Pavlovian conditioning is typically distinguished from sensitization but a Pavlovian conditional stimulus (CS) also results in sensitization. A Pavlovian CS can sensitize responding to a probe stimulus that is related to the unconditional stimulus (US) or to the US itself. Pavlovian sensitization has been studied in the defensive, sexual, and feeding systems. In Pavlovian sensitization, the focus is not on a conditional response (CR) directly elicited by the CS but on the response mode that is activated by the CS. Activation of a response mode increases the probability of particular responses and also increases reactivity to various stimuli. Pavlovian sensitization reflects this increased stimulus reactivity. Pavlovian sensitization helps uncover successful learning in situations where a conventional CR does not occur. Pavlovian sensitization also encourages broadening our conceptions of Pavlovian conditioning to include changes in afferent processes. Implications for biological fitness and for basic and translational research are discussed.

Pavlovian fear conditioning and extinction represent learning mechanisms underlying exposure-based interventions. While increasing evidence indicates a pivotal role of disgust in the development of contamination-based obsessive-compulsive disorder (C-OCD), dysregulations in conditioned disgust acquisition and maintenance, in particular driven by higher-order conceptual processes, have not been examined. Here, we address this gap by exposing individuals with high (HCC, n = 41) or low (LCC, n = 41) contamination concern to a conceptual-level disgust conditioning and extinction paradigm. Conditioned stimuli (CS+) were images from one conceptual category partially reinforced by unconditioned disgust-eliciting stimuli (US), while images from another category served as non-reinforced conditioned stimuli (CS-). Skin conductance responses (SCRs), US expectancy and CS valence ratings served as primary outcomes to quantify conditioned disgust responses. Relative to LCC, HCC individuals exhibited increased US expectancy and CS+ disgust experience, but comparable SCR levels following disgust acquisition. Despite a decrease in conditioned responses from the acquisition phase to the extinction phase, both groups did not fully extinguish the learned disgust. Importantly, the extinction resilience of acquired disgust was more pronounced in HCC individuals. Together, our findings suggest that individuals with high self-reported contamination concern exhibit increased disgust acquisition and resistance to extinction. The findings provide preliminary evidence on how dysregulated disgust learning mechanism across semantically related concepts may contribute to C-OCD.

Adolescence marks a sensitive period for neurodevelopment wherein exposure to drugs of abuse may disrupt maturation and induce persistent changes in neurophysiology which may exacerbate the risk for developing substance use disorders in adulthood. Adolescent nicotine exposure (ANE) enhances motivation to obtain drugs of abuse, particularly opioids, and increases vulnerability for the development of opioid use disorder (OUD). Here, we characterized ANE effects on learning about the adverse consequences of opioid consumption in adulthood in the absence of further nicotine administration. First, we show that ANE engenders punishment resistant fentanyl self-administration in a heterogenous seeking-taking chain schedule of reinforcement at least at the tested dose of fentanyl (0.75 μg/kg). We found that ANE rats consumed significantly more fentanyl and contingent foot shock punishment was less efficacious in limiting fentanyl seeking in ANE rats, relative to nicotine-naïve controls. Next, we demonstrated that ANE limits learning about the deleterious consequences of acute opioid intoxication in adulthood. In a combined conditioned taste avoidance and place preference paradigm we found that ANE resulted in significant reductions in the strength of morphine-induced CTA, and a simultaneous enhancement of CPP at a higher dose that was less capable of driving reinforcement in naïve controls. Finally, we examined the expression of perineuronal nets (PNNs) within insular cortex (IC) and found ANE rats to have increased density of PNNs across the anterior IC and significantly more parvalbumin-labeled IC cells relative to naïve controls. Together, these data lay the framework for a mechanistic explanation of the extreme comorbidity between nicotine use and development of OUDs.

Instrumental appetitive extinction involves the reduction of a previously reinforced response when its occurrence is no longer rewarded. Two experiments with terrestrial toads (Rhinella arenarum) tested whether the occurrence of a nonreinforced response is necessary for response extinction by varying the time of exposure to nonrewarded goal-box stimuli across groups. In Experiment 1, toads that received the same acquisition training (15 sessions, 1 session/day, 300 s of access to water in the goal box) were randomly assigned to two groups. In Group 600 (n=12), animals spent 600 s in the goal box in 8 daily extinction sessions (water present but inaccessible). In Group 0 (n=11), toads performed the runway response (i.e., walking from the start to the goal box) but were removed as soon as they entered the goal box, thus having minimal exposure to nonrewarded goal-box stimuli. The runway response was weakened in Group 600 across extinction trials, but exhibited little change in Group 0. In Experiment 2, toads were randomly assigned to two groups after the same acquisition training. Group 0 (n=7) was treated the same as Group 0 in the previous experiment. In Group RI (retention interval, n=7), toads remained in their home cage for 13 days. Finally, all animals received 4 extinction sessions with 300 s in the empty goal box. There was little behavioral change in Group 0 during the 13 sessions with minimal exposure to the goal box. In extinction, both groups reduced their runway response at similar rates. Although the procedures were instrumental, extinction of the runway response in toads can be accounted for in terms of a Pavlovian approach response to stimuli paired with reward and nonreward in the goal box.

Continuous treatment with drugs is a crucial requirement for managing various clinical conditions, including chronic pain and neuropsychiatric disorders such as depression or schizophrenia. Associative learning processes, i.e. Pavlovian conditioning, can play an important role for the effects of drugs and could open new avenues for optimizing patient treatment. In this narrative literature review, we summarize available data in experimental animals regarding the behaviorally conditioned effects of psychostimulants such as d-amphetamine and cocaine, the dopamine receptor agonist apomorphine, the dopamine receptor antagonist haloperidol, morphine and antidepressant drugs. In each section, the drug under discussion is briefly introduced, followed by a detailed examination of conditioning features, including doses and dosing regimens, characteristics of the conditioning process such as test environments or specific conditioned stimuli, testing and conditioned response characteristics, possible extinction or reconditioning or reversal training, neural mechanisms, and finally, the potential clinical relevance of the research area related to the drug. We focus on key outcomes, delve into methodical issues, identify gaps in current knowledge, and suggest future research directions.

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the lateral hypothalamus (LH). We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is partially dependent on dopamine D2 receptors (DRD2). Our results reveal previously unknown orexinergic coding of reward expectation and unveil an orexin-regulatory axis mediated by local dopamine inputs in the LH.

The orosensory features of alcoholic drinks are potent relapse triggers because they acquire incentive properties during consumption, including enhanced palatability. Whether mice similarly perceive alcoholic drinks to be more palatable after repeated consumption is complicated by reports showing that alcohol elicits aversive taste reactivity responses and conditions flavor avoidance. Here, by analyzing the microstructure of alcohol consumption, we report a gradual increase in lick bout duration relative to water that is partially maintained by an alcohol-paired flavor in extinction. We interpret lick bout duration to reflect an increase in the palatability alcohol and an alcohol-paired flavor. This finding demonstrates that bout duration is amenable to Pavlovian conditioning and highlights the importance of considering the microstructure of alcohol consumption in preclinical models of alcohol misuse.

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-value and stimulus-stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

In alcohol use disorder, the alcohol memories persist during abstinence, and exposure to stimuli associated with alcohol use can lead to relapse. This highlights the importance of investigating the neural substrates underlying not only relapse but also encoding and expression of alcohol memories. GABAergic neurons in the lateral hypothalamus (LH-GABA) have been shown to be critical for food-cue memories and motivation; however, the extent to which this role extends to alcohol-cue memories and motivations remains unexplored. In this study, we aimed to describe how alcohol-related memories are encoded and expressed in LH GABAergic neurons. Our first step was to monitor LH-GABA calcium transients during acquisition, extinction, and reinstatement of an alcohol-cue memory using fiber photometry. We trained the rats on a Pavlovian conditioning task, where one conditioned stimulus (CS+) predicted alcohol (20% EtOH) and another conditioned stimulus (CS-) had no outcome. We then extinguished this association through non-reinforced presentations of the CS+ and CS- and finally, in two different groups, we measured relapse under non-primed and alcohol-primed induced reinstatement. Our results show that initially both cues caused increased LH-GABA activity, and after learning only the alcohol cue increased LH-GABA activity. After extinction, this activity decreases, and we found no differences in LH-GABA activity during reinstatement in either group. Next, we inhibited LH-GABA neurons with optogenetics to show that activity of these neurons is necessary for the formation of an alcohol-cue association. These findings suggest that LH-GABA might be involved in attentional processes modulated by learning.

BACKGROUND: Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.
OBJECTIVE: This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.
METHODS: CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.
RESULTS: Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was largely absent in CIE-exposed rats. Re-conditioning after vapor exposure facilitated increased CTA magnitude to a similar degree in AIR- and CIE-exposed males. In contrast, CTA magnitude was unchanged by re-conditioning in females.
CONCLUSIONS: These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.