Gary Aston-Jones

Orexins (hypocretins) are involved in a large variety of behaviors and physiological processes including feeding, sleep/wake regulation, and reward. In this perspective, the authors propose a unifying function for orexins in translating motivational activation into sets of processes that support adaptive behaviors. 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.

Significance: Cocaine addiction is a major public health problem with no current pharmacotherapy approved by the US Food and Drug Administration. To accelerate discovery of treatments, we developed an animal model based on economics. Economics allows mathematical alignment of animal and human behavior, permitting more confident predictions of efficacy in addicts. Although economic models are strongly associated with addiction severity in humans, they have not yet been shown to be a marker of addiction in rats. In this report, we confirm that economic demand is strongly associated with addiction-like behavior in rats, and can predict the efficacy of a promising addiction therapy. Our findings indicate that this economic approach can be used to accelerate the development of novel addiction therapies.

Significance: Thousands of people each day receive general anesthesia. Recovery from the anesthetic state is a passive process that can be variable and unpredictable. Identifying neural systems involved in recovery of consciousness after general anesthesia is fundamental to optimizing anesthetic safety and our knowledge of anesthetic action. We examined how norepinephrine from the nucleus locus coeruleus (LC) affects general anesthesia, and found that blocking the action of norepinephrine, particularly in the CNS, delayed recovery from general anesthesia. Using genetic tools to selectively activate only LC neurons, we found that LC activation was sufficient to alter EEG measurements of anesthetic depth and accelerate recovery of consciousness. Our data show that LC activity can alter the anesthetic state, and that noradrenergic medications may affect clinical responses to anesthetic agents.

Recent studies have shown that post-retrieval extinction training attenuates fear and reward-related memories in both humans and rodents. This noninvasive, behavioral approach has the potential to be used in clinical settings to treat maladaptive memories that underlie several psychiatric disorders, including drug addiction. However, few studies to date have used a post-retrieval extinction approach to attenuate addiction-related memories. In the current study, we attempted to disrupt cocaine-related memories by using the post-retrieval extinction paradigm in male Sprague Dawley rats. Results revealed that starting extinction training 1 h after cocaine contextual memory was retrieved significantly attenuated cocaine-primed reinstatement of conditioned place preference (CPP) and relapse of cocaine CPP (drug-free and cocaine-primed) following 30 days of abstinence. However, animals that did not retrieve the contextual cocaine memory before extinction training, or animals that began extinction training 24 h after retrieval (outside of the reconsolidation window), demonstrated normal cocaine CPP. Conversely, animals that received additional CPP conditioning, rather than extinction training, 1 h after reactivation of cocaine memory showed enhanced cocaine CPP compared with animals that did not reactivate the cocaine memory before conditioning. These results reveal that a behavioral manipulation that takes advantage of reconsolidation and extinction of drug memories may be useful in decreasing preference for, and abuse of, cocaine.

Rationale The orexin (Orx)/hypocretin system has been implicated in reward-seeking, especially for highly salient food and drug rewards. We recently demonstrated that signaling at the OxR1 receptor is involved in sucrose reinforcement and reinstatement of sucrose-seeking elicited by sucrose-paired cues in food-restricted rats. Because sucrose reinforcement has both a hedonic and caloric component, it remains unknown what aspect of this reward drives its reinforcing value. Objectives The present study examined the involvement of the Orx system in operant responding for saccharin, a noncaloric, hedonic (sweet) reward, and in cue-induced reinstatement of extinguished saccharin-seeking in ad libitum-fed vs food-restricted male subjects. Methods Male Sprague Dawley rats were fed ad libitum or food-restricted and trained to self-administer saccharin. We determined the effects of pretreatment with the OxR1 receptor antagonist SB-334867 (SB; 10–30 mg/kg) on fixed ratio (FR) saccharin self-administration and on cue-induced reinstatement of extinguished saccharin-seeking. Results SB decreased responding and number of reinforcers earned during FR responding for saccharin and decreased cue-induced reinstatement of extinguished saccharin-seeking. All of these effects were obtained similarly in food-restricted and ad libitum-fed rats. Conclusions These results indicate that signaling at the OxR1 receptor is involved in saccharin reinforcement and reinstatement of saccharin-seeking elicited by saccharin-paired cues regardless of food restriction. These findings lead us to conclude that the Orx system contributes to the motivational effects of hedonic food rewards, independently of caloric value and homeostatic needs.

Rationale The orexin/hypocretin system has recently been implicated in reward-seeking, especially for highly salient food and drug rewards. We reasoned that this system may be strongly engaged during periods of reward restriction, including food restriction. Objectives This study examined the involvement of the orexin (Orx) system in responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed versus food-restricted male subjects. Methods Sprague–Dawley rats (n = 108) were trained to self-administer sucrose, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB-334867 (SB; 10–30 mg/kg) on fixed ratio (FR) or progressive ratio (PR) sucrose self-administration, as well as on cue-induced reinstatement of sucrose-seeking. Finally, expression of the immediate early gene c-fos in Orx neurons was examined after self-administration, late extinction or cue-induced reinstatement of sucrose seeking. Results SB decreased lever responding (by about 1/3) and the number of reinforcers earned during FR, and less so during PR, schedules and decreased cue-induced reinstatement to sucrose-seeking to extinction levels, predominately in food-restricted rats. Additionally, Fos expression in Orx neurons in perifornical and dorsomedial hypothalamus was increased during extinction. Conclusions These results indicate that signaling at the OxR1 receptor is involved in pronounced sucrose reinforcement, and reinstatement of sucrose-seeking elicited by sucrose-paired cues, in food-restricted subjects. These findings lead us to conclude that conditioned activation of Orx neurons increases motivation for food reward during food restriction.

Rationale Behavioral–economic demand curve analysis offers several useful measures of drug self-administration. Although generation of demand curves previously required multiple days, recent within-session procedures allow curve construction from a single 110-min cocaine self-administration session, making behavioral–economic analyses available to a broad range of self-administration experiments. However, a mathematical approach of curve fitting has not been reported for the within-session threshold procedure. Objectives We review demand curve analysis in drug self-administration experiments and provide a quantitative method for fitting curves to single-session data that incorporates relative stability of brain drug concentration. Methods Sprague–Dawley rats were trained to self-administer cocaine, and then tested with the threshold procedure in which the cocaine dose was sequentially decreased on a fixed ratio-1 schedule. Price points (responses/mg cocaine) outside of relatively stable brain cocaine concentrations were removed before curves were fit. Curve-fit accuracy was determined by the degree of correlation between graphical and calculated parameters for cocaine consumption at low price (Q ₀) and the price at which maximal responding occurred (P _max). Results Removing price points that occurred at relatively unstable brain cocaine concentrations generated precise estimates of Q ₀ and resulted in P _max values with significantly closer agreement with graphical P _max than conventional methods. Conclusion The exponential demand equation can be fit to single-session data using the threshold procedure for cocaine self-administration. Removing data points that occur during relatively unstable brain cocaine concentrations resulted in more accurate estimates of demand curve slope than graphical methods, permitting a more comprehensive analysis of drug self-administration via a behavioral–economic framework.