Pharmacological investigations of effort-based decision-making in humans: Naltrexone and nicotine.

Many mental health disorders are characterized by an impaired ability, or willingness, to exert effort to obtain rewards. This impairment is modeled in effort-based decision tasks, and neuropharmacological studies implicate dopamine in this process. However, other transmitter systems such as opioidergic and cholinergic systems have received less attention. Here, in two separate studies we tested the acute effects of naltrexone and nicotine on effort-based decision-making in healthy adults. In Study 1, we compared naltrexone (50mg and 25mg) to placebo, and in Study 2, a pilot study, we compared nicotine (7mg) to placebo. In both studies, participants completed the Effort Expenditure for Rewards Task (EEfRT), which measured effort-based decision-making related to monetary rewards. Although subjects expended greater effort for larger reward magnitude and when there was a higher probability of receiving the reward, neither naltrexone nor nicotine affected willingness to exert effort for monetary rewards. Although the drugs produced significant and typical drug effects on measures of mood and behavior, they did not alter effort-based decision-making. This has implications both for the clinical use of these drugs, as well as for understanding the neuropharmacology of effort-related behavior.

Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers.

BACKGROUND: Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100-200 µg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0-26 µg) on mood and behavior in healthy volunteers under double-blind conditions. METHODS: Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 µg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed. RESULTS: LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 µg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. CONCLUSIONS: Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 µg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.

Subjective responses to amphetamine in young adults with previous mood elevation experiences.

RATIONALE: One risk factor for alcohol and substance misuse is hypomanic experiences, or periods of mood elevation. Young people who report hypomanic states are more likely to develop bipolar disorder (BP), and BP and other mood disorders increase the risk of addiction. We recently reported that young adults with a history of mood elevation experience less subjective effects from a low dose of alcohol, which may be predictive of future alcohol use. The finding with alcohol raised the question of whether this dampened response to a drug also applies to other drugs, such as amphetamine. OBJECTIVE: This study assessed responses of d-amphetamine in healthy young adults with varying experiences of mood elevation, as measured by the Mood Disorders Questionnaire (MDQ). METHODS: Healthy 18-19-year-olds (N = 30) with a range of MDQ scores participated in three 4-h laboratory sessions in which they received placebo, 10 mg, or 20 mg d-amphetamine. They completed mood questionnaires and cardiovascular measures. RESULTS: Individuals with higher MDQ scores reported less stimulation and euphoria after 10 mg, but not 20 mg, d-amphetamine, than individuals with lower scores. MDQ scores were not related to cardiovascular responses to the drug. CONCLUSIONS: A history of mood elevation experiences or hypomania states is related to dampened response to a low dose of a psychostimulant drug, extending previous findings with dampened response to alcohol. This phenotype for mood disorders of dampened responses to drugs may contribute to risk for subsequent drug use or misuse.

Stress as a context: Stress causes relapse of inhibited food seeking if it has been associated with prior food seeking.

Three experiments with rats explored the hypothesis that inhibited food-seeking can be reinstated by stress if stress has been part of the context of earlier food-seeking. In all experiments, rats first learned to lever press for sucrose pellets and then had the response inhibited through extinction (where responding no longer yielded sucrose pellets). In a final test, inhibited responding was tested after exposure to a stressor or not. Previous research indicates that stress during testing does not normally reinstate extinguished food-seeking, although it reliably does so when animals are responding for drugs. In Experiment 1, stress caused a reinstatement of food seeking if and only if the rats had been exposed to stressors prior to sessions of lever press training. In Experiment 2, a new stressor that had not been associated with response acquisition also caused reinstatement if other stressors had been associated with response acquisition. Experiment 3 then established that stressors must be associated with the acquisition of lever pressing, rather than extinction, in order to allow a stressor to cause relapse of extinguished food seeking. The results support the view that stress can cause relapse of inhibited food seeking if it has been part of the context of original food seeking. The effect is therefore an example of the ABA renewal effect in which inhibited responding recovers after extinction when the response is returned to its training context. Implications for understanding relapse to overeating and other "addictive" behaviors are discussed.

Hunger as a Context: Food Seeking That Is Inhibited During Hunger Can Renew in the Context of Satiety.

At the end of a diet, even a successful one, people often return to overeating. One potential reason is that the behavioral inhibition that people learn while dieting might not readily transfer outside the context in which it is learned: Basic research indicates that after a behavior is inhibited, a return to the conditioning context or simple removal from the treatment context can cause the behavior to return (i.e., to renew). Can states of hunger and satiety play the role of context? In two experiments, rats learned a food-seeking response that earned sucrose or sweet, fatty food pellets while they were satiated. Responding was then inhibited (i.e., extinguished) while the rats were hungry. On the rats' return to the satiated state, their food seeking was renewed. Additional results suggest that associations with hunger or satiety stimuli were learned more readily than associations with other potentially useful exteroceptive stimuli. The findings have implications for understanding the role of interoceptive contexts in controlling the inhibition of motivated behavior.

Correction to Schepers and Bouton (2015).

Reports an error in "Effects of reinforcer distribution during response elimination on resurgence of an instrumental behavior" by Scott T. Schepers and Mark E. Bouton (Journal of Experimental Psychology: Animal Learning and Cognition, 2015[Apr], Vol 41[2], 179-192). The mean R2 responding during the resurgence test in the alternating group in the lower right panel of Figure 4 was incorrect. A corrected figure is given in the correction. (The following abstract of the original article appeared in record 2015-12206-001.) Resurgence has commonly been viewed as the recovery of an extinguished instrumental behavior that occurs when an alternative behavior that has replaced it is also extinguished. Three experiments with rat subjects examined the effects on resurgence of the temporal distribution of reinforcement for the alternative behavior that is presented while the first response is being eliminated. Experiments 1 and 2 examined resurgence when rich rates of reinforcement at the onset of response elimination became leaner over sessions (i.e., forward thinning) and when lean rates became richer (i.e., reverse thinning). Both procedures weakened resurgence compared with that in a group that received the richest rate during all sessions. However, forward thinning was more effective than reverse thinning at reducing the resurgence effect. Experiment 3 found that final resurgence was eliminated when the alternative behavior was reinforced and extinguished in alternating response elimination sessions. The results are consistent with the hypothesis that reinforcer delivery during response elimination provides a contextual stimulus for the extinction of the original behavior; its removal during resurgence testing causes ABC renewal to occur. The results are less consistent with an alternative account that emphasizes the removal of response disruption caused by alternative reinforcement (Shahan & Sweeney, 2011). Other theoretical and applied implications are discussed. (PsycINFO Database Record

A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory.

The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway.

Effects of reinforcer distribution during response elimination on resurgence of an instrumental behavior.

Resurgence has commonly been viewed as the recovery of an extinguished instrumental behavior that occurs when an alternative behavior that has replaced it is also extinguished. Three experiments with rat subjects examined the effects on resurgence of the temporal distribution of reinforcement for the alternative behavior that is presented while the first response is being eliminated. Experiments 1 and 2 examined resurgence when rich rates of reinforcement at the onset of response elimination became leaner over sessions (i.e., forward thinning) and when lean rates became richer (i.e., reverse thinning). Both procedures weakened resurgence compared with that in a group that received the richest rate during all sessions. However, forward thinning was more effective than reverse thinning at reducing the resurgence effect. Experiment 3 found that final resurgence was eliminated when the alternative behavior was reinforced and extinguished in alternating response elimination sessions. The results are consistent with the hypothesis that reinforcer delivery during response elimination provides a contextual stimulus for the extinction of the original behavior; its removal during resurgence testing causes ABC renewal to occur. The results are less consistent with an alternative account that emphasizes the removal of response disruption caused by alternative reinforcement (Shahan & Sweeney, 2011). Other theoretical and applied implications are discussed.

Renewal after the punishment of free operant behavior.

Three experiments examined the role of context in punishment learning. In Experiment 1, rats were trained to lever press for food in Context A and then punished for responding in Context B (by presenting response-contingent footshock). Punishment led to complete suppression of the response. However, when responding was tested (in extinction) in Contexts A and B, a strong renewal of responding occurred in Context A. In Experiment 2, renewal also occurred when initial reinforcement occurred in Context A, punishment occurred in Context B, and testing occurred in a new context (Context C). In both experiments, behavioral suppression and renewal were not observed in groups that received noncontingent (yoked) footshocks in Context B. In Experiment 3, 2 responses (lever press and chain pull) were separately reinforced in Contexts A and B and then punished in the opposite context. Although the procedure equated the contexts on their association with reinforcement and punishment, renewal of each response was observed when it was tested in its nonpunished context. The contexts also influenced response choice. Overall, the results suggest that punishment is specific to the context in which it is learned, and establish that its context-specificity does not depend on a simple association between the context and shock. Like extinction, punishment may involve learning to inhibit a specific response in a specific context. Implications for theories of punishment and for understanding the cessation of problematic operant behavior (e.g., drug abuse) are discussed.

Context change explains resurgence after the extinction of operant behavior.

Extinguished operant behavior can return or "resurge" when a response that has replaced it is also extinguished. Typically studied in nonhuman animals, the resurgence effect may provide insight into relapse that is seen when reinforcement is discontinued following human contingency management (CM) and functional communication training (FCT) treatments, which both involve reinforcing alternative behaviors to reduce behavioral excess. Although the variables that affect resurgence have been studied for some time, the mechanisms through which they promote relapse are still debated. We discuss three explanations of resurgence (response prevention, an extension of behavioral momentum theory, and an account emphasizing context change) as well as studies that evaluate them. Several new findings from our laboratory concerning the effects of different temporal distributions of the reinforcer during response elimination and the effects of manipulating qualitative features of the reinforcer pose a particular challenge to the momentum-based model. Overall, the results are consistent with a contextual account of resurgence, which emphasizes that reinforcers presented during response elimination have a discriminative role controlling behavioral inhibition. Changing the "reinforcer context" at the start of testing produces relapse if the organism has not learned to suppress its responding under conditions similar to the ones that prevail during testing.

Resurgence of instrumental behavior after an abstinence contingency.

In resurgence, an extinguished instrumental behavior (R1) recovers when a behavior that has replaced it (R2) is also extinguished. The phenomenon may be relevant to understanding relapse that can occur after the termination of "contingency management" treatments, in which an unwanted behavior (e.g., substance abuse) is reduced by reinforcing an alternative behavior. When reinforcement is discontinued, the unwanted behavior might resurge. However, unlike most resurgence experiments, contingency management treatments also introduce a negative contingency, in which reinforcers are not delivered unless the client has abstained from the unwanted behavior. In two experiments with rats, we therefore examined the effects of adding a negative "abstinence" contingency to the resurgence design. During response elimination, R2 was not reinforced unless R1 had not been emitted for a minimum period of time (45, 90, or 135 s). In both experiments, adding such a contingency to simple R1 extinction reduced, but did not eliminate, resurgence. In Experiment 2, we found the same effect in a yoked group that could earn reinforcers for R2 at the same points in time as the negative-contingency group, but without the requirement to abstain from R1. Thus, the negative contingency per se did not contribute to the reduction in resurgence. These results suggest that the contingency reduced resurgence by making reinforcers more difficult to earn and more widely spaced in time. This could have allowed the animal to learn that R1 was extinguished in the "context" of infrequent reinforcement-a context more like that of resurgence testing. The results are thus consistent with a contextual (renewal) account of resurgence. The method might provide a better model of relapse after termination of a contingency management treatment.