Ventral pallidum (VP) is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to ventral tegmental area (VTA) regulates neuronal activity there. However, VP is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. Here we demonstrate that projections to VTA from rostral (RVP), but not caudal VP (CVP) are robustly Fos-activated during cue-induced reinstatement of cocaine seeking—a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA, or functional connectivity between RVP and VTA dopamine neurons blocks the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition instead blocked cocaine-primed, but not cue-induced reinstatement. This novel double dissociation in VP sub-regional roles in drug seeking is likely important for understanding mesocorticolimbic circuits underlying reward seeking and addiction.

Orexins (hypocretins) are two peptides (orexin A and B) produced from the pre-pro-orexin precursor and expressed in a limited region of dorsolateral hypothalamus. Orexins were originally thought to specifically mediate feeding and promote wakefulness, but it is now clear that they participate in a wide range of behavioral and physiological processes under select circumstances. Orexins primarily mediate behavior under situations of high motivational relevance, such as during physiological need states, exposure to threats or reward opportunities. We hypothesize that many behavioral functions of orexins (including regulation of sleep/wake cycling) reflect a fundamentally integrated function for orexins in translating motivational activation into organized suites of psychological and physiological processes supporting adaptive behaviors. We also discuss how numerous forms of neural heterogeneity modulate this function, allowing orexin neurons to organize diverse, adaptive responses in a variety of motivationally relevant situations. Thus, the involvement of orexins in diverse behaviors may reflect a common underlying function for this peptide system.

Cannabinoid drugs such as D 9 -THC are euphoric and rewarding, and also stimulate food intake in humans and animals. Little is known about how naturally occurring endogenous brain cannabinoids mediate pleasure from food or other natural sensory rewards. The taste reactivity paradigm measures effects of brain manipulations on affective orofacial reactions to intraorally administered pleasant and unpleasant tastes. Here we tested if anandamide microinjection into medial nucleus accumbens shell enhances these affective reactions to sweet and bitter tastes in rats. Anandamide doubled the number of positive 'liking' reactions elicited by intraoral sucrose, without altering negative 'disliking' reactions to bitter quinine. Anandamide microinjections produced Fos plumes of approximately 0.02-1 mm 3 volume. Plume-based maps, integrated with behavioral data, identified the medial shell of accumbens as the anatomical hotspot responsible for hedonic amplification. Anandamide produced especially intense hedonic enhancement in a roughly 1.6 mm 3 'hedonic hotspot' in dorsal medial shell, where anandamide also stimulated eating behavior. These results demonstrate that endocannabinoid signals within medial accumbens shell specifically amplify the positive hedonic impact of a natural reward (though identification of the receptor specificity of this effect will require future studies). Identification of an endocannabinoid hotspot for sensory pleasure gives insight into brain mechanisms of natural reward, and may be relevant to understanding the neural effects of cannabinoid drugs of abuse and therapeutic agents.

Orexins/hypocretins are hypothalamic peptides involved in arousal and wakefulness, but also play a critical role in drug addiction and reward-related behaviors. Here, we review the roles played by orexins in a variety of animal models of drug addiction, emphasizing both commonalities and differences for orexin’s involvement in seeking of the major classes of abused drugs, as well as food. One common theme that emerges is an involvement of orexins in drug seeking triggered by external stimuli (e.g., cues, contexts or stressors). We also discuss the functional neuronal circuits in which orexins are embedded, and how these circuits mediate addiction-related behaviors, with particular focus on the role of orexin and glutamate interactions within the ventral tegmental area. Finally, we attempt to contextualize the role of orexins in reward by discussing ways in which these peptides, expressed in only a few thousand neurons in the brain, can have such wide-ranging effects on behavior.

The central nucleus of the amygdala (CeA) helps translate learning into motivation, and here, we show that opioid stimulation of CeA magnifies and focuses learned incentive salience onto a specific reward cue (pavlovian conditioned stimulus, or CS). This motivation enhancement makes that cue more attractive, noticeable, and liable to elicit appetitive and consummatory behaviors. To reveal the focusing of incentive salience, we exploited individual differences in an autoshaping paradigm in which a rat prefers to approach, nibble, and sniff one of two reward-associated stimuli (its prepotent stimulus). The individually prepotent cue is either a predictive CSϩ that signals reward (8 s metal lever insertion) or instead the metal cup that delivers sucrose pellets (the reward source). Results indicated that CeA opioid activation by microinjection of the agonist DAMGO (0.1 g) selectively and reversibly enhanced the attractiveness of whichever reward CS was that rat's prepotent cue. CeA DAMGO microinjections made rats more vigorously approach their particular prepotent CS and to energetically sniff and nibble it in a nearly frenzied consummatory manner. Only the prepotent cue was enhanced as an incentive target, and alternative cues were not enhanced. Conversely, inactivation of CeA by muscimol microinjection (0.25 g) suppressed approach, nibbles, and sniffs of the prepotent CS. Confirming modulation of incentive salience, unconditioned food intake was similarly increased by DAMGO microinjection and decreased by muscimol in CeA. We conclude that opioid neurotransmission in CeA helps determine which environmental stimuli become most "wanted," and how "wanted" they become. This may powerfully guide reward-seeking behavior.