Rationale Previous work has identified that different forms of Pavlovian conditioned approach, sign-tracking and goal-tracking, are governed by distinct neurochemical mechanisms when compared in animals predisposed to learning one form vs. the other. Objectives The present study aimed to investigate whether these are also neurochemically distinct processes in a population of animals capable of developing either response when this is manipulated via the use of distinct conditioned stimuli (CS). Methods Rats were trained on one of two Pavlovian conditioning procedures in which the CS was either a lever, which elicits sign-tracking, or an auditory click, which elicits goal-tracking. The differential involvement of dopamine D1- and D2-receptors (D1R; D2R) in the acquisition of approach types was investigated via systemic administration of antagonists selective to one or both receptor subtypes during Pavlovian training. Results Results indicate that dopaminergic signalling is important for the acquisition of both sign-tracking and goal-tracking responses. However, whilst development of sign-tracking to a lever depends on activity at both D1R and D2R, development of goal-tracking in response to a click was shown to depend only on activity at D1R. Conclusions We suggest that the importance of D1R activity in both sign- and goal-tracking acquisition reflects a general role in learning Pavlovian associations, which aligns with data implicating dopamine in prediction error processes. In contrast, the selective involvement of D2R activity in sign-tracking acquisition may reflect its importance in motivational processes such as incentive salience attribution. Electronic supplementary material The online version of this article (10.1007/s00213-019-5169-8) contains supplementary material, which is available to authorized users.

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsive disorders and related behaviors. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented rats from learning to avoid a lever that was punished with a stimulus that co-terminated with footshock. Our second experiment demonstrated that retrieval of punishment learning is also somewhat mOFC-dependent, as lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent rats from re-acquiring the ability to avoid a punished lever when it was learned prior to lesions being administered. In both experiments, Pavlovian fear conditioning to the stimulus was intact for all animals. Together, these results reveal that the mOFC regulates punishment learning and retrieval in a manner that is separate from any role in Pavlovian fear conditioning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

Recent work suggests complementary roles of the prelimbic and infralimbic regions of the rat medial prefrontal cortex in cognitive control processes, with the prelimbic cortex implicated in top-down modulation of associations and the infralimbic cortex playing a role in the inhibition of inappropriate responses. Following selective lesions made to prelimbic or infralimbic regions (or control sham-surgery) rats received simultaneous training on Pavlovian feature negative (A+, XA−) and feature positive (B−, YB+) discriminations designed to lead to hierarchical occasion-setting control by the features (X, Y) over their respective targets (A, B). Evidence for hierarchical control was assessed in a transfer test in which features and targets were swapped (YA, XB). All groups were able to learn the feature negative and feature positive discriminations. Whilst sham-lesioned animals showed no transfer of control by features to novel targets (a hallmark of hierarchical control), rats with lesions of prelimbic or infralimbic regions showed evidence of transfer from the positive feature (Y) to the negative target (A), and from the negative feature (X) to the positive target (B; although this only achieved significance in infralimbic-lesioned animals). These data indicate that damage to either of these regions disrupts hierarchical occasion-setting control, extending our knowledge of their role in cognitive control to encompass flexible behaviours dictated by discrete cues.

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsion and compulsive disorders. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented instrumental conditioned punishment learning in a manner that could not be attributed to differences in Pavlovian conditioned fear. We then showed that increasing the frequency of punishing outcomes allowed mOFC-lesioned animals to overcome their initial deficit. Our second experiment demonstrated that the retrieval of instrumental punishment is also mOFC-dependent, as mOFC lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent the re-acquisition of conditioned punishment that was learned prior to lesions being administered. Together, these results reveal that the mOFC does indeed regulate punishment learning and retrieval in a manner that is disassociated from any role in Pavlovian fear learning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

Dopamine neurotransmission has been ascribed multiple functions with respect to both motivational and associative processes in reward-based learning, though these have proven difficult to tease apart. In order to better describe the role of dopamine in associative learning, this series of experiments examined the potential of dopamine D1- and D2-receptor antagonism (or combined antagonism) to influence the ability of rats to learn neutral valence stimulus-stimulus associations. Using a sensory preconditioning task, rats were first exposed to pairings of two neutral stimuli (S2-S1). Subsequently, S1 was paired with a mild foot-shock and resulting fear to both S1 (directly conditioned) and S2 (preconditioned) was examined. Initial experiments demonstrated the validity of the procedure in that measures of sensory preconditioning were shown to be contingent on pairings of the two sensory stimuli. Subsequent experiments indicated that systemic administration of dopamine D1- or D2-receptor antagonists attenuated learning when administered prior to S2-S1 pairings. However, the administration of a more generic D1R/D2R antagonist was without effect. These effects remained constant regardless of the affective valence of the conditioning environment and did not differ between male and female rats. The results are discussed in the context of recent suggestions that dopaminergic systems encode more than a simple reward prediction error, and provide potential avenues for future investigation.