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Three studies explored the sensitivity of aversive Pavlovian to instrumental transfer (PIT) to Pavlovian extinction in rodents. Rats underwent Pavlovian conditioning prior to avoidance training. The PIT test then involved assessment of the effects of the Pavlovian conditioned stimulus (CS) on the performance of the avoidance response (AR). Conducting extinction prior to avoidance training and transfer testing, allowed spontaneous recovery and shock reinstatement of extinguished motivation, whereas conducting extinction following avoidance training and just prior to PIT testing successfully reduced transfer effects. This was also the case in a design that compared responding to an extinguished CS against a non-extinguished CS rather than comparing extinguished and non-extinguished groups to one another. While extinction treatments in many appetitive PIT studies do not successfully reduce transfer, and can sometimes enhance the effect, the current findings show that an extinction treatment temporally close to transfer testing can reduce the motivational impact of the aversive Pavlovian CS on instrumental avoidance responding.

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21Addiction is a chronic relapsing disorder, and during recovery many people experience several relapse events as 22 they attempt to voluntarily abstain from drug. New preclinical relapse models have emerged which capture this 23 common human experience of relapse after voluntary abstinence, and mounting evidence indicates that 24 reinstatement of drug seeking after voluntary abstinence recruits neural circuits distinct from reinstatement 25 following experimenter-imposed abstinence, or abstinence due to extinction training. Ventral pallidum (VP), a key 26 limbic node involved in drug seeking, has well-established roles in conventional reinstatement models tested 27 following extinction training, but it is unclear whether this region also participates in more translationally-relevant 28 models of relapse. Here we show that chemogenetic inhibition of VP neurons strongly attenuates cocaine-, 29 context-, and cue-induced reinstatement tested after voluntary, punishment-induced abstinence. This effect was 30 strongest in the most compulsive, punishment-resistant rats, and reinstatement was associated with neural 31 activity in anatomically-defined VP subregions. VP inhibition also attenuated the propensity of rats to display 32 'hesitations,' a risk assessment behavior seen during punished drug taking that is likely due to concurrent 33 approach and avoidance motivations. These results indicate that VP, unlike other connected limbic brain regions, 34 is essential for reinstatement of drug seeking after voluntary abstinence. Since VP inhibition effects were 35 strongest in the most compulsively cocaine-seeking individuals, this could indicate that VP plays a particularly 36 important role in the most pathological, addiction-like behavior, making it an attractive target for future 37 therapeutic interventions. 38 39 40 41 42