The anterior insula and its projection to amygdala nuclei modulate the abstinence-exacerbated expression of conditioned place preference.

RATIONALE: Relapse into substance use is often triggered by exposure to drug-related environmental cues. The magnitude of drug seeking depends on the duration of abstinence, a phenomenon known as the incubation of drug craving. Clinical and preclinical research shows that the insular cortex is involved in substance use disorders and cue-induced drug seeking. However, the role of the insula on memory retrieval and motivational integration for cue-elicited drug seeking remains to be determined. OBJECTIVES: We investigated the role of the anterior insular cortex (aIC) and its glutamatergic projection to amygdala nuclei (aIC-AMY) on the expression of conditioned place preference (CPP) during early and late abstinence. METHODS: Male adult C57BL/6J mice underwent amphetamine-induced CPP, and their preference was tested following 1 or 14 days of abstinence. aIC and aIC-AMY functional role in CPP expression was assessed at both abstinence periods by employing optogenetic silencing and behavioral pharmacology. RESULTS: Compared to a single day, an exacerbated preference for the amphetamine-paired context was observed after 14 days of abstinence. Photoinhibition of either aIC or aIC-AMY projection reduced CPP expression following late but not early abstinence. Similarly, the antagonism of aIC NMDA receptors reduced CPP expression after 14 days of abstinence but not 1 day. CONCLUSIONS: These results suggest that aIC and its glutamatergic output to amygdala nuclei constitute critical neurobiological substrates mediating enhanced motivational cue reactivity during the incubation of amphetamine craving rather than contextual memory recall. Moreover, cortical NMDA receptor signaling may become sensitized during abstinence, ultimately modulating disproportioned drug seeking.

Impaired cognitive control moderates the relation between the attribution of incentive salience and severity of consumption in patients with methamphetamine dependence.

BACKGROUND: Cognitive control and the attribution of incentive salience are two key neuropsychological processes proposed to explain substance use disorder (SUD). However, little is known about how they interact to influence the severity of drug use in people with SUD. OBJECTIVE: To determine if cognitive control exerts a moderating effect on the relation between the attribution of salience to drug/reward-related cues and the severity of drug use in SUD cases. METHOD: Sixty-nine SUD cases with methamphetamine as the main drug of consumption were selected and evaluated. Participants performed the Stroop, Go/No-Go, and Flanker tasks to identify a latent cognitive control factor, and the Effort-Expenditure for Reward task, as well as answering the Methamphetamine Incentive Salience Questionnaire to measure the attribution of incentive salience. Severity of drug use was determined by the KMSK scale and an exploratory clinical interview. RESULTS: As expected, higher incentive salience attribution predicted greater severity of methamphetamine use. Unexpectedly, however, we found a moderating effect of impaired cognitive control on the relations between higher incentive salience scores and higher monthly drug use, and between younger age at onset of systematic drug use and higher incentive salience scores. CONCLUSION: Results show the moderating role of cognitive control on the relation between incentive salience attribution and severity of drug use in SUD cases, and help explain the chronic, relapsing nature of addiction, knowledge necessary to develop more precise prevention and treatment strategies.

Pre-clinical evidence that methylphenidate increases motivation and/or reward preference to search for high value rewards.

Methylphenidate is a stimulant used to treat attention deficit and hyperactivity disorder (ADHD). In the last decade, illicit use of methylphenidate has increased among healthy young adults, who consume the drug under the assumption that it will improve cognitive performance. However, the studies that aimed to assess the methylphenidate effects on memory are not consistent. Here, we tested whether the effect of methylphenidate on a spatial memory task can be explained as a motivational and/or a reward effect. We tested the effects of acute and chronic i.p. administration of 0.3, 1 or 3 mg/kg of methylphenidate on motivation, learning and memory by using the 8-arm radial maze task. Adult male Wistar rats learned that 3 of the 8 arms of the maze were consistently baited with 1, 3, or 6 sucrose pellets, and the number of entries and reentries into reinforced and non-reinforced arms of the maze were scored. Neither acute nor chronic (20 days) methylphenidate treatment affected the number of entries in the non-baited arms. However, chronic, but not acute, 1-3 mg/kg methylphenidate increased the number of reentries in the higher reward arms, which suggests a motivational/rewarding effect rather than a working memory deficit. In agreement with this hypothesis, the methylphenidate treatment also decreased the approach latency to the higher reward arms, increased the approach latency to the low reward arm, and increased the time spent in the high, but not low, reward arm. These findings suggest that methylphenidate may act more as a motivational enhancer rather than a cognitive enhancer in healthy people.

ß-caryophyllene, a cannabinoid receptor 2 agonist, decreases the motivational salience and conditioning place preference for palatable food in female mice.

ß-caryophyllene (BCP) is a cannabinoid receptor CB2 agonist plant-derived terpenoid found in different essential oil plants, including rosemary, black pepper, copaiba and cannabis. It has GRAS (generally recognized as safe) status and is approved by the FDA (Food and Drug Administration) for food use. BCP displays agonist activity on the CB2 receptor and is a potential therapeutic target in several neuropsychiatric disorders, including anxiety and drug addiction. Unlike CB1 receptors, activation of the CB2 receptors is devoid of psychotomimetic and addictive properties. In this regard, this study aimed to evaluate the effects of BCP on incentive salience ("wanting") performance and motivational properties elicited by sweetened palatable foods in female Swiss mice. After 9 days of training for incentive salience performance for a sweet reward (hazelnut cream with chocolate), food-restricted mice received a systemic injection of BCP (50 and 100 mg/kg) before testing over 3 days. Moreover, independent groups of female mice were tested on sweet reward-induced conditioned place preference (CPP) for 22 consecutive days. To evaluate BCP effects on the expression of seeking behaviour for sweetened food, mice received a single intraperitoneal injection of BCP (50 mg/kg) 30 min before testing on the CPP task. BCP significantly decreased the incentive performance for a sweet reward compared with the control group in a CB2 receptor-dependent manner. Also, BCP suppressed the expression of sweet reward-CPP. Altogether, these preclinical data demonstrate the potential role of BCP in treating disorders associated with food addiction-like behaviour.

Suboptimal choice by pigeons is eliminated when key-pecking behavior is replaced by treadle-pressing.

In the study of suboptimal choice, a reliable result is that pigeons strongly prefer an alternative that signals whether a reinforcer will be delivered or not over another alternative without that information even if the first provides a lower probability of reinforcement. In the aforementioned research, key pecking has been the operant response and illuminated keys the discriminative stimuli. In the present study we modified both of these aspects of the procedure in order to analyze the generality of suboptimal preferences of pigeons and to investigate the effect of changes in the incentive salience of the discriminative stimuli. To accomplish this, we presented pigeons a choice situation with the same parameters of reinforcement than previous research, but with treadle pressing as the choice response and ambient lights as discriminative stimuli. Under these conditions, most of the pigeons showed optimal behavior and a high degree of discrimination of the stimuli associated with the discriminative alternative. A control condition with key pecking as choice response and keylights as discriminative stimuli showed that the same pigeons turned to be suboptimal, a result that discards the possibility that the optimality found in the main condition was a consequence of a particular characteristic of our sample of subjects or of our procedure. We discuss the influence that the attribution of incentive salience to the discriminative stimuli has on suboptimal choice in both pigeons and rats.

Anxiety-like behavior in acute and protracted withdrawal after morphine-induced locomotor sensitization in C57BL/6 male mice: The role of context.

Contextual memory plays an important role in development and maintenance of drug addiction. However, little is known about of the role contextual memory in the emergence of a negative emotional state in the withdrawal period. Therefore, this study investigated anxiety-like behavior in acute and protracted morphine withdrawal of mice submitted to a locomotor sensitization protocol and the influence of contextual memory on this behavior. Male adult C57Bl6 mice were subjected to morphine locomotor sensitization and anxiety-like behavior was assessed by using the elevated plus maze test (EPM). To evaluate associative memory, the mice were re-exposed to the context of locomotor sensitization immediately before EPM. As expected, repeated morphine administrations promoted locomotor sensitization, seen as a gradual increase in the distance traveled during the acquisition phase. There was an increase in anxiety-like behavior upon acute withdrawal, as indicated by a decrease in open arms activity (OAA), but this effect dissipated over time. However, when the context was presented, mice in protracted withdrawal showed enhanced anxiety-like behavior, indicated by an increase in closed arms activity (CAA). This effect was context specific since re-exposure in an alternative context did not change the anxiety-like behavior. Treatment with diazepam counteracted the decrease in OAA in acute withdrawal and the increase in CAA induced by context re- exposure during protracted abstinence. Thus, repeated morphine administration induced a negative emotional state when the drug was discontinued. The context associated with drug exposure played a pivotal role in the appearance of anxiety-like behavior, even long after drug discontinuation. There were differences in the patterns of anxiety behaviors in acute (unconditioned anxiety-like behavior) and protracted (conditioned anxiety-like behavior) withdrawal since the former was characterized by a passive behavioral strategy and the latter by an active behavioral strategy.

Rats' preferences in the suboptimal choice procedure: Evaluating the impact of reinforcement probability and conditioned inhibitors.

Previous research has shown that pigeons and other birds display a strong and consistent preference for an alternative of reinforcement that presents stimuli that allow to discriminate whether a reinforcer will be delivered or not, even when its probability of reinforcement is lower than that of another alternative without those stimuli. In contrast, most of the studies performed with rats report that they show the opposite preference, choosing the alternative with higher probability of reinforcement. To explain these opposite preferences, it has been proposed that rats and pigeons have a differential sensitivity to the conditioned inhibition that emerges from the stimulus that predicts non-reinforcement: While it does not have an impact in pigeons, it strongly influences rats´ preferences. Alternatively, it was recently proposed that there is not a fundamental difference in the behavior of rats and pigeons, but that the procedure employed to evaluate each of these species has generated the difference; in particular, it was proposed that both species prefer the discriminative alternative when the discriminative stimuli have incentive salience. Two recent studies provide support for each of these hypotheses, so that the available evidence does not allow to distinguish between them. In the present report, we present three studies that systematically explore the influence of the procedural differences between the studies with discrepant results. The obtained results provide support for the following ideas: a) there is a fundamental difference between pigeons and rats in their choice behavior in the "suboptimal choice procedure", b) considering the incentive salience of the discriminative stimuli does not resolve it, and c) rats' optimality is a consistent phenomenon, which resists manipulations in reinforcement probabilities and the absence of conditioned inhibitors in the discriminative alternative.

Incentive salience attribution is not the sole determinant of suboptimal choice in rats: Conditioned inhibition matters.

Previous research has identified clear differences between pigeons and rats in the suboptimal choice procedure. Pigeons behave suboptimally, preferring an alternative with discriminative stimuli and a smaller probability of reinforcement, over another with a higher probability of reinforcement, but without discriminative stimuli. In contrast, rats behave optimally showing the opposite preference. It has been proposed that these dissimilarities are consequence of a higher sensitivity to conditioned inhibition in rats than in pigeons. Alternatively, recent research suggests that differences in optimality can be accounted for by a differential incentive salience of the stimuli employed as discriminative stimuli, and that both species are suboptimal when such stimuli have high incentive salience; specifically, rats were found to be suboptimal when levers were used as discriminative stimuli. However, in the evaluation of this hypothesis, a conditioned inhibitor was not employed. In the present report, eight rats were exposed to a choice procedure that integrated both variables discussed above: a conditioned inhibitor was associated with the discriminative alternative and the stimuli had high incentive salience. A clear preference for the optimal alternative was found, suggesting that the conditioned inhibitor had a considerable impact on rats' preference, and that species-differences remain even in procedures in which the discriminative stimuli have incentive salience.

Partial lesion of dopamine neurons of rat substantia nigra impairs conditioned place aversion but spares conditioned place preference.

Midbrain dopamine neurons play critical roles in reward- and aversion-driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning. Partial lesions of dopamine neurons in the rat substantia nigra pars compacta (SNc) induced by bilateral intranigral infusion of 6-hydroxydopamine (6-OHDA, 3µg/side) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 200µg/side) impaired learning of conditioned place aversion (CPA) without affecting conditioned place preference (CPP) learning. Control experiments demonstrated that these lesions did not impair motor performance and did not alter the hedonic value of the sucrose and quinine. The number of dopamine neurons in the caudal part of the SNc positively correlated with the CPP scores of the 6-OHDA rats and negatively correlated with CPA scores of the SHAM rats. In addition, the CPA scores of the 6-OHDA rats positively correlated with the tissue content of striatal dopamine. Insomuch as reward-driven learning depends on an increase in dopamine release by nigral neurons, these findings show that this mechanism is functional even in rats with a partial lesion of the SNc. On the other hand, if aversion-driven learning depends on a reduction of extracellular dopamine in the striatum, the present study suggests that this mechanism is no longer functional after the partial SNc lesion.