Mike J.F. Robinson

Central but not peripheral beta-adrenergic antagonism blocks reconsolidation for a morphine place preference.

Blocking the process of memory reconsolidation by means of amnestic agents may prove to have therapeutic applications. Here we used a morphine-induced conditioned place preference as an index of drug seeking. After inducing in rats a preference for a distinctive compartment paired with morphine, the memory for drug experience was reactivated by a 20-min test session and saline, the beta-antagonist propranolol, or the peripherally acting beta-antagonist nadolol were administered. Animals which received saline or nadolol upon reactivation, or propanolol without memory reactivation, maintained their preference for the drug-paired compartment 24h and seven days later. However, animals that received propranolol upon reactivation no longer displayed a morphine preference on either test, although these animals once again expressed a preference when given a morphine-primed retest at 10 days. Our results suggest that beta-blockers may have potential for attenuating the impact of cue-induced craving which is a major cause of relapse in detoxified addicts.

Reward uncertainty enhances incentive salience attribution as sign-tracking

Conditioned stimuli (CSs) come to act as motivational magnets following repeated association with unconditioned stimuli (UCSs) such as sucrose rewards. By traditional views, the more reliably predictive a Pavlovian CS-UCS association, the more the CS becomes attractive. However, in some cases, less predictability might equal more motivation. Here we examined the effect of introducing uncertainty in CS-UCS association on CS strength as an attractive motivation magnet. In the present study, Experiment 1 assessed the effects of Pavlovian predictability versus uncertainty about reward probability and/or reward magnitude on the acquisition and expression of sign-tracking (ST) and goal-tracking (GT) responses in an autoshaping procedure. Results suggested that uncertainty produced strongest incentive salience expressed as sign-tracking. Experiment 2 examined whether a within-individual temporal shift from certainty to uncertainty conditions could produce a stronger CS motivational magnet when uncertainty began, and found that sign-tracking still increased after the shift. Overall, our results support earlier reports that ST responses become more pronounced in the presence of uncertainty regarding CS-UCS associations, especially when uncertainty combines both probability and magnitude. These results suggest that Pavlovian uncertainty, although diluting predictability, is still able to enhance the incentive motivational power of particular CSs.

Reconsolidation of a morphine place preference: impact of the strength and age of memory on disruption by propranolol and midazolam.

Reactivation of memories may render them labile and subject to disruption by amnestic drugs thus reducing their impact on future behavior, but whether it is possible with well-established memories is not known. Here we examined the effect of two amnestic agents on reconsolidation of a conditioned place preference (CPP) for morphine when memory strength and memory age were varied. In a three-compartment apparatus animals received 4 or 8 experiences of morphine in one compartment and saline in the alternative compartment. The memory was then reactivated drug-free, and immediately afterwards animals received an injection of propranolol (10mg/kg, SC), midazolam (1mg/kg, IP), both amnestic agents combined, or saline. Animals conditioned with 4 pairings were re-tested 2 and 7 days after reactivation. After conditioning with 8 drug experiences memories were reactivated and treated 8 times, once every 48h, beginning 1 or 30 days after training. Propranolol, midazolam and their combination, disrupted reconsolidation for weak memories (4 pairings), but had little effect on stronger memories (8 pairings) reactivated 1 day after training. Extending the reactivation-amnestic treatments to 8 sessions did not disrupt the strong memory. Delaying reactivation sessions by 30 days enabled all three amnestic treatments to disrupt reconsolidation. Repeating amnestic treatment appeared to increase the effect of midazolam, but combining propranolol and midazolam did not enhance the amnestic effect. The amount of training and the age of the memory may be boundary conditions for reconsolidation.

Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity

Pavlovian cues associated with junk-foods (caloric, highly sweet, and/or fatty foods), like the smell of brownies, can elicit craving to eat and increase the amount of food consumed. People who are more susceptible to these motivational effects of food cues may have a higher risk for becoming obese. Further, overconsumption of junk-foods leading to the development of obesity may itself heighten attraction to food cues. Here, we used a model of individual susceptibility to junk-foods diet-induced obesity to determine whether there are pre-existing and/or diet-induced increases in attraction to and motivation for sucrose-paired cues (ie, incentive salience or ‘wanting’). We also assessed diet- vs obesity-associated alterations in mesolimbic function and receptor expression. We found that rats susceptible to diet-induced obesity displayed heightened conditioned approach prior to the development of obesity. In addition, after junk-food diet exposure, those rats that developed obesity also showed increased willingness to gain access to a sucrose cue. Heightened ‘wanting’ was not due to individual differences in the hedonic impact (‘liking’) of sucrose. Neurobiologically, Mu opioid receptor mRNA expression was lower in striatal ‘hot-spots’ that generate eating or hedonic impact only in those rats that became obese. In contrast, prolonged exposure to junk-food resulted in cross-sensitization to amphetamine-induced locomotion and downregulation of striatal D2R mRNA regardless of the development of obesity. Together these data shed light on individual differences in behavioral and neurobiological consequences of exposure to junk-food diets and the potential contribution of incentive sensitization in susceptible individuals to greater food cue-triggered motivation.

Received signal strength based location estimation of a wireless LAN client

We consider the problem of identifying the location of a mobile client in an IEEE 802.11b wireless LAN. We propose an estimation algorithm that utilizes received signal strength (RSS) measurements provided by most 802.11b physical layer implementations. In contrast to traditional radio map-based methods that require a burdensome map building phase, the proposed algorithm requires no prior training by employing a probabilistic RSS model that is derived from indoor signal propagation models and the blueprint of the building in which the location estimation system is being deployed. Experimental studies demonstrate the accuracy of the proposed method.

Effects of anisomycin on consolidation and reconsolidation of a morphine-conditioned place preference

Protein synthesis inhibitors block consolidation of memory and may also block the reconsolidation of a reactivated memory in paradigms of aversive learning, but the evidence for reconsolidation effects is conflicting in appetitive paradigms. We now report that intra-cerebroventricular (ICV) anisomycin (400microg) prevents consolidation of morphine-induced place preference (CPP), but does not impair its reconsolidation unless the reactivation procedure associates anisomycin with the morphine context. Rats were injected alternately with morphine (5mg/kg, IP) or vehicle, and confined to one of two distinctive compartments in a three compartment apparatus. On a subsequent day rats were allowed to choose the compartment they preferred in a 20min test session. In the first experiment, rats that were injected with vehicle or with anisomycin before or 3h after training sessions, developed a CPP. However, rats that received anisomycin ICV immediately after training sessions did not develop a CPP. In experiment 2, rats received no ICV injections during initial training. Once a CPP was established, they received four additional training sessions on which they received vehicle or anisomycin ICV. All groups continued to prefer the morphine-paired compartment after reactivation sessions with vehicle or anisomycin ICV. In experiment 3, ICV anisomycin was administered selectively on morphine-paired reactivation trials or saline-paired reactivation trials and the CPP was weakened or strengthened, respectively. This suggests that associations between aversive effects of the amnestic treatment and the morphine context might mimic disruption of reconsolidation.

Optogenetic Excitation of Central Amygdala Amplifies and Narrows Incentive Motivation to Pursue One Reward Above Another

Choosing one reward above another is important for achieving adaptive life goals. Yet hijacked into excessive intensity in disorders such as addiction, single-minded pursuit becomes maladaptive. Here, we report that optogenetic channelrhodopsin stimulation of neurons in central nucleus of amygdala (CeA), paired with earning a particular sucrose reward in rats, amplified and narrowed incentive motivation to that single reward target. Therefore, CeA rats chose and intensely pursued only the laser-paired sucrose reward while ignoring an equally good sucrose alternative. In contrast, reward-paired stimulation of basolateral amygdala did not hijack choice. In a separate measure of incentive motivation, CeA stimulation also increased the progressive ratio breakpoint or level of effort exerted to obtain sucrose reward. However, CeA stimulation by itself failed to support behavioral self-stimulation in the absence of any paired external food reward, suggesting that CeA photo-excitation specifically transformed the value of its external reward (rather than adding an internal reinforcement state). Nor did CeA stimulation by itself induce any aversive state that motivated escape. Finally, CeA stimulation also failed to enhance ‘liking’ reactions elicited by sucrose taste and did not simply increase the general motivation to eat. This pattern suggests that CeA photo-excitation specifically enhances and narrows incentive motivation to pursue an associated external reward at the expense of another comparable reward.

Amphetamine-induced sensitization and reward uncertainty similarly enhance incentive salience for conditioned cues.

Amphetamine and stress can sensitize mesolimbic dopamine-related systems. In Pavlovian autoshaping, repeated exposure to uncertainty of reward prediction can enhance motivated sign-tracking or attraction to a discrete reward-predicting cue (lever-conditioned stimulus; CS+), as well as produce cross-sensitization to amphetamine. However, it remains unknown how amphetamine sensitization or repeated restraint stress interact with uncertainty in controlling CS+ incentive salience attribution reflected in sign-tracking. Here rats were tested in 3 successive phases. First, different groups underwent either induction of amphetamine sensitization or repeated restraint stress, or else were not sensitized or stressed as control groups (either saline injections only, or no stress or injection at all). All next received Pavlovian autoshaping training under either certainty conditions (100% CS-UCS association) or uncertainty conditions (50% CS-UCS association and uncertain reward magnitude). During training, rats were assessed for sign-tracking to the CS+ lever versus goal-tracking to the sucrose dish. Finally, all groups were tested for psychomotor sensitization of locomotion revealed by an amphetamine challenge. Our results confirm that reward uncertainty enhanced sign-tracking attraction toward the predictive CS+ lever, at the expense of goal-tracking. We also reported that amphetamine sensitization promoted sign-tracking even in rats trained under CS-UCS certainty conditions, raising them to sign-tracking levels equivalent to the uncertainty group. Combining amphetamine sensitization and uncertainty conditions did not add together to elevate sign-tracking further above the relatively high levels induced by either manipulation alone. In contrast, repeated restraint stress enhanced subsequent amphetamine-elicited locomotion, but did not enhance CS+ attraction.

Initial uncertainty in Pavlovian reward prediction persistently elevates incentive salience and extends sign-tracking to normally unattractive cues.

Uncertainty is a component of many gambling games and may play a role in incentive motivation and cue attraction. Uncertainty can increase the attractiveness for predictors of reward in the Pavlovian procedure of autoshaping, visible as enhanced sign-tracking (or approach and nibbles) by rats of a metal lever whose sudden appearance acts as a conditioned stimulus (CS+) to predict sucrose pellets as an unconditioned stimulus (UCS). Here we examined how reward uncertainty might enhance incentive salience as sign-tracking both in intensity and by broadening the range of attractive CS+s. We also examined whether initially induced uncertainty enhancements of CS+ attraction can endure beyond uncertainty itself, and persist even when Pavlovian prediction becomes 100% certain. Our results show that uncertainty can broaden incentive salience attribution to make CS cues attractive that would otherwise not be (either because they are too distal from reward or too risky to normally attract sign-tracking). In addition, uncertainty enhancement of CS+ incentive salience, once induced by initial exposure, persisted even when Pavlovian CS-UCS correlations later rose toward 100% certainty in prediction. Persistence suggests an enduring incentive motivation enhancement potentially relevant to gambling, which in some ways resembles incentive-sensitization. Higher motivation to uncertain CS+s leads to more potent attraction to these cues when they predict the delivery of uncertain rewards. In humans, those cues might possibly include the sights and sounds associated with gambling, which contribute a major component of the play immersion experienced by problematic gamblers.

Incentive Salience and the Transition to Addiction

Most adults have used a potentially addictive drug at least once in their lifetime, if caffeine, alcohol, and nicotine are included in addition to illicit drugs. In some cases, contact with a substance is so frequent and socially accepted that many in society fail to recognize it as a “drug.” However, relatively few people develop sufficient problems with drug use to meet the formal criteria for addiction, even for potent illegal drugs such as cocaine or heroin. Drug addiction is characterized by compulsive drug seeking, an impairment of social and psychological functions and/or damage to one’s health. It typically involves overwhelming involvement with drug procurement and intake, a loss of control, and a narrowing of interests away from other forms of reward besides the drug of choice. According to a 2004 survey, less than 10% of the US population meet the criteria for alcohol abuse or any illegal drug abuse disorder, and an even smaller proportion suffer from chronic drug addiction. Yet, the worldwide monetary and social costs associated with drug control measures, corruption, lost productivity, and treatment of drug addiction are enormous. The chief problem in treating drug addiction is chronic or repeated relapse by those who have become addicted in the above sense. Even after prolonged periods of withdrawal and abstinence, a high percentage of addicted individuals in treatment programs eventually relapse to drug taking. For example, in the case of a study of heroin users, relapse rates to reuse after cessation were approximately 60% within 3 months and at least 75% within 12 months. For this reason, drug addiction is characterized as a chronic relapsing disorder; relapse is the rule rather than the exception and often occurs repeatedly. There are three reasons frequently suggested to explain relapse: (1) drug euphoria – that addicts resume drug taking to experience the intense pleasure