Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

Fear in the theater of the mind: Mental imagery of conditioned stimuli undergo the acquisition and generalization of differential fear conditioning

Many symptoms of anxiety and post-traumatic stress disorder are elicited by mental imagery of a conditioned stimulus (CS). Yet, little is known about how visual imagery of CSs interacts with the acquisition of differential fear conditioning. Across three experiments (n1=33, n2=27, n3=26), we observed that healthy human participants acquired differential fear conditioning to both viewed and imagined percepts serving as the conditioned stimuli as measured via self-reported fear and the skin conductance response (SCR). Additionally, this differential conditioning generalized across CS percept modalities, such that differential conditioning acquired to visual percepts generalized to the corresponding imagined percepts and vice versa. This is novel evidence that perceived and imagined stimuli engage learning processes in very similar ways and is consistent with theory that mental imagery is depictive and recruits neural resources shared with visual perception. Our findings also provide new insight into the mechanisms of anxiety and related disorders.

Higher-Order Conditioning With Simultaneous and Backward Conditioned Stimulus: Implications for Models of Pavlovian Conditioning

In a new environment, humans and animals can detect and learn that cues predict meaningful outcomes, and use this information to adapt their responses. This process is termed Pavlovian conditioning. Pavlovian conditioning is also observed for stimuli that predict outcome-associated cues; a second type of conditioning is termed higher-order Pavlovian conditioning. In this review, we will focus on higher-order conditioning studies with simultaneous and backward conditioned stimuli. We will examine how the results from these experiments pose a challenge to models of Pavlovian conditioning like the Temporal Difference (TD) models, in which learning is mainly driven by reward prediction errors. Contrasting with this view, the results suggest that humans and animals can form complex representations of the (temporal) structure of the task, and use this information to guide behavior, which seems consistent with model-based reinforcement learning. Future investigations involving these procedures could result in important new insights on the mechanisms that underlie Pavlovian conditioning.

Unconscious Knowledge Produces Adaptive Decisions via Conscious Judgments in a Novel Instrumental Conditioning Paradigm

The demonstration of unconscious instrumental conditioning (i.e., unconsciously learning to choose stimuli that lead to rewards) is central for the tenet that unconscious learning supports human adaptation. Recent studies, using reliable subliminal conditioning procedures, have found evidence against unconscious instrumental conditioning. The present preregistered study proposes an alternative paradigm, in which unconscious processing is stimulated not by the subliminal exposure of the predictive (conditioned) stimuli, but by employing predictive regularities that are complex and difficult to detect consciously. Participants (N = 211) were exposed to letter strings that, unknown to them, were built from two complex artificial grammars: an “rewarded’’ or a “non-rewarded” grammar. On each trial, participants memorized a string, and subsequently had to discriminate the memorized string from a distractor. Correct discriminations were rewarded only when the identified string followed the rewarded grammar, but not when it followed the non-rewarded grammar. In a subsequent test phase, participants were presented with new strings from the rewarded and from the unrewarded grammar. Their task was now to directly choose the strings from the rewarded grammar, in order to collect more rewards. Employing a trial-by-trial awareness measure widely used in implicit learning, we found that participants accurately choose novel strings from the rewarded grammar when they had no conscious knowledge of the grammar. The awareness measure also showed that participants were accurate only when the unconsciously learned grammar led to conscious judgments. The present study provides an alternative to subliminal conditioning paradigms and shows evidence for unconscious instrumental conditioning.

Differentiated evaluation of counter-conditioned stimuli as a function of right-wing authoritarianism

Right Wing Authoritarianism (i.e., RWA) is associated with enhanced conservatism and social prejudice. Because research linking RWA to attitudes is largely correlational (i.e., it provides control for neither RWA nor attitude learning), it is not clear how RWA relates to attitude learning dynamics. We addressed this question in 11 evaluative conditioning experiments that ensured rigorous control of the affective learning setting. Results from two integrative data analyses suggest that (i) individuals scoring higher in RWA show a stronger acquisition of positive attitudes, and that (ii) the residuals of this stronger acquisition remain even after exposure to counter-attitudinal information. Implications of these findings for research on RWA and its link to social prejudice are discussed.

Generalization gradients for fear and disgust in human associative learning

Previous research indicates that excessive fear is a critical feature in anxiety disorders; however, recent studies suggest that disgust may also contribute to the etiology and maintenance of some anxiety disorders. It remains unclear if differences exist between these two threat-related emotions in conditioning and generalization. Evaluating different patterns of fear and disgust learning would facilitate a deeper understanding of how anxiety disorders develop. In this study, 32 college students completed threat conditioning tasks, including conditioned stimuli paired with frightening or disgusting images. Fear and disgust were divided into two randomly ordered blocks to examine differences by recording subjective US expectancy ratings and eye movements in the conditioning and generalization process. During conditioning, differing US expectancy ratings (fear vs. disgust) were found only on CS-, which may demonstrated that fear is associated with inferior discrimination learning. During the generalization test, participants exhibited greater US expectancy ratings to fear-related GS1 (generalized stimulus) and GS2 relative to disgust GS1 and GS2. Fear led to longer reaction times than disgust in both phases, and the pupil size and fixation duration for fear stimuli were larger than for disgust stimuli, suggesting that disgust generalization has a steeper gradient than fear generalization. These findings provide preliminary evidence for differences between fear- and disgust-related stimuli in conditioning and generalization, and suggest insights into treatment for anxiety and other fear- or disgust-related disorders.

Right Hemisphere Dominance for Unconscious Emotionally Salient Stimuli

The present review will focus on evidence demonstrating the prioritization in visual processing of fear-related signals in the absence of awareness. Evidence in hemianopic patients without any form of blindsight or affective blindsight in classical terms will be presented, demonstrating that fearful faces, via a subcortical colliculo-pulvinar-amygdala pathway, have a privileged unconscious visual processing and facilitate responses towards visual stimuli in the intact visual field. Interestingly, this fear-specific implicit visual processing in hemianopics has only been observed after lesions to the visual cortices in the left hemisphere, while no effect was found in patients with damage to the right hemisphere. This suggests that the subcortical route for emotional processing in the right hemisphere might provide a pivotal contribution to the implicit processing of fear, in line with evidence showing enhanced right amygdala activity and increased connectivity in the right colliculo-pulvinar-amygdala pathway for unconscious fear-conditioned stimuli and subliminal fearful faces. These findings will be discussed within a theoretical framework that considers the amygdala as an integral component of a constant and continuous vigilance system, which is preferentially invoked with stimuli signaling ambiguous environmental situations of biological relevance, such as fearful faces.

Regulation of blood pressure by the central nucleus of the amygdala in dynamically changing appetitive and aversive classical conditioning tasks in rats

In an environment of dynamically changing conditions, humans and animals can determine whether a current situation is favorable to them and accordingly select actions. Autonomic cardiovascular tuning is as important as motor control for this function. However, neuronal mechanisms underlying the dynamic adjustments of autonomic cardiovascular responses remain unclear. In this study, we hypothesized that the amygdala plays a role in autonomic cardiovascular tuning in a dynamically changing situation. We recorded the blood pressures and heart rates of head-restrained rats during appetitive and aversive classical conditioning tasks. Rats learned varying associations between conditioned stimuli and unconditioned stimuli in appetitive, neutral, and aversive blocks. Blood pressure and heart rate in the appetitive block gradually increased in response to reward-predicting cue, preceded by a vigorously increased response to the actual reward. The predictive response was significantly higher than the responses in the neutral and aversive condition blocks. Blood pressure and heart rate responses to the air puff-predicting cue in the aversive block were significantly lower than that of the responses in the neutral block. The conditioned blood pressure response rapidly changed through condition switching. Furthermore, bilateral pharmacological inactivation of the central nucleus of the amygdala has significantly decreased reward-predictive pressor responses in the latter phase, but not in the initial phase of block change. These results suggest that blood pressure is adaptively tuned by positive and negative conditioned stimuli and that the central nucleus of the amygdala likely assists in maintaining pressor response in dynamically changing situations.