Conditioned place preference (CPP) continues to be one of the most popular models to study the motivational effects of drugs and non-drug treatments in experimental animals. This is obvious from a steady year-to-year increase in the number of publications reporting the use this model. Since the compilation of the preceding review in 1998, more than 1000 new studies using place conditioning have been published, and the aim of the present review is to provide an overview of these recent publications. There are a number of trends and developments that are obvious in the literature of the last decade. First, as more and more knockout and transgenic animals become available, place conditioning is increasingly used to assess the motivational effects of drugs or non-drug rewards in genetically modified animals. Second, there is a still small but growing literature on the use of place conditioning to study the motivational aspects of pain, a field of pre-clinical research that has so far received little attention, because of the lack of appropriate animal models. Third, place conditioning continues to be widely used to study tolerance and sensitization to the rewarding effects of drugs induced by pre-treatment regimens. Fourth, extinction/reinstatement procedures in place conditioning are becoming increasingly popular. This interesting approach is thought to model certain aspects of relapse to addictive behavior and has previously almost exclusively been studied in drug self-administration paradigms. It has now also become established in the place conditioning literature and provides an additional and technically easy approach to this important phenomenon. The enormous number of studies to be covered in this review prevented in-depth discussion of many methodological, pharmacological or neurobiological aspects; to a large extent, the presentation of data had to be limited to a short and condensed summary of the most relevant findings.

Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade.

A stereotaxic atlas of the rat brain

Nitric oxide (NO) is a small highly diffusible gas and a ubiquitous bioactive molecule. Its chemical properties make NO a versatile signal molecule that functions through interactions with cellular targets via either redox or additive chemistry. In plants, NO plays a role in a broad spectrum of pathophysiological and developmental processes. Although nitric oxide synthase (NOS)-dependent NO production has been reported in plants, no gene, cDNA, or protein has been isolated to date. In parallel, precise and regulated NO production can be measured from the activity of the ubiquitous enzyme nitrate reductase (NR). In addition to endogenous NO formation, high NO emissions are observed from fertilized soils, but their effects on the physiology of plants are largely unknown. Many environmental and hormonal stimuli are transmitted either directly or indirectly by NO signaling cascades. The ability of NO to act simultaneously on several unrelated biochemical nodes and its redox homeostatic properties suggest that it might be a synchronizing molecule in plants.

Nitric oxide: the versatility of an extensive signal molecule.

Implication of free radical mechanisms in ethanol-induced cellular injury

Alcohol consumption is an integral part of daily life in many societies. The benefits associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societie...

Alcoholism: a systems approach from molecular physiology to addictive behavior.

Toll-like receptors (TLRs) play an important role in the innate immune response, and emerging evidence indicates their role in brain injury and neurodegeneration. Our recent results have demonstrated that ethanol is capable of activating glial TLR4 receptors and that the elimination of these receptors in mice protects against ethanol-induced glial activation, induction of inflammatory mediators and apoptosis. This study was designed to assess whether ethanol-induced inflammatory damage causes behavioral and cognitive consequences, and if behavioral alterations are dependent of TLR4 functions. Here we show in mice drinking alcohol for 5months, followed by a 15-day withdrawal period, that activation of the astroglial and microglial cells in frontal cortex and striatum is maintained and that these events are associated with cognitive and anxiety-related behavioral impairments in wild-type (WT) mice, as demonstrated by testing the animals with object memory recognition, conditioned taste aversion and dark and light box anxiety tasks. Mice lacking TLR4 receptors are protected against ethanol-induced inflammatory damage, and behavioral associated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioral effects associated with neuroinflammatory damage. We show that chronic alcohol treatment decreases H4 histone acetylation and histone acetyltransferases activity in frontal cortex, striatum and hippocampus of WT mice. Alterations in chromatin structure were not observed in TLR4(-/-) mice. These results provide the first evidence of the role that TLR4 functions play in the behavioral consequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-induced behavioral or cognitive dysfunctions.

Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage.

Ethanol metabolism in rat brain homogenates by a catalase-H2O2 system.

Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2.

The effect of 3-amino-1,2,4-triazole on voluntary ethanol consumption: evidence for brain catalase involvement in the mechanism of action.

There is evidence to suggest that acetaldehyde is involved in the control of ethanol-seeking behavior and reward. d-penicillamine, a thiol amino acid, is a highly selective agent for the inactivation of acetaldehyde. Previous studies from our laboratory have demonstrated that d-penicillamine prevents both behavioral stimulation induced by ethanol and acetaldehyde-produced locomotor depression in mice. The contribution of ethanol-derived acetaldehyde to the affective effects of ethanol (preference and aversion) was assessed using an unbiased place conditioning design. Male mice received four pairings of a distinctive floor stimulus (CS+: GRID+ or HOLE+) with injections of saline and ethanol (2 g/kg) given before (preference) or after (aversion) the 5-min exposure to the place conditioning apparatus. A different floor stimulus (CS−: GRID− or HOLE−), associated with saline-saline injections on alternate days, was presented. For a different group of animals, the pairings with the CS+ were associated with saline and ethanol injections, but on alternate days, they received d-penicillamine (50 or 75 mg/kg) and ethanol injections paired with the CS−floor stimulus. A 60-min preference test was carried out 24 h after the last conditioning trial. A similar procedure was followed to test the effect of d-penicillamine on morphine (16 mg/kg) and cocaine-induced (20 mg/kg) conditioned place preference (CPP). CPP and conditioned place aversion (CPA) were observed for ethanol, but d-penicillamine only blocked CPP. d-penicillamine, by itself, did not produce either rewarding or aversive effects. CPP observed for morphine and cocaine was unaffected by d-penicillamine pretreatment. The results of the present study suggest that the selective inactivation of acetaldehyde blocked the rewarding, but not aversive, effects of ethanol and support the role of this ethanol metabolite in the affective properties of ethanol.

Carlos M.G. Aragon

Papers

Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage.

Ethanol metabolism in rat brain homogenates by a catalase-H2O2 system.

Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: role of TLR4 and TLR2.

The effect of 3-amino-1,2,4-triazole on voluntary ethanol consumption: evidence for brain catalase involvement in the mechanism of action.

Ethanol-induced conditioned place preference, but not aversion, is blocked by treatment with D -penicillamine, an inactivation agent for acetaldehyde.