NM A22834 (Albrecht) 3 Across a spectrum of living organisms, ranging from cyanobacteria to humans, it has been observed that biological functions follow a pattern of circadian rhythmicity.These endogenous rhythms display a periodicity close to 24 hours in the absence of environmental cues, thus reflecting the existence of an intrinsic biological clock. In mammals, circadian rhythms in different tissues are coordinated by a master clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus 1 . This circadian clock is thought to be advantageous in synchronising physiological and biochemical pathways, allowing the organism to anticipate daily changes, thus ensuring better adaptation to the environment 2 .The oscillatory mechanism of the circadian clock has been unraveled by means of genetic analysis in Drosophila and mammals [3][4][5] . In the latter, the heterodimeric complex of two transcriptional activators, CLOCK and BMAL1 (MOP3), induce the expression of several genes by interacting with the enhancer elements, termed E-boxes, of their promoters. Amongst these genes are Per1, Per2, Cry1 and Cry2, whose protein products, upon entering the nucleus, inhibit the activity of the CLOCK/BMAL1 complex, and thereby generating an inhibitory feedback loop driving recurrent rhythms in mRNA and protein levels of their own genes. This molecular mechanism seems to be present in the local clocks of most tissues and brain regions. Furthermore, these different clocks may then be synchronized by the SCN via neural and endocrine outputs 6 . Transporter 1, also known as Glast) is found to be reduced in these mice. Excess glutamate is cleared from the synaptic cleft by glutamate transporters 10 , located on astroglial cells and transported back to the neuron via the glutamine-glutamate cycle.A deficit in the removal of glutamate from the synaptic cleft, results in a hyperglutamatergic state and is suggested to produce alterations at the behavioral level 10,11 .Importantly, a hyper-glutamatergic state has been implicated in the aetiology of alcohol dependence [12][13][14] . We observe that in Per2 Brdm1 mutant mice voluntary alcohol consumption is enhanced. In humans we find an association between alcoholic patients and genetic variations in the human PER2 gene. Acamprosate, a medication thought to dampen a hyper-glutamatergic state in the alcohol dependent human brain 15-17 reduces augmented glutamate levels and normalizes enhanced alcohol consumption in Per2 Brdm1 mutant mice. These findings support the view that a hyperglutamatergic state can be involved in several aspects of alcohol dependence [12][13][14][18][19][20] . RESULTS Glutamate transporters in Per2 Brdm1 miceWild type and Per2 Brdm1 mutant mice differ in their behavioral response to a light pulse administered at zeitgeber time (ZT) 14 9 (ZT0 corresponds to lights on and ZT12 to lights off). Therefore, we set out to search for a difference in gene expression between wild type and Per2 Brdm1 mutant mice at ZT15. This time point has been chosen beca...

Some psychoactive drugs are abused because of their ability to act as reinforcers. As a consequence behavioural patterns (such as drug-seeking/drug-taking behaviours) are promoted that ensure further drug consumption. After prolonged drug self-administration, some individuals lose control over their behaviour so that these drug-seeking/taking behaviours become compulsive, pervading almost all life activities and precipitating the loss of social compatibility. Thus, the syndrome of addictive behaviour is qualitatively different from controlled drug consumption. Drug-induced reinforcement can be assessed directly in laboratory animals by either operant or non-operant self-administration methods, by classical conditioning-based paradigms such as conditioned place preference or sign tracking, by facilitation of intracranial electric self-stimulation, or, alternatively by drug-induced memory enhancement. In contrast, addiction cannot be modelled in animals, at least as a whole, within the constraints of the laboratory. However, various procedures have been proposed as possible rodent analogues of addiction's major elements including compulsive drug seeking, relapse, loss of control/impulsivity, and continued drug consumption despite negative consequences. This review provides an extensive overview and a critical evaluation of the methods currently used for studying drug-induced reinforcement as well as specific features of addictive behaviour. In addition, comic strips that illustrate behavioural methods used in the drug abuse field are provided given for free download under http://www.zi-mannheim/psychopharmacology.de.

Cocaine strengthens excitatory synapses onto midbrain dopamine neurons through the synaptic delivery of GluR1-containing AMPA receptors. This cocaine-evoked plasticity depends on NMDA receptor activation, but its behavioral significance in the context of addiction remains elusive. Here, we generated mice lacking the GluR1, GluR2, or NR1 receptor subunits selectively in dopamine neurons. We report that in midbrain slices of cocaine-treated mice, synaptic transmission was no longer strengthened when GluR1 or NR1 was abolished, while in the respective mice the drug still induced normal conditioned place preference and locomotor sensitization. In contrast, extinction of drug-seeking behavior was absent in mice lacking GluR1, while in the NR1 mutant mice reinstatement was abolished. In conclusion, cocaine-evoked synaptic plasticity does not mediate concurrent short-term behavioral effects of the drug but may initiate adaptive changes eventually leading to the persistence of drug-seeking behavior.

Negative cognitive biasFthe tendency to interpret ambiguous situations pessimisticallyFis a central feature of stress-related disorders such as depression. The underlying neurobiology of this bias, however, remains unclear, not least because of a lack of translational tools. We established a new ambiguous-cue interpretation paradigm and, with respect to the etiology of depression, evaluated if environmental and genetic factors contribute to a negative bias. Rats were trained to press a lever to receive a food reward contingent to one tone and to press another lever in response to a different tone to avoid punishment by electric foot-shock. In the ambiguous-cue test, the leverpress responses to tones with frequencies intermediate to the trained tones were taken as indicators for the rats' expectation of a positive or negative event. A negative response bias because of decreased positive and increased negative responding was found in congenitally helpless rats, a genetic animal model of depression. Moreover, treatment with a combined noradrenergic-glucocorticoid challenge, mimicking stress-related changes in endogenous neuromodulation, biased rats away from positive responding. This response shift was accompanied by neuronal activation in dentate gyrus and amygdala. Thus, environmental and genetic risk factors for depression induce a response bias, which resembles the pessimistic bias of patients suffering from depression. The behavioral paradigm described constitutes a useful tool to study the neuronal basis of decision making under ambiguous conditions and may promote innovative pharmaco-and psychotherapy for depression.

Background: Recent evidence suggests that epigenetic mechanisms have an important role in the development of addictive behavior. However, little is known about the role of epigenetic mechanisms in the extinction of drug-induced behavioral changes. In this study we examined the ability of histone deacetylase (HDAC) inhibitors to facilitate extinction and attenuate reinstatement of cocaine-induced conditioned place preference (CPP). Methods: C57BL/6 mice were subject to cocaine-induced CPP using 20mg/kg dose. To facilitate extinction, mice were administered an HDAC inhibitor following non-reinforced exposure to the conditioned context. To measure persistence, mice were subject to a reinstatement test using 10mg/kg dose of cocaine. Results: We demonstrate that HDAC inhibition during extinction consolidation can facilitate extinction of cocaine-induced CPP. Animals treated with an HDAC inhibitor extinguished cocaine-induced CPP both more quickly and to a greater extent than did vehicle-treated animals. We also show that the extinction of context-drug associated memories via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. Acetylation of histone H3 in the nucleus accumbens following extinction was increased by HDAC inhibition. Conclusions: This study provides the first evidence that modulation of chromatin modification can facilitate extinction and prevent reinstatement of drug-induced behavioral changes. These findings provide a potential novel approach to the development of treatments that facilitate extinction of drug-seeking behavior.

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Craving and relapse are core symptoms of drug addiction and alcoholism. It is suggested that, after chronic drug consumption, longlasting neuroplastic changes within the glutamatergic system are important determinants of addictive behavior. Here, we show that the AMPA type glutamate receptor plays a crucial role in alcohol craving and relapse. We observed, in two animal models of alcohol craving and relapse, that the AMPA antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine] dosedependently reduced cue-induced reinstatement of alcohol-seeking behavior and the alcohol deprivation effect. The involvement of the AMPA receptor in these phenomena was further studied using mice deficient for the GluR-C AMPA subunit [GluR-C knock-out (KO)]. GluR-C KOs displayed a blunted, cue-induced reinstatement response and alcohol deprivation effect, when compared with wild-type controls; however, no differences between genotypes could be observed regarding ethanol self-administration under operant or home cage drinking conditions. These results imply a role for GluR-C in alcohol relapse, although this phenotype could also be attributable to a reduction in the total number of AMPA receptors in specific brain areas. In conclusion, AMPA receptors seem to be involved in the neuroplastic changes underlying alcohol seeking behavior and relapse. Thus, AMPA receptors represent a novel therapeutic target in preventing relapse.