<p>Cocaine disrupts the physiological function of the prefrontal cortex and impairs attention, short-term memory, and other cognitive functions. However, the specific cellular basis of maladaptation remains poorly understood. Here, using neuronal activity-dependent tagging, rabies retrograde tracing, electrophysiological recording, and behavioral analyses in mice, we show that a single injection of cocaine increases the recruitment of both the <i>Npas4</i> transcription-dependent ensemble (<i>N</i>-RAM) and the <i>N</i>-RAM⁺ somatostatin-expressing interneuron (<i>N</i>-RAM⁺ SST-IN) ensemble in the medial prefrontal cortex (mPFC). Npas4 induction in mPFC SST-INs upregulates plasticity and excitatory synaptic input from the mediodorsal thalamus (MD). Chemogenetic inhibition of either the <i>N</i>-RAM⁺ or <i>N</i>-RAM⁺ SST-IN ensemble in the mPFC impaired attention in the 5‑choice serial reaction time task (5-CSRTT). Our study identifies a unique role of the mPFC <i>N</i>-RAM⁺ SST-IN ensemble in regulating attention following acute cocaine injection, providing a potential therapeutic target for attention deficits.</p>