Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals

Deep Brain Stimulation Reveals a Dissociation of Consummatory and Motivated Behaviour in the Medial and Lateral Nucleus Accumbens Shell of the Rat

Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa

Unidirectional relationship between heroin self-administration and impulsive decision-making in rats

Rationale: There is growing clinical evidence for a strong relationship between drug addiction and impulsivity. However, it is not fully clear whether impulsivity is a pre-existing trait or a consequence of drug abuse. Recent observations in the animal models show that pre-existing levels of impulsivity predict cocaine and nicotine seeking. Whether such relationships also exist with respect to non-stimulant drugs is largely unknown. Objective: We studied the relationship between impulsive choice and vulnerability to heroin taking and seeking. Materials and methods: Rats were selected in the delayed reward task based on individual differences in impulsive choice. Subsequently, heroin intravenous self-administration behaviour was analysed, including acquisition of heroin intake, motivation, extinction and drug- and cue-induced reinstatement. Throughout the entire experiment, changes in impulsive choice were monitored weekly. Results and discussion: High impulsivity did not predict measures of heroin taking. Moreover, high impulsive rats did not differ from low impulsive rats in extinction rates or heroin- and cue-induced reinstatement. However, both groups became more impulsive as heroin self-administration continued. During abstinence, impulsivity levels returned towards baseline (pre-heroin) levels. Our results indicate that, in contrast to psychostimulants, impulsive choice does not predict vulnerability to heroin seeking and taking. Conclusion: These data implicate that different neural mechanisms may underlie the vulnerability to opiate and psychostimulant dependence. Moreover, our data suggest that elevated impulsivity levels as observed in heroin-dependent subjects are a consequence of heroin intake rather than a pre-existing vulnerability trait. © 2011 The Author(s)

Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies Genome Editing Techniques and Their Therapeutic Applications

The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2