Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression

Reversing LRP5-Dependent Osteoporosis and SOST Deficiency-Induced Sclerosing Bone Disorders by Altering WNT Signaling Activity

The bone formation inhibitor sclerostin encoded by SOST binds in vitro to low-density lipoprotein receptor-related protein (LRP) 5/6 Wnt co-receptors, thereby inhibiting Wnt/β-catenin signaling, a central pathway of skeletal homeostasis. Lrp5/LRP5 deficiency results in osteoporosis-pseudoglioma (OPPG), whereas Sost/SOST deficiency induces lifelong bone gain in mice and humans. Here, we analyzed the bone phenotype of mice lacking Sost (Sost(-/-) ), Lrp5 (Lrp5(-/-) ), or both (Sost(-/-) ;Lrp5(-/-) ) to elucidate the mechanism of action of Sost in vivo. Sost deficiency-induced bone gain was significantly blunted in Sost(-/-) ;Lrp5(-/-) mice. Yet the Lrp5 OPPG phenotype was fully rescued in Sost(-/-) ;Lrp5(-/-) mice and most bone parameters were elevated relative to wild-type. To test whether the remaining bone increases in Sost(-/-) ;Lrp5(-/-) animals depend on Lrp6, we treated wild-type, Sost(-/-) , and Sost(-/-) ;Lrp5(-/-) mice with distinct Lrp6 function blocking antibodies. Selective blockage of Wnt1 class-mediated Lrp6 signaling reduced cancellous bone mass and density in wild-type mice. Surprisingly, it reversed the abnormal bone gain in Sost(-/-) and Sost(-/-) ;Lrp5(-/-) mice to wild-type levels irrespective of enhancement or blockage of Wnt3a class-mediated Lrp6 activity. Thus, whereas Sost deficiency-induced bone anabolism partially requires Lrp5, it fully depends on Wnt1 class-induced Lrp6 activity. These findings indicate: first, that OPPG syndrome patients suffering from LRP5 loss-of-function should benefit from principles antagonizing SOST/sclerostin action; and second, that therapeutic WNT signaling inhibitors may stop the debilitating bone overgrowth in sclerosing disorders related to SOST deficiency, such as sclerosteosis, van Buchem disease, and autosomal dominant craniodiaphyseal dysplasia, which are rare disorders without viable treatment options

Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats

RATIONALE: Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the Bed Nucleus of the Stria Terminalis (BNST) which have been implicated in the production of anxiogenic states. OBJECTIVES: The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration. METHODS: Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0μg/side) were administered to inhibit local 5-HT release via activation of 5-HT(1B) autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT(1B) antagonist NAS-181. RESULTS: Intra-BNST infusions of the 5-HT(1B) autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT(1B) antagonist. Neither start latencies (a measure of the subject’s motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment. CONCLUSIONS: Inhibition of 5-HT(1B) signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug

Differential vulnerability to relapse into heroin versus cocaine-seeking as a function of setting

RATIONALE Previous studies have shown that the effect of setting on drug-taking is substance specific in both humans and rats. In particular, we have shown that when the setting of drug self-administration (SA) coincides with the home environment of the rats (resident rats), the rats tend to prefer heroin to cocaine. The opposite was found in nonresident rats, for which the SA chambers represented a distinct environment. OBJECTIVES The aim of the present study was to investigate the influence of setting on the ability of different doses of cocaine and heroin to prime cocaine- versus heroin-seeking in rats that had been trained to self-administer both drugs and had then undergone an extinction procedure. METHODS Resident (N = 62) and nonresident (N = 63) rats with double-lumen intra-jugular catheters were trained to self-administer cocaine (400 μg/kg/infusion) and heroin (25 μg/kg/infusion) on alternate days for 10 consecutive daily sessions (3 h each). After the extinction phase, independent groups of rats were given a noncontingent intravenous infusion of heroin (25, 50, or 100 μg/kg) or cocaine (400, 800, or 1600 μg/kg), and drug-seeking was quantified by counting nonreinforced lever presses. RESULTS All resident and nonresident rats acquired heroin and cocaine SA. However, cocaine primings reinstated cocaine-seeking only in nonresident rats, whereas heroin primings reinstated heroin-seeking only in resident rats. CONCLUSIONS We report here that the susceptibility to relapse into drug-seeking behavior is drug-specific and setting-specific, confirming the crucial role played by drug, set, and setting interactions in drug addiction