Translating concepts of risk and loss in rodent models of gambling and the limitations for clinical applications.

Gambling involves placing something of value at risk in exchange for the opportunity to potentially gain something of greater value in return. A variety of gambling paradigms have been designed to study the maladaptive decision-making that underlies problematic gambling. Central to these gambling models are the definitions of "risk" and "loss", especially when translating the results from rodent studies to clinical applications. Risk and loss are not mutually exclusive but rather share some overlap. With careful interpretation and consideration of the limitations of these behavioral paradigms, results from rodent models may provide insights into the neurobiology of risky decision-making that leads to problematic gambling in humans.

Roles of "Wanting" and "Liking" in Motivating Behavior: Gambling, Food, and Drug Addictions.

The motivation to seek out and consume rewards has evolutionarily been driven by the urge to fulfill physiological needs. However in a modern society dominated more by plenty than scarcity, we tend to think of motivation as fueled by the search for pleasure. Here, we argue that two separate but interconnected subcortical and unconscious processes direct motivation: "wanting" and "liking." These two psychological and neuronal processes and their related brain structures typically work together, but can become dissociated, particularly in cases of addiction. In drug addiction, for example, repeated consumption of addictive drugs sensitizes the mesolimbic dopamine system, the primary component of the "wanting" system, resulting in excessive "wanting" for drugs and their cues. This sensitizing process is long-lasting and occurs independently of the "liking" system, which typically remains unchanged or may develop a blunted pleasure response to the drug. The result is excessive drug-taking despite minimal pleasure and intense cue-triggered craving that may promote relapse long after detoxification. Here, we describe the roles of "liking" and "wanting" in general motivation and review recent evidence for a dissociation of "liking" and "wanting" in drug addiction, known as the incentive sensitization theory (Robinson and Berridge 1993). We also make the case that sensitization of the "wanting" system and the resulting dissociation of "liking" and "wanting" occurs in both gambling disorder and food addiction.

The effect of propranolol dose and novelty of the reactivation procedure on the reconsolidation of a morphine place preference.

Previously consolidated memories may become labile when they are reactivated and require reconsolidation. It has been suggested that when novel information is present at the time of memory reactivation reconsolidation is engaged but when no new information is present, reconsolidation may not occur, and extinction may be the dominant process instead. To test this idea we trained rats to associate a context with the rewarding properties of morphine (5 mg/kg, sc) over four conditioning pairings. Following training, animals were reactivated by a 30-min test session, once a day for 3 days. Rats were injected with the amnestic drug propranolol (10 or 40 mg/kg, sc) following reactivation either on the first or on the second day. They received saline on the alternate day. Propranolol disrupted reconsolidation for a conditioned place preference only when given on the first reactivation day, and this effect was more robust following the higher dose of propranolol. In contrast, animals given propranolol on the second reactivation day still displayed a preference for the morphine-paired context on the final test day. These results support the view that for memory to return to a labile state, the situation that evokes reactivation needs to be novel in some way. If the reactivation situation is familiar, reconsolidation may not occur.

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.

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.

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.