Drug-induced conditioned place preference and aversion in mice

Relapse to drug abuse is often caused by exposure to drug-associated cues that evoke craving. Therefore, disruption of the cue-drug memory can prevent relapse. Memories destabilize and become temporarily labile upon their retrieval, and re-stabilize in a process termed reconsolidation. Pharmacological disruption of reconsolidation prevents relapse in animal models, yet may evoke side effects. Therefore, behavioral procedures capable of preventing cue-induced craving and relapse are extremely valuable. Aversion therapies, in which drugpaired cues are re-associated (counterconditioned) with aversive consequences, have limited success, because the previous cue-drug memory may recover, triggering relapse. Here, we prevented the memory recovery and relapse to cocaine seeking by applying aversive counterconditioning during memory reconsolidation. Mice were trained to seek cocaine in a conditioned place preference procedure. The cocaine-associated compartment was then counterconditioned with lithium chloride (LiCl)-induced malaise, preceded by a brief exposure to the compartment (memory retrieval). Relapse was assessed in a reinstatement test. We found that aversive counterconditioning conducted shortly after memory retrieval (during reconsolidation) induced a long-lasting prevention of relapse to cocaine seeking. However, mice relapsed when counterconditioned without, before, or long after memory retrieval, or when receiving LiCl without place counterconditioning. Our findings suggest that post-retrieval aversive counterconditioning leads to relapse prevention, possibly by replacing the cue-drug with a cue-aversion memory, thereby the cue ceases to evoke craving. Moreover, we found that a similar memory replacement procedure prevented relapse of conditioned place aversion. Hence, this novel procedure can also prevent relapse of aversive memories, providing a safe approach to alter various maladaptive behaviors.

Section: Place Conditioning Counterconditioning and Reinstatementmentioning

confidence: 99%

Section: Experiments 1a and 1b: Aversive Counterconditioning During Mmentioning

confidence: 99%

Counterconditioning During Reconsolidation Prevents Relapse of Cocaine Memories

Goltseker¹,

Bolotin²,

Barak

2016

“…The procedure was performed in eight Plexiglas cages covered with transparent lids with ventilation holes (Cunningham et al, 2006;Vashchinkina et al, 2012). Two types of preselected floor material (plastic 1.2-cm-wide flat bars separated by 0.5-cm gaps and a metal grid with 1-mm-spacing between wires) were used as conditioning stimuli.…”

Section: Behavioral Experimentsmentioning

confidence: 99%

“…During 15-min preliminary tests for material preference, naive mice showed no preference for either one of the floor materials (data not shown). Therefore, we followed the unbiased conditioned place preference (CPP) procedure (Cunningham et al, 2006). Three independent batches of adult mice were tested.…”

Section: Behavioral Experimentsmentioning

confidence: 99%

Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons

Vashchinkina

Manner

Vekovischeva

et al. 2013

The main fast-acting inhibitory receptors in the mammalian brain are g-aminobutyric acid type-A (GABA A ) receptors for which neurosteroids, a subclass of steroids synthesized de novo in the brain, constitute a group of endogenous ligands with the most potent positive modulatory actions known. Neurosteroids can act on all subtypes of GABA A receptors, with a preference for d-subunitcontaining receptors that mediate extrasynaptic tonic inhibition. Pathological conditions characterized by emotional and motivational disturbances are often associated with perturbation in the levels of endogenous neurosteroids. We studied the effects of ganaxolone (GAN)-a synthetic analog of endogenous allopregnanolone that lacks activity on nuclear steroid receptors-on the mesolimbic dopamine (DA) system involved in emotions and motivation. A single dose of GAN in young mice induced a dose-dependent, longlasting neuroplasticity of glutamate synapses of DA neurons ex vivo in the ventral tegmental area (VTA). Increased a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate ratio and rectification of AMPA receptor responses even at 6 days after GAN administration suggested persistent synaptic targeting of GluA2-lacking AMPA receptors. This glutamate neuroplasticity was not observed in GABA A receptor d-subunit-knockout (d-KO) mice. GAN (500 nM) applied locally to VTA selectively increased tonic inhibition of GABA interneurons and triggered potentiation of DA neurons within 4 h in vitro. Place-conditioning experiments in adult wild-type C57BL/6J and d-KO mice revealed aversive properties of repeated GAN administration that were dependent on the d-subunits. Prolonged neuroadaptation to neurosteroids in the VTA might contribute to both the physiology and pathophysiology underlying processes and changes in motivation, mood, cognition, and drug addiction.

“…CPP paradigm was used as described in (Nuutinen et al, 2010a) and it followed the principles of an unbiased, fully counterbalanced conditioning described by (Cunningham et al, 2006). Conditioning cages were individual transparent plastic cages (42 Â 26 Â 20 cm) covered with clear plastic lids with ventilation holes.…”

Section: Alcohol-induced Cppmentioning

confidence: 99%

Evidence for the Role of Histamine H3 Receptor in Alcohol Consumption and Alcohol Reward in Mice

Nuutinen

Lintunen

Vanhanen

et al. 2011

Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a 'drinking in the dark' model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future.