Tests of emotionality conducted outside the home-cage show that rodents from standard laboratory housing are more anxious than animals from enriched housing; however, it is not known if this also indicates increased anxiety within the home-cage. We used a novel method, recording the self-administration of a psychoactive anxiolytic, to examine home-cage anxiety levels of laboratory mice (three per cage) in Standard (n = 10 cages), Unpredictable (n = 10 cages) and Enriched (n = 6 cages) housing. The mice were given a choice of drinking either non-drugged water or a solution of the benzodiazepine Midazolam. There was a significant effect of housing on the proportion of total fluid consumed from the bottle containing Midazolam solution (P = 0.02). Mice from Standard and Unpredictable cages drank a greater proportion than mice from Enriched cages. This indicates that mice from the Standard and Unpredictable laboratory caging may have been experiencing greater anxiety than mice from the Enriched cages. There was also a significant effect of bottle position (P = 0.002). Mice from the Standard and Unpredictable cages drank a greater proportion of total fluid from the bottle containing Midazolam solution when this was toward the rear of the cage rack, ie in a location that was less susceptible to extraneous disturbance. Monitoring self-administration of psychoactive drugs as a method of welfare assessment could be applied to a wide variety of housing conditions, husbandry practices, or experimental procedures that putatively induce negative mental states. The major finding is that standard cages for laboratory rodents may induce greater anxiety than enriched cages. This is discussed in terms of animal welfare and the validity of data from animals housed in minimalistic environments.

Monoamine releasers with varying selectivity for dopamine (DA)/norepinephrine and serotonin (5-HT) release are potential treatment medications for cocaine abuse. Although DA-selective monoamine releasers effectively reduce cocaine abuse, their clinical usefulness is limited by abuse liability. It is hypothesized that increasing 5-HT neurotransmission may reduce the abuse-related effects of DA releasers, but the optimal DA:5-HT release ratio remains to be determined. This study in rhesus monkeys compared the effects of two compounds with differing potency for 5-HT release. Methcathinone and 3-Cl-methcathinone (PAL-434) have equal potency for DA release, but PAL-434 has 10-fold higher potency for 5-HT release. In drug discrimination studies, monkeys were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline in a two-key, food-reinforced procedure. In drug self-administration studies, a separate group of monkeys was trained to respond for cocaine [0.01 mg/kg/injection (inj)] and food (1 g pellets) under a second order schedule of reinforcement [FR2(VR16:S)]. When responding was stable, methcathinone (0.1–0.56 mg/kg.h i.v.) or PAL-434 (0.32–1.8 mg/kg.h i.v.) was administered chronically (one injection every 20 min for 23 h/d) for 7–10 d. In discrimination studies, both compounds dose-dependently increased cocaine-like responding but with different potencies (cocaine=methcathinone >PAL-434). Chronic treatment with methcathinone or PAL-434 dose-dependently and selectively reduced cocaine self-administration. PAL-434 was about 4-fold and methcathinone about 1.6-fold more potent at decreasing cocaine- over food-maintained responding. These data suggest that compounds with moderate selectivity for DA vs. 5-HT release (8–15-fold) may be effective for the treatment of cocaine dependence.

Brain-derived neurotrophic factor (BDNF) dynamic changes were investigated in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during use and the early phases of cocaine abstinence after 14 sessions (2 h self-administration/d; 0.25 mg/0.1 ml.6 s infusion) by employing a ‘yoked control-operant paradigm’. The effect on BDNF was region-specific and dependent on the withdrawal time. In the NAc, BDNF protein levels increased immediately after the last self-administration session, with a larger increase in passively cocaine-exposed rats. In the mPFC, BDNF expression was elevated 24 h after the last self-administration session, independently of how the drug was encountered. No changes were found in NAc and mPFC 7 d after the last self-administration session. Analysis of transcript levels in the mPFC indicated that action on exon I might contribute to BDNF's cortical induction. These findings indicate a finely tuned modulation of BDNF expression during use and early phases of cocaine abstinence.

Nicotine addiction represents a major health problem in the world with dramatic socio-economic consequences. Recent studies using genetically modified mice have provided a better understanding of the neurobiological mechanisms involved in nicotine responses. However, the study of nicotine addiction requires sophisticated behavioural models that are still not fully developed in mice. Here, we report the validation of a new reliable operant model of nicotine-seeking behaviour in mice. C57BL/6 mice were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio 1 schedule of reinforcement for 10 d. A light cue was contingently associated with the nicotine infusion. After reaching the acquisition criteria of nicotine self-administration, mice were exposed to extinction sessions similar to the self-administration training except that nicotine was not available and the associated cues were not presented. Nicotine-seeking behaviour was then reinstated by exposure to nicotine-associated environment cues, a priming injection of nicotine or stress, the three main conditions leading to nicotine relapse in humans. The exposure to the cues associated with nicotine infusion was the most effective stimulus reinstating nicotine-seeking behaviour in 90% of mice. A priming injection of nicotine (0.18 mg/kg) produced nicotine reinstatement in 30% of the animals, whereas stress exposure (0.22 mA footshock) reinstated nicotine-seeking behaviour in 50% of mice. The validation of this new model of nicotine-seeking behaviour and reinstatement in mice provides an important tool to help clarify the genetic and neurochemical bases of nicotine addiction.