Editorial: Neurobehavioral Mechanisms of Reward: Theoretical and Technical Perspectives and Their Implications for Psychopathology

In summary, various basic and translational investigations, including those gathered in this issue and many others, are beginning to find common ground on the need to dissociate specific components of the brain reward system and their relationship with behavior. Although they mostly derive from very different perspectives (pharmacological, behavioral, genetic, epigenetic, computational. . . ), the results of these studies are beginning to fit together like the pieces of a puzzle, revealing a complex picture of the functioning of brain reward mechanisms. It shows that the mesolimbic dopaminergic system continues to play a key part (as a “primum inter pares”) but other systems also have a role. This supports the design of better-targeted treatments of the different neuropathological disorders in which these systems are altered

Endocannabinoid Regulation of Acute and Protracted Nicotine Withdrawal: Effect of FAAH Inhibition

Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use

Adolescent Female Cannabinoid Exposure Diminishes the Reward-Facilitating Effects of Δ9-Tetrahydrocannabinol and d-Amphetamine in the Adult Male Offspring

Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to Δ9-tetrahydrocannabinol (Δ9-THC) induces transgenerational effects on the reward-facilitating effects of Δ9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received Δ9-THC (0.1 or 1 mg/kg, i.p.) or vehicle during postnatal days 28–50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the Δ9-THC’s (0, 0.1, 0.5, and 1 mg/kg, i.p.) and d-amphetamine’s (0, 0.1, 0.5, and 1 mg/kg, i.p.) reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS) procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of Δ9-THC was abolished in the F1 offspring of females that were exposed to Δ9-THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of Δ9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to Δ9-THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female Δ9-THC exposure during adolescence can diminish the reward-facilitating effects of Δ9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that Δ9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs

ORIGINAL INVESTIGATION CB 1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat

Abstract Rationale: Addictive drugs have a number of commonalities in animal behavioral models. They lower intracranial self-stimulation (ICSS) thresholds, support selfadministration, and produce conditioned place preference (CPP). However, cannabinoids appear atypical as drugs of abuse, since there are controversial data in the literature concerning their reinforcing properties. Objectives: The aim of the present study was to examine the effects of cannabinoids on brain reward using the rate-frequency curve shift paradigm of ICSS. Methods: Male Sprague-Dawley rats were implanted with electrodes into the medial forebrain bundle (MFB). Rate-frequency functions were deterined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain stimulation reward thresholds stabilized rats received intraperitoneal (IP) injections of the potent CB 1 receptor agonists WIN 55,212-2 (graded doses 0.1, 0.3, 1 and 3 mg/kg), CP 55,940 (graded doses 10, 30, 56 and 100 μg/kg), or HU-210 (graded doses 10, 30, 100 μg/kg). Results: With the exception of the highest dose of all cannabinoid agonists tested, which significantly increased the threshold frequency required for MFB ICSS, all other doses of the tested drugs did not affect ICSS thresholds. The CB 1 receptor antagonist SR141716A reversed the actions of WIN 55,212-2 and CP 55,940, but not HU-210. However, the selective CB 1 cannabinoid receptor antagonist AM 251 counteracted the effect of HU-210. Both CB 1 receptor antagonists, at the doses used in the present study, did not affect reward thresholds by themselves. Conclusions: The present results indicate that cannabinoid agonists do not exhibit reinforcing properties in the ICSS paradigm, but rather have an inhibitory influence on reward mechanisms. The results suggest that the anhedonic effects of cannabinoids are probably mediated by cannabinoid CB 1 receptors

The role of the ventral pallidum in reward

In the present study the role of the ventral pallidum (VP)in self-stimulation behavior was examined in ratw. The distribution of electrical self-stimulation foci within the ventral pallidum was mapped using moveable electrodes. Our results show that 98% of VP sites supported self-stimulation behavior. A comparable high rate of positive sites was not obtained from adjacent brain areas. The estimation of poststimulation excitability of ventral pallidum neurons point to the suggestion that the self-stimulation substrate in the VP involves heterogeneous neurons.These excitability properties are different from those characterising catecholaminergic neurons. Studies using the psychophysical technique of collision show that the VP and the ipsilateral lateral hypothalamus and the ipsilateral or contralateral ventral tegmental area share no common reward fibres. Immunohistochemical studies show that rewarding electrical stimulation of the VP increased c-fos expression in several structures known to participate in the regulation of reward, such as the medial prefrontal cortex, the nucleus accumbens, the intermidiate aspect of the lateral septum,the prosterior lateral hypothalamus and the ventral tegmental area and failed to do so in structures devoid of such involvement(dorsolateral striatum and substantia nigra reticulata).Στην παρούσα εργασία εξετάσθηκε σε επίμυες ο ρόλος ωχράς σφαίρας στηνεκδήλωση συμπεριφοράς ενδοκρανιακού αθτοερεθισμού.Με τη χρήση κινητών ηλεκτροδίων χαρτογραφήθηκε η ευρύτερη περιοχή της κοιλιακής ωχράς σφαίρας. Αποδείχθηκε ότι το 98% των θέσεων που μελέτηθηκαν εντός της κοιλίακης ωχράς σφαίρας είναι θετικές για ενδοκρανιακό αυτοερεθισμό,που αποδείχθηκε περισσότερο ενισχυτικός από αυτόν που εκλύεται από το 66% γειτονικών προς την κοιλιακή ωχρά σφαίρα μελετηθεισών θέσεων. Η μελέτη των χαρακτηριστικών διεγερσιμότητας των νευρώνων οδήγησε στο συμπέρασμα ότι το ερεθιζόμενο υπόστρωμα της κοιλιακής ωχράς σφαίρας αποτελείται από ανομοιογενείς νευρώνες που στο μεγαλύτερό τους ποσοστό δεν είναι κατεχολαμινεργικοί. Μελέτες με την ψυχοφυσική τεχνική της σύγκρουσης των ερεθισμάτων μεταξύ πυρήνων απέκλεισε τη συμμετοχή της περιοχής του ομόπλευρου έξω υποθαλάμου και του ομόπλευρου ή ετερόπλευρου κοιλιακού καλυπτρικού πεδίου στο κύκλωμα μετάδοσης του μηνύματος της ανταμοιβής. Μελέτες με ανοσοϊστοχημική προσέγγιση των εγκεφαλικών περιοχών που εκφράζουν c-fos μετά από ενδοκρανιακό αυτοερεθισμό της κοιλιακής ωχράς σφαίρας έδειξε ότι παραμένουν ανενεργείς περιοχές που δεν αποτελούν υπόστρωμα ανταμοιβής, όπως το ραχιαίο-έξω ραβδωτό και η δικτυωτή μοίρα της μέλαινας ουσίας,ενώ περιοχές που ενέρχονται στην ανταμοιβή, όπως ο προμετωπιαίος φλοιός, ο επικλινής πυρήνας, το διάφραγμα, ο έξω υποθάλαμος και το κοιλιακό καλυπτρικό πεδίο, εμφανίζουν ομόπλευρα ή/και ετερόπλευρα έντονη δραστηριοποίησης

Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future

Over the last decades the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain reward circuits and the regulation of motivational processes. Importantly, behavioural studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioural experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the reinstatement of drug-seeking behaviour procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1) receptor agonists, antagonists and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggests that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction related disorders

Lack of rewarding effects of 9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference paradigms

Data on the ability of [DELTA]9-tetrahydrocannabinol (THC) to modify reward processes in experimental animals are inconsistent. This study examined the effects of [DELTA]9-THC on brain reward function using the rate-frequency curve shift paradigm of intracranial self-stimulation (ICSS) and the conditioned place preference (CPP) paradigm. In ICSS tests, rats were implanted with electrodes into the medial forebrain bundle. After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of [DELTA]9-THC (0, 0.5, 1 and 2 mg/kg) or the CB1 receptor antagonist SR141716A (0, 0.02 mg/kg) and [DELTA]9-THC (0, 2 mg/kg). The two highest doses of [DELTA]9-THC significantly increased the threshold ICSS frequency. SR141716A reversed the action of [DELTA]9-THC (2 mg/kg), without affecting reward thresholds by itself. In the CPP test, mice received intraperitoneal injections of [DELTA]9-THC (0, 1 or 3 mg/kg). [DELTA]9-THC showed neither statistically significant preference nor aversion in either of the doses tested. These findings indicate that [DELTA]9-THC, in contrast to other drugs of abuse, does not facilitate ICSS or support CPP under the present experimental conditions, but rather has a dose-dependent inhibitory influence on ICSS

5-HT2C receptor involvement in the control of persistence in the Reinforced Spatial Alternation animal model of obsessive-compulsive disorder

Objective: The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. Methods: Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5 mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. Results: Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. Conclusions: These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD. (C) 2013 Elsevier B.V. All rights reserved

A cellular and molecular spatial atlas of dystrophic muscle.

Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery