Relapse after intermittent access to cocaine: Discriminative cues more effectively trigger drug seeking than do conditioned cues.

RATIONALE: When people with drug addiction encounter cues associated with drug use, this can trigger cravings and relapse. These cues can include conditioned stimuli (CSs) signaling drug delivery and discriminative stimuli (DSs) signaling drug availability. Compared to CS effects, DS effects are less explored in preclinical studies on cue-induced relapse. OBJECTIVE: We compared CS and DS effects on reward seeking following abstinence from intermittent-access cocaine (or sucrose) self-administration. METHODS: During 15-20 intermittent-access sessions, rats self-administered i.v. cocaine or sucrose pellets paired with a light-tone CS. Cocaine/sucrose was available for 5-min (signalled by a light; DS+) and unavailable for 25 min (signalled by different lighting conditions; DS-), and this cycled for 4 h/session. Following abstinence, we measured cocaine/sucrose seeking under extinction triggered by CS and DS presentation, and instrumental responding reinforced by these cues. RESULTS: Across intermittent-access sessions, rats increased lever pressing for cocaine or sucrose during DS+ periods and decreased responding during DS- periods. On days 2 and 21 of abstinence, only presentation of the DS+ or DS+ and CS combined elicited increased cocaine/sucrose-seeking behaviour (i.e., increased active lever presses). Presenting the DS- alongside the DS+ suppressed the increased cocaine-seeking behaviour otherwise produced by the DS+ . Finally, on day 21 of abstinence, rats showed equivalent levels of lever pressing reinforced by the DS+ , CS and by the DS+ and CS combined, suggesting comparable conditioned reinforcing value. CONCLUSIONS: After intermittent self-administration, cocaine-associated DSs and CSs acquire similar conditioned reinforcing properties, but DSs more effectively trigger increases in drug seeking.

Unpredictable, intermittent access to sucrose or water promotes increased reward pursuit in rats.

Reward uncertainty can sensitize reward pathways, promoting increased reward-seeking and -taking behaviours. This is relevant to human conditions such as pathological gambling, eating disorders and drug addiction. In the context of addiction, preclinical self-administration procedures have been developed to model the intermittency of human drug use. These intermittent-access (IntA) procedures involve intermittent but predictable access to drug during self-administration sessions. However, human drug use typically involves intermittent and unpredictable drug access. We introduce a new procedure modeling unpredictable, intermittent access (UIntA) to a reinforcer, and we compare it to procedures that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Female rats self-administered water or liquid sucrose in daily hour-long sessions. IntA and ContA rats had access to a fixed volume of water or sucrose (0.1 ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had predictable 5-min reinforcer ON and 25-min reinforcer OFF periods. ContA rats had 60 min of reinforcer access during each session. For UIntA rats, variation in the length of ON and OFF periods (1, 5 or 9 min/period), response requirement (variable ratio 3 schedule of reinforcement), reinforcer probability (50%) and quantity (0, 0.1 or 0.2 ml) introduced reward uncertainty. Following 14 daily self-administration sessions, UIntA rats showed the highest levels of responding for water or sucrose under progressive ratio conditions, responding under extinction conditions, and cue-induced reinstatement of sucrose seeking. Thus, unpredictable, intermittent reward access promotes increased reward pursuit. This has implications for modeling addiction and other disorders of increased reward seeking.

Metabotropic group II glutamate receptors mediate cue-triggered increases in reward-seeking behaviour.

RATIONALE: Reward-associated cues can invigorate reward-seeking actions via Pavlovian-to-instrumental transfer (PIT). Glutamatergic neurotransmission mediates the appetitive effects of reward-associated cues. We characterized the expression of PIT and its mediation by metabotropic group II glutamate (mGlu2/3) receptor activity in female and male rats. OBJECTIVES: Across the sexes, we used PIT procedures to determine (i) cue-triggered increases in instrumental responding for water reward (experiment 1) and (ii) the respective influences of the mGlu2/3 receptor agonist LY379268 and thirst satiation on this effect (experiment 2). METHODS: Water-restricted female and male Sprague-Dawley rats learned to lever press for water. Separately, they learned that one of two auditory stimuli predicts free water (CS + vs CS -). On PIT test days, the CS + and CS - were presented independent of instrumental responding, and we measured effects on lever pressing under extinction (no water). In experiment 1, we characterized PIT across the sexes. In experiment 2, we measured PIT after systemic LY379268 administration (0, 0.3 and 1 mg/kg) and thirst satiation, respectively. RESULTS: Female and male rats showed similar PIT, with CS + but not CS - presentations potentiating water-seeking behaviour. LY379268 (1 mg/kg) attenuated CS + evoked increases in both water-associated lever pressing and conditioned approach to the water port. Thirst satiation attenuated both water-seeking and CS + evoked conditioned approach behaviour. CONCLUSIONS: The sexes show similar cue-triggered increases in reward seeking, and thirst satiation suppresses both water-seeking and cue-triggered anticipation of water reward. Finally, across the sexes, mGlu2/3 receptor activity mediates cue-triggered increases in reward seeking.

Quantifying the instrumental and noninstrumental underpinnings of Pavlovian responding with the Price equation.

The Price equation is a mathematical expression of selectionist and non-selectionist pressures on biological, cultural, and behavioral change. We use it here to specify instrumental and noninstrumental behaviors as they arise within the context of the Pavlovian autoshaping procedure, for rats trained under reward certainty and reward uncertainty. The point of departure for this endeavor is that some portion of autoshaped behavior referred to as goal-tracking appears instrumental-a function of resource attainment (the individual approaches the location where the unconditioned stimulus is to be delivered). By contrast, some other portion of autoshaped behavior referred to as sign-tracking is noninstrumental-irrelevant to making contact with the to-be-delivered unconditioned stimulus. A Price equation model is proposed that unifies our understanding of Pavlovian autoshaping behavior by isolating operant and respondent influences on goal-tracking (instrumental) and sign-tracking (noninstrumental) behavior.

Optogenetic Stimulation of the Central Amygdala Using Channelrhodopsin.

Optogenetics allows for the targeted temporary inhibition or stimulation of specific brain regions in vivo with precise temporal resolution. Here, we describe the steps to perform intracranial optogenetic surgery in rodents as well as instructions to build an optogenetic headcap and set up an optogenetic testing environment to conduct experiments. Behavioral studies have implemented these methods to stimulate the central amygdala (CeA) to create an addictive-like preference for reward.

A novel seed treatment-based multiplication approach for cassava planting material.

Cassava (Manihot esculenta Crantz) is an important food security crop in many parts of the developing world. The crop's high yield potential and multitude of uses-both for nutrition and processing-render cassava a promising driver for the development of rural value chains. It is traditionally propagated from stem cuttings of up to 30 cm in length, giving a multiplication rate as low as 1:10. Propagating cassava traditionally is very inefficient, which leads to challenges in the production and distribution of quality planting material and improved cultivars, greatly limiting the impact of investments in crop breeding. The work described in the present study aimed to develop a seed treatment approach to facilitate the use of shorter seed pieces, increasing the multiplication rate of cassava and thus making the crop's seed systems more efficient. After several tests, formulation was identified, consisting of thiamethoxam 21 g ha-1, mefenoxam 1.0 g ha-1, fludioxonil 1.3 g ha-1, thiabendazole 7.5 g ha-1 and Latex 2% as a binder. Plant growing from seed pieces treated with this formulation displayed increased crop establishment and early crop vigor, leading to an improved productivity throughout a full growing cycle. This allowed to reduce the cassava seed piece size to 8 cm with no negative effects on germination and crop establishment, leading to yields comparable to those from untreated 16 cm pieces. This, in turn, will allow to increase the multiplication ratio of cassava by a factor of up to 3. Notably, this was possible under regular field conditions and independently of any specialised treatment facilities. Compared with existing seed production protocols, the increased multiplication rates allowed for efficiency gains of between 1 to 1.9 years compared to conventional five-year cycles. We believe that the technology described here holds considerable promise for developing more reliable and remunerative delivery channels for quality cassava planting material and improved genetics.

From sign-tracking to attentional bias: Implications for gambling and substance use disorders.

Sign-tracking behavior in Pavlovian autoshaping is known to be a relevant index of the incentive salience attributed to reward-related cues. Evidence has accumulated to suggest that animals that exhibit a sign-tracker phenotype are especially vulnerable to addiction and relapse due to their proneness to attribute incentive salience to drug cues, and their relatively weak cognitive and attentional control over their behavior. Interestingly, sign-tracking is also influenced by reward uncertainty in a way that may promote gambling disorder. Research indicates that reward uncertainty sensitizes sign-tracking responses and favors the development of a sign-tracker phenotype, compatible with the conditioned attractiveness of lights and sounds in casinos for problem gamblers. The study of attentional biases in humans (an effect akin to sign-tracking in animals) leads to similar observations, notably that the propensity to develop attraction for conditioned stimuli (CSs) is predictive of addictive behavior. Here we review the literature on drug addiction and gambling disorder, highlighting the similarities between studies of sign-tracking and attentional biases.

Reward uncertainty attributes incentive value to reward proximal cues, while amphetamine sensitization reverts attention to more predictive reward distal cues.

Slot-machine gambling incorporates numerous audiovisual cues prior to and during reward delivery (e.g. spinning wheels, flashing lights, celebratory sounds). Over time, these cues may motivate playing and even elicit cravings and relapse in those affected by gambling disorder. Animal studies suggest a heightened attraction to these cues despite diminished predictive ability under reward uncertainty, as evidenced by sign-tracking behavior in rats. Repeated amphetamine administration may also enhance the incentive value attributed to cues. Here, we explored the impact of reward uncertainty and prior amphetamine sensitization on the relative attractiveness and conditioned reinforcing properties of serial Pavlovian cues with different degrees of predictive and incentive value in rats. Animals were sensitized through repeated injections of amphetamine (1-4 mg/kg) or saline and then trained in a Pavlovian autoshaping task involving two sequential lever-auditory cue combinations (CS1, CS2) under Certain (100%-1) or Uncertain (50%-1-2-3) reward conditions. Subsequently, we evaluated the impact of acute amphetamine exposure on cue attraction. Our results suggest that Uncertainty alone enhanced attraction towards the reward-proximal CS2. However, combined sensitization and Uncertainty reversed cue preference relative to Uncertainty alone, enhancing attraction towards the more predictive reward-distal CS1. Both cues acquired conditioned reinforcing properties, despite the CS2 being otherwise ignored in all groups besides Uncertainty. However, combined sensitization and Uncertainty increased the reinforcing value of both cues and doubled the amount of interaction with the CS1 lever per presentation. Our results imply competitive mechanisms for attributing incentive value to gambling-related cues between reward uncertainty, prior amphetamine sensitization, and acute amphetamine administration.

Nineteenth-century nanotechnology: The plasmonic properties of daguerreotypes.

Plasmons, the collective oscillations of mobile electrons in metallic nanostructures, interact strongly with light and produce vivid colors, thus offering a new route to develop color printing technologies with improved durability and material simplicity compared with conventional pigments. Over the last decades, researchers in plasmonics have been devoted to manipulating the characteristics of metallic nanostructures to achieve unique and controlled optical effects. However, before plasmonic nanostructures became a science, they were an art. The invention of the daguerreotype was publicly announced in 1839 and is recognized as the earliest photographic technology that successfully captured an image from a camera, with resolution and clarity that remain impressive even by today's standards. Here, using a unique combination of daguerreotype artistry and expertise, experimental nanoscale surface analysis, and electromagnetic simulations, we perform a comprehensive analysis of the plasmonic properties of these early photographs, which can be recognized as an example of plasmonic color printing. Despite the large variability in size, morphology, and material composition of the nanostructures on the surface of a daguerreotype, we are able to identify and characterize the general mechanisms that give rise to the optical response of daguerreotypes. Therefore, our results provide valuable knowledge to develop preservation protocols and color printing technologies inspired by past ones.

Distinguishing between predictive and incentive value of uncertain gambling-like cues in a Pavlovian autoshaping task.

The flashing lights and celebratory sounds that dominate slot-machine gambling are believed to promote engagement and motivation to keep playing. However, these cues are often presented in the absence of reward, and previous research suggests that this reward uncertainty, which degrades their predictive value, also increases their incentive value. Here, we used autoshaping to tease apart the impact of reward uncertainty on the predictive and incentive value of a conditioned stimulus (CS) using serial cues. Each CS trial began with the presentation of a predictive CS1, followed by a CS2, holding primarily incentive value, because of its proximity to sucrose reward delivery, under Certain (100%-1) or Uncertain (50%-1- 2-3) reward conditions. Subsequently, we tested the impact of amphetamine and nicotine on cue attraction, and the ability of these cues to either serve as a conditioned reinforcer, or promote motivation for sucrose during a progressive ratio task. Finally, we measured anxiety behavior, and examined its interaction with each cue and uncertainty. Our results suggest that reward uncertainty increases attraction to the incentive CS2 and its ability to trigger motivation and reward-seeking. However, although the CS2 is largely ignored under Certain conditions, both CS1 and CS2 become conditioned reinforcers for both groups. Finally, amphetamine reduced the attraction of the CS1 for both groups but had no effect on the attraction of the CS2. These results suggest that reward uncertainty recruits and increases the incentive value of cues with limited predictive value and highlights the distinction between cue attraction, reward-seeking and conditioned reinforcer properties.

Evidence for motivational enhancement of sign-tracking behavior under reward uncertainty.

Reward uncertainty has been shown to invigorate rather than attenuate cue attraction and responding. For example, a number of findings have shown that partial reinforcement in autoshaping increases response rates to a conditioned stimulus (conditional stimulus) in comparison with continuous reinforcement. However, identifying the nature of this effect remains a topical question. The frustration theory posits that animals are frustrated by reward loss and predicts that enhanced responding results from higher response rates to conditional stimulus presentations that follow nonrewarded trials rather than rewarded trials. In contrast, the incentive hope hypothesis suggests that animals are motivated by possible future rewards and predicts similar response rates after rewarded and nonrewarded trials. Our results, which consist of a reanalysis of previously published data (Hellberg, Levit, & Robinson, 2018), are consistent with the incentive hope hypothesis because no differences were found between trials that follow rewarded or nonrewarded trials, or between trials that follow small or larger amounts of food reward in rats. There was also no evidence for an accumulation of frustration across each training session, with rats instead displaying enhanced yet stable responding from beginning to end. The incentive hope hypothesis is also briefly discussed in relation to the concept of incentive salience. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Hoarding all of the chips: Slot machine gambling and the foraging for coins.

Predictions made by the "incentive hope" hypothesis account for overconsumption in unpredictable food environments. However, when applied to uncertain gambling situations, there are several areas where this theory falls short. Most notably, it has trouble explaining why, in slot machine gambling, players are motivated by extended play to spend time trying to resolve uncertainty, rather than hoarding monetary gains.

Effects of nicotine exposure and anxiety on motivation for reward and gambling-like cues under reward uncertainty.

Reward uncertainty is a common characteristic of gambling and may powerfully enhance attraction to gambling-related cues, thus promoting maladaptive gambling behaviors in susceptible individuals. The co-occurrence of gambling disorder with tobacco use disorder (60.4%) suggests a common mechanism for their pathology, and comorbid anxiety (41.3%) might further promote the maintenance of these behaviors. However, it is unknown how nicotine or anxiety might contribute to cue and reward attraction, or promote disordered gambling behavior. In the present study, we investigated the effects of nicotine (0.4 mg/kg, SC) on the desire for uncertain rewards and their cues in male and female Sprague-Dawley rats. During an autoshaping task, rats learned to associate a lever + tone cue with the delivery of sucrose pellet rewards under either certain or uncertain (probability and magnitude) reward conditions. Subsequently, we tested the ability of gambling-like cues to serve as a conditioned reinforcer, and to promote motivation for sucrose rewards during a progressive ratio task. Finally, anxiety behavior was measured to examine its interaction with nicotine and uncertainty. Here, we found that nicotine enhanced attraction to the magazine under certain but not uncertain reward conditions, and increased cue-triggered behaviors. Conversely, in the progressive ratio task, exposure to uncertain conditions and nicotine enhanced motivation for reward, compared with certain conditions. These results suggest that nicotine may interact with both certain and uncertain reward conditions to increase cue-triggered behavior and enhance motivation for rewards, providing possible insight into the comorbid relationship between pathological gambling and tobacco use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Optogenetic activation of the central amygdala generates addiction-like preference for reward.

Drug and behavioural addictions are characterized by an intense and focused pursuit of a single reward above all others. Pursuit of the addictive reward is often compulsively sought despite adverse consequences and better alternative outcomes. Here, we explored the ability of the central amygdala (CeA) to powerfully bias choice, causing specific rewards to be almost compulsively preferred. Rats were trained on an operant choice task in which they could choose to respond on either of the two levers to receive a sucrose reward, one of which was paired with optogenetic stimulation of the CeA using channelrhodopsin-2 (ChR2). Rats developed an almost exclusive preference for the laser-paired reward over the otherwise equal unpaired reward. We found that this preference for stimulation-paired reward persists even when a much larger sucrose reward is offered as an alternative (contingency management) or when this preferred reward is paired with adverse consequences such as progressively larger electric foot shock, time delays or effort requirements. We also report that when challenged with foot shock, a small proportion of these animals (≈20%) retained an exclusive laser-paired reward preference, whereas others began to seek the alternate reward when the shock reached high levels. Lastly, we confirmed that optogenetic CeA stimulation was not independently rewarding if delivered in the absence of a paired sucrose reward. These results suggest a role for the CeA in focusing motivation and desire to excessive levels, generating addiction-like behaviour that persists in the face of more rewarding alternatives and adverse consequences.

Cued for risk: Evidence for an incentive sensitization framework to explain the interplay between stress and anxiety, substance abuse, and reward uncertainty in disordered gambling behavior.

Gambling disorder is an impairing condition confounded by psychiatric co-morbidity, particularly with substance use and anxiety disorders. Yet, our knowledge of the mechanisms that cause these disorders to coalesce remains limited. The Incentive Sensitization Theory suggests that sensitization of neural "wanting" pathways, which attribute incentive salience to rewards and their cues, is responsible for the excessive desire for drugs and cue-triggered craving. The resulting hyper-reactivity of the "wanting' system is believed to heavily influence compulsive drug use and relapse. Notably, evidence for sensitization of the mesolimbic dopamine pathway has been seen across gambling and substance use, as well as anxiety and stress-related pathology, with stress playing a major role in relapse. Together, this evidence highlights a phenomenon known as cross-sensitization, whereby sensitization to stress, drugs, or gambling behaviors enhance the sensitivity and dopaminergic response to any of those stimuli. Here, we review the literature on how cue attraction and reward uncertainty may underlie gambling pathology, and examine how this framework may advance our understanding of co-mordidity with substance-use disorders (e.g., alcohol, nicotine) and anxiety disorders. We argue that reward uncertainty, as seen in slot machines and games of chance, increases dopaminergic activity in the mesolimbic pathway and enhances the incentive value of reward cues. We propose that incentive sensitization by reward uncertainty may interact with and predispose individuals to drug abuse and stress, creating a mechanism through which co-mordidity of these disorders may emerge.

Optogenetic self-stimulation in the nucleus accumbens: D1 reward versus D2 ambivalence.

The nucleus accumbens (NAc) contains multiple subpopulations of medium spiny neurons (MSNs). One subpopulation expresses D1-type dopamine receptors, another expresses D2-type receptors, and a third expresses both. The relative roles in NAc of D1 neurons versus D2 neurons in appetitive motivation were assessed here. Specifically, we asked whether D1-Cre mice would instrumentally seek optogenetic self-stimulation specifically targeted at D1 MSNs in NAc, and similarly if D2-Cre mice would self-stimulate D2 neurons in NAc. Mice were implanted with Cre-targeted channelrhodopsin (ChR2) virus and optic fibers in NAc. Subsequently, mice could earn brief NAc laser illuminations by actively touching a metal spout in one task, or by going to a particular location in a separate task. Results indicated that D1 neuronal excitation in NAc supported intense self-stimulation in both tasks. D1-Cre mice earned hundreds to thousands of spout-touches per half-hour session, and also sought out locations that delivered NAc laser to excite D1 MSNs. By comparison, D2 ChR2 mice showed lower but still positive levels of self-stimulation in the spout-touch task, earning dozens to hundreds of NAc laser illuminations. However, in the location task, D2 mice failed to show positive self-stimulation. If anything, a few D2 individuals gradually avoided the laser location. Brain-wide measures indicated that D1 and D2 stimulations in NAc recruited heavily overlapping patterns of Fos activation in distant limbic structures. These results confirm that excitation of D1 MSNs in NAc supports strong incentive motivation to self-stimulate. They also suggest that excitation of D2 neurons in NAc supports self-stimulation under some conditions, but fails under others and possibly may even shift to negative avoidance.

Under the influence: Effects of adolescent ethanol exposure and anxiety on motivation for uncertain gambling-like cues in male and female rats.

Gambling disorder (GD) frequently co-occurs with alcohol use and anxiety disorders, suggesting possible shared mechanisms. Recent research suggests reward uncertainty may powerfully enhance attraction towards reward cues. Here, we examined the effects of adolescent ethanol exposure, anxiety, and reward uncertainty on cue-triggered motivation. Male and female adolescent rats were given free access to ethanol or control jello for 20days. Following withdrawal, rats underwent autoshaping on a certain (100%-1) or uncertain (50%-1-2-3) reward contingency, followed by single-session conditioned reinforcement and progressive ratio tasks, and 7days of omission training, during which lever pressing resulted in omission of reward. Finally, anxiety levels were quantified on the elevated plus maze. Here, we found that uncertainty narrowed cue attraction by significantly increasing the ratio of sign-tracking to goal-tracking, particularly amongst control jello and high anxiety animals, but not in animals exposed to ethanol during adolescence. In addition, attentional bias towards the lever cue was more persistent under uncertain conditions following omission training. We also found that females consumed more ethanol, and that uncertainty mitigated the anxiolytic effects of ethanol exposure observed in high ethanol intake animals under certainty conditions. Our results further support that reward uncertainty biases attraction towards reward cues, suggesting also that heightened anxiety may enhance vulnerability to the effects of reward uncertainty. Chronic, elevated alcohol consumption may contribute to heightened anxiety levels, while high anxiety may promote the over-attribution of incentive value to reward cues, highlighting possible mechanisms that may drive concurrent anxiety, heavy drinking, and problematic gambling.