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The serotonin (5-HT) system, particularly the 5-HT2C receptor, has consistently been implicated in behavioural control. However, while some studies have focused on the role 5-HT2C receptors play in regulating motivation to work for reward, others have highlighted its importance in response restraint. To date, it is unclear how 5-HT transmission at this receptor regulates the balance of response invigoration and restraint in anticipation of future reward. In addition, it remains to be established how 5-HT2C receptors gate the influence of internal versus cue-driven processes over reward-guided actions. To elucidate these issues, we investigated the effects of administering the 5-HT2C receptor antagonist SB242084, both systemically and directly into the nucleus accumbens core (NAcC), in rats performing a Go/No-Go task for small or large rewards. The results were compared to the administration of d-amphetamine into the NAcC, which has previously been shown to promote behavioural activation. Systemic perturbation of 5-HT2C receptors—but crucially not intra-NAcC infusions—consistently boosted rats' performance and instrumental vigour on Go trials when they were required to act. Concomitantly, systemic administration also reduced their ability to withhold responding for rewards on No-Go trials, particularly late in the holding period. Notably, these effects were often apparent only when the reward on offer was small. By contrast, inducing a hyperdopaminergic state in the NAcC with d-amphetamine strongly impaired response restraint on No-Go trials both early and late in the holding period, as well as speeding action initiation. Together, these findings suggest that 5-HT2C receptor transmission, outside the NAcC, shapes the vigour of ongoing goal-directed action as well as the likelihood of responding as a function of expected reward. [ABSTRACT FROM AUTHOR]

[Display omitted] • Distinct anatomical inputs define anterior and posterior regions in rat lateral OFC. • Anterior–posterior differences as distinct as established medial–lateral ones in OFC. • Amygdala inputs to OFC predominantly target posterior lateral OFC. • Submedius thalamic input patterns are a key characteristic of distinct OFC subregions. • Anatomical heterogeneity within the OFC maps onto recent functional heterogeneity. The orbitofrontal cortex (OFC) has been anatomically divided into a number of subregions along its medial–lateral axis, which behavioral research suggests have distinct functions. Recently, evidence has emerged suggesting functional diversity is also present along the anterior–posterior axis of the rodent OFC. However, the patterns of anatomical connections that underlie these differences have not been well characterized. Here, we use the retrograde tracer cholera toxin subunit B (CTB) to simultaneously label the projections into the anterior lateral (ALO), posterior lateral (PLO), and posterior ventral (PVO) portions of the rat OFC. Our methodological approach allowed us to simultaneously compare the density and input patterns into these OFC subdivisions. We observed distinct and topographically organized projection patterns into ALO, PLO, and PVO from the mediodorsal and the submedius nuclei of the thalamus. We also observed different levels of connectivity strength into these OFC subdivisions from the amygdala, motor cortex, sensory cortices and medial prefrontal cortical structures, including medial OFC, infralimbic and prelimbic cortices. Interestingly, while labelling in some of these input regions revealed only a gradient in connectivity strength, other regions seem to project almost exclusively to specific OFC subdivisions. Moreover, differences in input patterns between ALO and PLO were as pronounced as those between PLO and PVO. Together, our results support the existence of distinct anatomical circuits within lateral OFC along its anterior–posterior axis. [ABSTRACT FROM AUTHOR]

Restricting when and where smoking can occur is a major focus of public health policies in Western countries. In conjunction with increased taxation, these approaches have contributed to a reduction in smoking uptake among adolescents, yet the consequences for established smokers are less clear. In order to further explore this relationship, we developed a novel animal model of restricted nicotine self-administration. Rats were trained to choose between three doses of nicotine (15, 30 and 60 μg/kg/infusion) under conditions where nicotine was (1) freely available at a low cost (20-second post-infusion time-out, fixed-ratio 1 [FR1]), (2) available under restricted access at a low cost (300-second post-infusion time-out, FR1), or (3) freely available at a high cost (20-second post-infusion time-out, FR5). We demonstrate that as access to nicotine is restricted or when cost increases, rats compensate for these changes by increasing their intake of the highest dose of nicotine available. This preference was impervious to treatment with the smoking cessation medication varenicline, but was reduced when the cost of the highest dose only was increased, or when nicotine was again made freely available at a low cost. These results provide the first evidence in rats that nicotine availability and cost influence nicotine choice independently of variations in nicotine and context exposure. They imply that established smokers may compensate for changes in the availability and cost of tobacco by increasing their rate of smoking when they are free to do so. [ABSTRACT FROM AUTHOR]