Medial prefrontal cortical neurotransmitters reactive to relapse-promoting and relapse-suppressing cues in male rats trained to self-administer cocaine or alcohol.

Environmental cues signaling drug availability (S+) vs. omission (S-) each recruit specific prefrontal cortical neurons to promote vs. suppress drug seeking in rats, suggesting similarly cue-specific neurotransmission regulates such behavior. We here determined extracellular neurotransmitter fluctuations in the infralimbic (IL) and prelimbic (PL) cortices of rats reactive to S+ vs. S-. For this, male rats were trained to recognize both S+ and S- within the context of either cocaine or alcohol self-administration and then subjected to S+ vs. S- cue-tests during which animals engaged in active drug seeking vs. suppression of this behavior. In cocaine-trained rats, serotonin, taurine and adenosine in PL were preferentially modulated during the S+ (vs. S-) cue-test, while glutamate in PL was preferentially modulated during the S- (vs. S+) cue-test. In alcohol-trained rats, γ-aminobutyric acid (GABA) in IL was preferentially modulated during the S+ cue-test, while histamine in PL as well as glutamate and dopamine in IL were preferentially modulated during the S- cue-test. In summary, prefrontal neurotransmissions reactive to drug discriminative cues are dependent on cue types (S+ vs. S-), brain regions (IL vs. PL) and drugs used for cue-conditioning (cocaine vs. alcohol), thereby suggesting cocaine- and alcohol-seeking are each regulated by distinct neurochemical processes.