Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior

The Last Glacial Maximum in the Tropics: Human Responses to Global Change, 30–10 ka

The world at 18,000 BP, published by Gamble and Soffer (The world at 18,000 BP. Vol. 2: low latitude, Unwin Hyman, 1990), represents the first, and so far the only, attempt at characterising and discussing the impact of the Last Glacial Maximum (LGM) on human societies on a global scale. At the time, they highlighted that research and data on the LGM in southern latitudes and the tropics in particular were scant. Since 1990, however, many sites dated to the LGM and located in tropical latitudes have been published. Many paradigms have changed regarding the peopling of the Americas, which allows the archaeology of this continent to be integrated into global scale studies of the LGM. The development of Pleistocene archaeology in tropical contexts, in parallel with methodological advances in cultural, geosciences and palaeoenvironmental studies have strongly reshaped what we know of the antiquity of human occupation in tropical regions and specific human–environment interactions. This article provides for the first time a pan-tropical perspective on the impact of the LGM on human groups living within the tropical latitudes, drawing from case studies in Southeast Asia, Africa and South America, specifically regions which have up until now never been discussed together. To this end, we focus on six different tropical regions between 30 and 10 ka. We present the archaeological and paleoenvironmental data available in these areas, along with proposed relationships for variations in these two records. Finally, we discuss at the regional scale the presence or absence of human changes (site density and techno-cultural change or continuity) before, during and immediately after the LGM.Introduction What are the Tropics? Last Glacial Maximum The Last Glacial Maximum in the Tropics: Some Consequences for the Preservation of Pleistocene Archaeological Sites A Qualitative Approach to Track the Last Glacial Maximum in the Tropics Regional Overviews West Africa (c. 6 million km2) Archaeological Assemblages Dated to the Period 30–10 ka Palaeoenvironmental Data for the Period 30–10 ka Human–Environment Interactions in the Period 30–10 ka in West Africa Central Africa (Congo Basin: c. 3.8 Million km2) Cultural Diversification in Central Africa from c. 40 ka Asynchronous Environmental Changes During the Last Glacial Maximum Across Central Africa Horn of Africa (c. 1.8 million km2) Site Distribution in Light of Regional Environmental Diversity Human–Environment Interaction at the Local Scale Discussion Mainland Southeast Asia (c. 2.5 million km2) The Example of One Cave in Cambodia: Laang Spean Regional Human–Environment Interactions Around the Last Glacial Maximum in Mainland Southeast Asia Insular Southeast Asia (c. 2 million km2) Significance of Song Terus Cave (Central Java, Indonesia) Ambarawa Significance of Tabon Cave (Palawan Island, the Philippines) Discussion Central Brazil (c. 2 million km2) Focus on the Stratigraphic Sequence of Santa Elina Discussion Different Types of Last Glacial Maximum Archaeological Data in the Tropics A Changing Environment at the Last Glacial Maximum in the Tropics? Low Sea Levels and Palaeolandscapes of Continental Shelves in the Tropics at the Last Glacial Maximum Site Distribution over the Period 30–10 ka Cultural Changes over the Period 30–10 ka Some Conclusion

Natural Reward Experience Alters AMPA and NMDA Receptor Distribution and Function in the Nucleus Accumbens

Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS3) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward

Arqueologia e história indígena no Pantanal

O artigo apresenta uma síntese dos dados arqueológicos sobre o Pantanal e o seu entorno, principalmente em Mato Grosso e Mato Grosso do Sul. Elaborado com base na noção de arqueologia como história indígena de longa duração, o artigo considera as trajetórias de estabelecimento e consolidação territorial da ocupação indígena regional, os processos de formação da configuração etnográfica encontrada pelos europeus e os impactos do colonialismo. O principal objetivo consiste em mostrar que a diversidade cultural característica do cenário etnográfico pantaneiro está associada à dinâmica histórica e cultural da ocupação indígena desde períodos anteriores à chegada dos conquistadores e colonizadores de origem europeia.The article presents an overview of the archaeological data on the Pantanal and its surrounding areas, mainly in Mato Grosso and Mato Grosso do Sul. Prepared based on the notion of archeology as long term indigenous history, the article considers the trajectories of territorial establishment and consolidation of the regional indigenous occupation, the formation processes of ethnographic setting found by Europeans and the impact of colonialism. The main objective is to show that cultural diversity characteristic of the Pantanal ethnographic scenario is associated with historical and cultural dynamics of indigenous occupation from periods prior to the arrival of the conquistadors and settlers of European origin

Mapping anhedonia onto reinforcement learning: A behavioural meta-analysis

BACKGROUND: Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. METHODS: Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. RESULTS: MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. CONCLUSION: Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior