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Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. We previously provided a computer program to facilitate recording tic occurrence and to automate reward delivery during the several experimental conditions of the TSP. The present article describes a web-based program that performs the same functions. Implementing this program on the web allows research sessions to be performed remotely, in tandem with a video calling program. Relevant data for each session, such as the timing of tics and dispensed rewards, are stored in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Black JK et al.)

Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. We previously provided a computer program to facilitate recording tic occurrence and to automate reward delivery during the several experimental conditions of the TSP. The present article describes a web-based program that performs the same functions. Implementing this program on the web allows research sessions to be performed remotely, in tandem with a video calling program. Relevant data for each session, such as the timing of tics and dispensed rewards, are stored in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Black JK et al.)

Introduction: Neurofeedback (NF) using real-time functional magnetic resonance imaging (fMRI) has proven to be a valuable neuroscientific tool for probing cognition and promising therapeutic approach for several psychiatric disorders. Even though learning constitutes an elementary aspect of NF, the question whether certain training schemes might positively influence its dynamics has largely been neglected., Methods: To address this issue, participants were trained to exert control on their subgenual anterior cingulate cortex (sgACC) blood-oxygenation-level-dependent signal, receiving either exclusively positive reinforcement (PR, "positive feedback") or also positive punishment (PP, "negative feedback"). The temporal dynamics of the learning process were investigated by individually modeling the feedback periods and trends, offering the possibility to assess activation changes within and across blocks, runs and sessions., Results: The results show faster initial learning of the PR + PP group by significantly lower deactivations of the sgACC in the first session and stronger regulation trends during the first runs. Independent of the group, significant control over the sgACC could further be shown with but not without feedback., Conclusion: The beneficial effect of PP is supported by previous findings of multiple research domains suggesting that error avoidance represents an important motivational factor of learning, which complements the reward spectrum. This hypothesis warrants further investigation with respect to NF, as it could offer a way to generally facilitate the process of gaining volitional control over brain activity., (Copyright © 2020 Klöbl, Michenthaler, Godbersen, Robinson, Hahn and Lanzenberger.)

Aims: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic., Methods: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues., Results: LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule., Conclusions: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs., (Copyright © 2018. Published by Elsevier Inc.)

A variety of evidence suggests that bipolar disorder is associated with disruptions of reward related processes, although the properties, and scope of these changes are not well understood. In the present study, we aimed to address this question by examining performance of patients with bipolar disorder (30 depressed bipolar; 35 euthymic bipolar) on a motivated choice reaction time task. We compared performance with a group of healthy control individuals ( n = 44) and a group of patients with unipolar depression ( n = 41), who were matched on several demographic variables. The task consists of an "odd-one-out" discrimination, in the presence of a cue signaling the probability of reward on a given trial (10, 50, or 90%) given a sufficiently fast response. All groups showed similar reaction time (RT) performance, and similar shortening of RT following the presentation of a reward predictive cue. However, compared to healthy individuals, the euthymic bipolar group showed a relative increase in commission errors during the high reward compared to low condition. Further correlational analysis revealed that in the healthy control and unipolar depression groups, participants tended either to shorten RTs for the high rather than low reward cue a relatively large amount with an increase in error rate, or to shorten RTs to a lesser extent but without increasing errors to the same degree. By contrast, reward-related speeding and reward-related increase in errors were less well coupled in the bipolar groups, significantly so in the BPD group. These findings suggest that although RT performance on the present task is relatively well matched, there may be a specific failure of individuals with bipolar disorder to calibrate RT speed and accuracy in a strategic way in the presence of reward-related stimuli.

Aims: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic., Methods: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues., Results: LS-3-134 did not alter spontaneous locomotion, but at 5.6 mg/kg, it reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule., Conclusions: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs., (Copyright © 2018. Published by Elsevier Inc.)

This review article addresses the biological factors that influence: (i) the acquisition of alcohol intake; (ii) the maintenance of chronic alcohol intake; and (iii) alcohol relapse-like drinking behavior in animals bred for their high-ethanol intake. Data from several rat strains/lines strongly suggest that catalase-mediated brain oxidation of ethanol into acetaldehyde is an absolute requirement (up 80%-95%) for rats to display ethanol's reinforcing effects and to initiate chronic ethanol intake. Acetaldehyde binds non-enzymatically to dopamine forming salsolinol, a compound that is self-administered. In UChB rats, salsolinol: (a) generates marked sensitization to the motivational effects of ethanol; and (b) strongly promotes binge-like drinking. The specificity of salsolinol actions is shown by the finding that only the R-salsolinol enantiomer but not S-salsolinol accounted for the latter effects. Inhibition of brain acetaldehyde synthesis does not influence the maintenance of chronic ethanol intake. However, a prolonged ethanol withdrawal partly returns the requirement for acetaldehyde synthesis/levels both on chronic ethanol intake and on alcohol relapse-like drinking. Chronic ethanol intake, involving the action of lipopolysaccharide diffusing from the gut, and likely oxygen radical generated upon catechol/salsolinol oxidation, leads to oxidative stress and neuro-inflammation, known to potentiate each other. Data show that the administration of N-acetyl cysteine (NAC) a strong antioxidant inhibits chronic ethanol maintenance by 60%-70%, without inhibiting its initial intake. Intra-cerebroventricular administration of mesenchymal stem cells (MSCs), known to release anti-inflammatory cytokines, to elevate superoxide dismutase levels and to reverse ethanol-induced hippocampal injury and cognitive deficits, also inhibited chronic ethanol maintenance; further, relapse-like ethanol drinking was inhibited up to 85% for 40 days following intracerebral stem cell administration. Thus: (i) ethanol must be metabolized intracerebrally into acetaldehyde, and further into salsolinol, which appear responsible for promoting the acquisition of the early reinforcing effects of ethanol; (ii) acetaldehyde is not responsible for the maintenance of chronic ethanol intake, while other mechanisms are indicated; (iii) the systemic administration of NAC, a strong antioxidant markedly inhibits the maintenance of chronic ethanol intake; and (iv) the intra-cerebroventricular administration of anti-inflammatory and antioxidant MSCs inhibit both the maintenance of chronic ethanol intake and relapse-like drinking .

The cholinergic system plays important roles in both learning and addiction. Medications that modify cholinergic tone can have pronounced effects on behaviors reinforced by natural and drug reinforcers. Importantly, enhancing the action of acetylcholine (ACh) in the nucleus accumbens and ventral tegmental area (VTA) dopamine system can either augment or diminish these behaviors. A threshold model is presented that can explain these seemingly contradictory results. Relatively low levels of ACh rise above a lower threshold, facilitating behaviors supported by drugs or natural reinforcers. Further increases in cholinergic tone that rise above a second upper threshold oppose the same behaviors. Accordingly, cholinesterase inhibitors, or agonists for nicotinic or muscarinic receptors, each have the potential to produce biphasic effects on reward behaviors. Pretreatment with either nicotinic or muscarinic antagonists can block drug- or food- reinforced behavior by maintaining cholinergic tone below its lower threshold. Potential threshold mediators include desensitization of nicotinic receptors and biphasic effects of ACh on the firing of medium spiny neurons. Nicotinic receptors with high- and low- affinity appear to play greater roles in reward enhancement and inhibition, respectively. Cholinergic inhibition of natural and drug rewards may serve as mediators of previously described opponent processes. Future studies should evaluate cholinergic agents across a broader range of doses, and include a variety of reinforced behaviors., (Published by Elsevier B.V.)

Previous work by our laboratory has shown that tacrine can produce long-lasting reductions in cocaine-reinforced behavior, when administered to rats as daily intravenous infusions over four days. Tacrine causes dose-related liver toxicity in different species, and its manufacture for human use was recently discontinued. This study was conducted to further characterize its actions on cocaine reward. Cocaine-experienced animals that had no contact with drug over one week resumed self-administration at levels similar to their initial baseline. When tacrine was administered over four days which were preceded and followed by washout periods to allow elimination of cocaine and tacrine respectively, subsequent cocaine self-administration was attenuated by more than one-half. Tacrine administered at 10 mg/kg-day as a chronic infusion by osmotic pump did not modify cocaine-induced increases in locomotor activity or conditioned-place preference. In rats that exhibited persistent attenuation of cocaine-self-administration after receiving tacrine, cocaine-induced reinstatement was also attenuated. No changes in plasma measures of renal or hepatic function were observed in rats receiving tacrine. In conclusion, pretreatment with tacrine can decrease cocaine-motivated behavior measured by self-administration or reinstatement, but not conditioned-place preference. Reductions in cocaine self-administration following pretreatment with tacrine do not require direct interaction with cocaine and are not secondary to either liver or kidney toxicity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a "pro-drug" is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). Recent experiments have established that numerous metabolites of alcohol have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism.

A coordinate transformation framework for understanding how neurons compute sensorimotor behaviors has generated significant advances toward our understanding of basic brain function. This influential scaffold focuses on neuronal encoding of spatial information represented in different coordinate systems (e.g., eye-centered, hand-centered) and how multiple brain regions partake in transforming these signals in order to ultimately generate a motor output. A powerful analogy can be drawn from the coordinate transformation framework to better elucidate how the nervous system computes cognitive variables for social behavior. Of particular relevance is how the brain represents information with respect to oneself and other individuals, such as in reward outcome assignment during social exchanges, in order to influence social decisions. In this article, I outline how the coordinate transformation framework can help guide our understanding of neural computations resulting in social interactions. Implications for numerous psychiatric disorders with impaired representations of self and others are also discussed.

Goldfish were taught to press a lever for food reinforcement and were placed on a 1-minute fixed-interval schedule. They developed the characteristic temporal discrimination (scalloping) seen in rats and pigeons. There was no change in their relative response rate through the 1-minute interval when ambient temperature was decreased by 10 degrees C. This 10 degrees C temperature drop, which approximately halves the metabolic rate, approximately halved the absolute response rate. These results indicate that a temporal discrimination can be established in the goldfish, and suggest that discriminations of short intervals in fish are not dependent on a mechanism tied directly to metabolic rate.

Pigeons were trained to peck with differing force requirements on a key specially designed to measure and control force of pecking without changes in the mechanical threshold. Following training on a key illuminated by a single wavelength, a generalization test was given. Force and rate gradients were obtained. Force gradients were shown to have a form similar to rate gradients. The slope of the force gradients was a direct function of the force of responding at the conclusion of training. Rate gradients were independent of the force of responding.

The performance maintained by reinforcing responses only when they terminated interresponse times (IRTs) of 20 sec or greater (DRL schedule) was almost the same during the first session of reconditioning as before extinction. As few as two reinforcements accurately reinstated both the pre-extinction rate of responding and the function relating the duration of an IRT to its conditional probability of occurrence (IRTs/op).