Reward-Related Behavioral Paradigms for Addiction Research in the Mouse: Performance of Common Inbred Strains

The mouse has emerged as a uniquely valuable species for studying the molecular and genetic basis of complex behaviors and modeling neuropsychiatric disease states. While valid and reliable preclinical assays for reward-related behaviors are critical to understanding addiction-related processes, and various behavioral procedures have been developed and characterized in rats and primates, there have been relatively few studies using operant-based addiction-relevant behavioral paradigms in the mouse. Here we describe the performance of the C57BL/6J inbred mouse strain on three major reward-related paradigms, and replicate the same procedures in two other commonly used inbred strains (DBA/2J, BALB/cJ). We examined Pavlovian-instrumental transfer (PIT) by measuring the ability of an auditory cue associated with food reward to promote an instrumental (lever press) response. In a separate experiment, we assessed the acquisition and extinction of a simple stimulus-reward instrumental behavior on a touchscreen-based task. Reinstatement of this behavior was then examined following either continuous exposure to cues (conditioned reinforcers, CRs) associated with reward, brief reward and CR exposure, or brief reward exposure followed by continuous CR exposure. The third paradigm examined sensitivity of an instrumental (lever press) response to devaluation of food reward (a probe for outcome insensitive, habitual behavior) by repeated pairing with malaise. Results showed that C57BL/6J mice displayed robust PIT, as well as clear extinction and reinstatement, but were insensitive to reinforcer devaluation. DBA/2J mice showed good PIT and (rewarded) reinstatement, but were slow to extinguish and did not show reinforcer devaluation or significant CR-reinstatement. BALB/cJ mice also displayed good PIT, extinction and reinstatement, and retained instrumental responding following devaluation, but, unlike the other strains, demonstrated reduced Pavlovian approach behavior (food magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research

Preventive drugs in the last year of life of older adults with cancer: Is there room for deprescribing?

BACKGROUND: The continuation of preventive drugs among older patients with advanced cancer has come under scrutiny because these drugs are unlikely to achieve their clinical benefit during the patients' remaining lifespan. METHODS: A nationwide cohort study of older adults (those aged ≥65 years) with solid tumors who died between 2007 and 2013 was performed in Sweden, using routinely collected data with record linkage. The authors calculated the monthly use and cost of preventive drugs throughout the last year before the patients' death. RESULTS: Among 151,201 older persons who died with cancer (mean age, 81.3 years [standard deviation, 8.1 years]), the average number of drugs increased from 6.9 to 10.1 over the course of the last year before death. Preventive drugs frequently were continued until the final month of life, including antihypertensives, platelet aggregation inhibitors, anticoagulants, statins, and oral antidiabetics. Median drug costs amounted to $1482 (interquartile range [IQR],$700-$2896]) per person, including$213 (IQR, $77-$490) for preventive therapies. Compared with older adults who died with lung cancer (median drug cost, $205; IQR,$61-$523), costs for preventive drugs were higher among older adults who died with pancreatic cancer (adjusted median difference,$13; 95% confidence interval, $5-$22) or gynecological cancers (adjusted median difference, $27; 95$18-$36). There was no decrease noted with regard to the cost of preventive drugs throughout the last year of life. CONCLUSIONS: Preventive drugs commonly are prescribed during the last year of life among older adults with cancer, and often are continued until the final weeks before death. Adequate deprescribing strategies are warranted to reduce the burden of drugs with limited clinical benefit near the end of life

Heroin versus cocaine: opposite choice as a function of context but not of drug history in the rat

Rationale Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine whereas rats tested outside the home prefer cocaine to heroin. Here we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. Methods Rats with double-lumen catheters were first trained to self-administer either heroin (25 μg/kg) or cocaine (400 μg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home) whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self-administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for 7 sessions. Results Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. Conclusion Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other

New technologies for examining neuronal ensembles in drug addiction and fear

Correlational data suggest that learned associations are encoded within neuronal ensembles. However, it has been difficult to prove that neuronal ensembles mediate learned behaviours because traditional pharmacological and lesion methods, and even newer cell type-specific methods, affect both activated and non-activated neurons. Additionally, previous studies on synaptic and molecular alterations induced by learning did not distinguish between behaviourally activated and non-activated neurons. Here, we describe three new approaches—Daun02 inactivation, FACS sorting of activated neurons and c-fos-GFP transgenic rats — that have been used to selectively target and study activated neuronal ensembles in models of conditioned drug effects and relapse. We also describe two new tools — c-fos-tTA mice and inactivation of CREB-overexpressing neurons — that have been used to study the role of neuronal ensembles in conditioned fear

Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats

RATIONALE: Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon. METHODS: Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context-cocaine (15 mg/kg, i.p.) and context-saline (1 ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15 mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2, 2 mg/kg, Experiment 2), using counterbalanced within-subjects testing designs. RESULTS: Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose-dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline. CONCLUSION: Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access

Differential vulnerability to relapse into heroin versus cocaine-seeking as a function of setting

RATIONALE Previous studies have shown that the effect of setting on drug-taking is substance specific in both humans and rats. In particular, we have shown that when the setting of drug self-administration (SA) coincides with the home environment of the rats (resident rats), the rats tend to prefer heroin to cocaine. The opposite was found in nonresident rats, for which the SA chambers represented a distinct environment. OBJECTIVES The aim of the present study was to investigate the influence of setting on the ability of different doses of cocaine and heroin to prime cocaine- versus heroin-seeking in rats that had been trained to self-administer both drugs and had then undergone an extinction procedure. METHODS Resident (N = 62) and nonresident (N = 63) rats with double-lumen intra-jugular catheters were trained to self-administer cocaine (400 μg/kg/infusion) and heroin (25 μg/kg/infusion) on alternate days for 10 consecutive daily sessions (3 h each). After the extinction phase, independent groups of rats were given a noncontingent intravenous infusion of heroin (25, 50, or 100 μg/kg) or cocaine (400, 800, or 1600 μg/kg), and drug-seeking was quantified by counting nonreinforced lever presses. RESULTS All resident and nonresident rats acquired heroin and cocaine SA. However, cocaine primings reinstated cocaine-seeking only in nonresident rats, whereas heroin primings reinstated heroin-seeking only in resident rats. CONCLUSIONS We report here that the susceptibility to relapse into drug-seeking behavior is drug-specific and setting-specific, confirming the crucial role played by drug, set, and setting interactions in drug addiction