, VAMP2 – was controlled by the tetracycline-responsive element, to selectively abolish synaptic transmission in each MSN subtype. Consistent with our optogenetic approach, these data showed a role of D1+ MSN activity in enhancing cocaine CPP as well as cocaine-induced locomotor activity, since abolishing synaptic transmission in D1+ MSNs diminished both behavioral effects. In contrast to the optogenetic studies, the authors found no alterations in cocaine CPP after abolishing synaptic transmission in D2+ MSNs, but did observe reduced cocaine-induced locomotor activity in response to the first two cocaine exposures. Interestingly, this group showed that inactivation of the D2+ MSNs played a more profound role in mediating aversive behaviors.
