Breast cancer is one of the most prevalent and deadly forms of cancer in women and is not restricted by race or ethnicity. Although a wealth of knowledge has been amassed on the biology of breast cancer, including its risk factors, diagnosis, prognosis, prevention, and treatment, it remains a serious health concern and active area of research. Initial response to standard chemotherapeutic and radiotherapeutic regimens is generally strong for many patients, yet breast tumors often recur, leading to more aggressive and resistant tumors. Because recurrence is such a clinical issue, more effective therapeutic approaches are needed to eliminate partial clinical responses and undesirable side effects. Molecular chaperones like the heat shock protein 90 (Hsp90) family are regarded as ubiquitous, highly conserved proteins that mainly respond upon induction of stress or disruption in cellular homeostasis. Chaperones are critically involved in controlling the conformation, stability, function, and degradation of many oncogenic client proteins by assisting in trafficking, remodeling of improperly folded client proteins, and suppression of protein aggregation. Hsp90-mediated folding events are an ATP-dependent process that involves the association with various co-chaperones and stimulators, including Hsp70, Hsp40, HOP, p23, and Aha1 for client stabilization and modification. Notably, Hsp90 seems to be particularly associated with cell signaling clientele, such as nuclear hormone receptors, protein kinases, and many other oncogenic proteins that directly influence the hallmarks of cancer. In order to define the role of chaperones in breast cancer progression, we assessed chaperone expression levels in normal and tumor lines. Based on our initial finding of increased expression of Hsp90 and p23 in immortal and cancer cell lines, it is possible that this phenomenon may be reflected in normal breast tissue as well as breast carcinoma specimens. Indeed, we observed high Hsp90 expression in invasive carcinomas, such that high nuclear expression correlates with a greater TNM stage, while high cytoplasmic Hsp90 correlates with ER negativity, suggesting that elevated Hsp90 may be an indicator or marker of advanced disease. p23 expression also increases appreciably in established breast cancer cell lines with invasive breast tissue specimens displaying an opposite trend. Although p23 does not appear to have any relationship with TNM stage, significant relationships with ER and PR emerged, with higher nuclear p23 correlating to ER positivity and higher total p23 being positively associated with PR presence. Due to the differential expression of Hsp90 in normal, DCIS, and invasive breast carcinomas, we determined the impact on Hsp90 function, finding that total Hsp90 in tumor cells is associated with an increase in both complexed and uncomplexed Hsp90, which is in contrast to a previously reported study. The intrinsic nature of heat shock proteins makes them especially relevant to a cell’s defense against cancer initiation. The preferential accumulation of Hsp90 in cancer cells also forms the basis for the unique sensitivity of tumor cells to Hsp90 inhibition. The Hsp90 specific inhibitor, radicicol, is more potent in terms of blocking ATPase activity than other Hsp90-related compounds like geldanamycin, which is much more toxic. All Hsp90 inhibitors prevent the association of the co-chaperone p23 with Hsp90, resulting in destabilization of the client protein. For these reasons, it may be possible that Hsp90 inhibition would sensitize breast cancer cells to be more responsive to standard chemotherapeutics. We determined that radicicol negatively alters cellular proliferation, and in combination with Adriamycin, elicits a more robust decline in growth and the expression of Hsp90 client proteins. This finding was associated with an increase in senescent cells without a detectable affect on apoptosis. Radicicol in combination with cisplatin or Taxol contributed to an increase in cell death (apoptosis) and differentially altered the expression of client proteins. Finally, ER negative breast cancer cells do not display altered p53 expression upon radicicol and Adriamycin treatment. Blockade of ER activity in ER positive cells with tamoxifen induced significant reductions in proliferation and decreased p53 expression without a corresponding decrease in p21 levels. In conclusion, these results point to the utility of Hsp90 inhibition as a valid form of targeted therapy for breast cancer, and the value of radicicol as a potential adjuvant treatment option in combination with standard chemotherapeutics.

Le modèle de sensibilisation comportementale permet d'étudier les changements neuronaux induits par les drogues. Chez les rongeurs, l'activité locomotrice augmente au fur et à mesure des injections et se maintient à long terme. En parallèle à cette sensibilisation, on observe une sensibilisation neurochimique des transmissions noradrénergique (NA) et sérotoninergique (5-HT) jusqu'à un mois après la dernière injection. Cette sensibilisation neurochimique, qui se traduit par des libérations de NA et de 5-HT potentialisées mesurées au niveau du cortex préfrontal, est commune à toutes les drogues et fortement corrélée à la sensibilisation comportementale. Le but de ce travail était d'identifier les mécanismes qui maintiennent à long terme cette hyper-réactivité. Nous avons tout d'abord montré que la réponse locomotrice potentialisée à l'amphétamine se maintient durant le premier mois de sevrage, et décroit de 60% entre 2 et 4 mois. Toutefois les souris restent plus vulnérables à la drogue et ce, même après de longs sevrages. Nous avons également démontré que l'hyper-réactivité des systèmes se maintient à long terme notamment grâce à une désensibilisation fonctionnelle persistante des récepteurs ?2A- adrénergiques et 5-HT1A, responsables du rétrocontrôle inhibiteur des transmissions NA et 5-HT. On observe une diminution de l'expression des protéines G?i couplées à ces récepteurs, dans le locus coeruleus et dans le raphé dorsal, respectivement. La même altération des rétrocontrôles ayant été mesurée chez les animaux sensibilisés au MDMA, les résultats suggèrent que les récepteurs ?2A-adrénergiques et 5-HT1A pourraient être des cibles indirectes des psychostimulants. / The behavioral sensitization model allows the study of the neuronal changes induced by drugs of abuse. In rodents, the locomotor activity increases progressively with the injections of drug, and stays long-lastingly potentiated. Concurrent with this sensitization, a neurochemical sensitization of noradrenergic and serotonergic transmissions is developed until one month after the last injection. This sensitization, quantified through potentiated noradrenergic and serotonergic releases in the prefrontal cortex, was shown to be common to almost all drugs of abuse and highly correlated to behavioral sensitization. The aim of this study was to identify the mechanisms sustaining this hyper-reactivity. We first showed that the potentiated response persists after the first month of withdrawal, and decreases to 40% of the response after 2 to 4 months of withdrawal. However, all mice remain more vulnerable to the drug, even after long (4 months) withdrawals. We also showed that the systems? hyper-reactivity is sustained in the long term by a functional and persistent desensitization of the ?2A-adrenergic and 5-HT1A receptors, responsible for the inhibitory feed-back of noradrenergic and serotonergic transmissions. We observed a decreased expression of G?i proteins coupled receptors in the locus coeruleus and the dorsal raphe.The same feed-back dysfunctions were found in animals sensitized to MDMA, which suggests that ?2A-adrenergic and 5-HT1A receptors are indirect targets of psychostimulant drugs

O enriquecimento ambiental (EA) reverte a sensibilização comportamental (SC) ao etanol em camundongos e diminui os níveis de BDNF no córtex pré-frontal (CPF). O objetivo deste trabalho foi estudar os efeitos do EA sobre parâmetros comportamentais, resposta de corticosterona ao estresse, expressão de microRNAS e a participação da via BDNF-TrkB no CPF frente à SC ao etanol. Camundongos mantidos em EA foram submetidos a testes comportamentais (ansiedade, depressão, anedonia e comportamentos repetitivos). Também foram tratados repetidamente com etanol e expostos ao EA para a avaliação da corticosterona plasmática e da expressão de microRNAs no CPF. A via BDNF-TrkB foi inibida no CPF de camundongos que desenvolveram a SC ao etanol. O EA diminuiu a atividade locomotora e exploratória, a ativação do eixo HPA após estresse agudo, aumentou o peso do baço e diminuiu a expressão de miR-132 e let-7d. Os resultados sugerem o envolvimento de microRNAs na reversão da SC ao etanol; contudo, a via BDNF-TrkB no CPF não parece estar diretamente envolvida neste processo. / The environmental enrichment (EE) reverts the ethanol-induced behavioral sensitization (EIBS) in mice and decreases BDNF levels in the prefrontal cortex (PFC). The aim of this work was to evaluate the effects of EE on behavioral parameters, on the corticosterone response to stress and on microRNA expression and to assess the involvement of the BDNF-TrkB pathway in the PFC on the EIBS. Mice kept in EE were submitted to behavioral tests (anxiety, depression, anhedonia and repetitive behaviors). Mice were also treated repeatedly with ethanol and exposed to EE for the assessment of plasma corticosterone levels and microRNA expression in the PFC. The BDNF-TrkB pathway was blocked in the PFC of mice that developed EIBS. EE decreased locomotion, exploratory activity and HPA axis activation after acute stress, increased spleen weight and decreased miR-132 and let-7d expression. The results suggest the involvement of microRNAs in the reversal of EIBS promoted by EE; however, the BDNF-TrkB pathway in the PFC does not seem to be directly involved in this process.

A fase da adolescência difere da adulta em parâmetros comportamentais e neurológicos. A proteína de ligação responsiva ao AMPc (CREB) é um fator de transcrição regulado por três vias principais: PKA, CaMK e ERK, as quais apresentam atividade alterada em resposta à cocaína. Neste trabalho, foram avaliadas as atividades dessas vias, bem como os níveis de um de seus genes alvo (prodinorfina), do inibidor endógeno de CRE (Icer) e da proteína ativadora de CREB (CBP) em resposta à administração de cocaína, além dos comportamentos induzidos pelo psicoestimulante. Os adolescentes apresentaram maior sensibilização psicomotora, atividade exploratória e comportamento tipo ansiedade em comparação aos adultos. Os adolescentes exibiram aumento da atividade da via da PKA e da expressão de Icer, CBP e Pdyn; os adultos apresentaram diminuição de CaMKs, GluR1 e Icer. Essas diferentes respostas neuroadaptativas podem ajudar na compreensão dos mecanismos ontogênicos envolvidos na dependência. / The adolescence differs from adulthood in behavioral and neurochemichal aspects. The cAMP responsive binding protein (CREB) is a transcription factor regulated by three main pathways in the mesolimbic-dopaminergic circuit: PKA, CaMK and ERK, which are modulated by cocaine. This study evaluated the activity of these pathways, as well as the levels of one of its main target genes (prodynorphin), endogenous CRE inhibitor (Icer) and CREB binding protein (CBP) in response to cocaine administration, besides the behaviors induced by the psychostimulant. Adolescents presented greater locomotor activation, psychomotor sensitization, exploratory activity and anxiety-like behavior compared to adults. Adolescents exhibited increased PKA pathway activity and expression of Icer, CBP, and Pdyn; adults showed decreased levels of CaMKs, GluR1 and Icer. These different neuroadaptive responses may help understanding the ontogenic mechanisms involved in addiction.

Fêmeas da espécie Aedes aegypti são vetores de importantes doenças como dengue, febre amarela, Chikungunya e Zika. A alimentação sanguínea realizada pelo mosquito fêmea é importante e necessária para a maturação dos ovos. Durante este processo, os mosquitos hematófagos precisam lidar com desafios impostos pelo hospedeiro vertebrado como a barreira da hemostasia e seu sistema imunológico. Estudos clássicos mostraram que a exposição à saliva do mosquito é capaz de sensibilizar o homem, embora boa parte dos indivíduos apresente dessensibilização às proteínas salivares ao longo da vida. Resultados recentes do nosso grupo sugerem que o processo de sensibilização e dessensibilização pode ser reproduzido em modelo murino. Diante do exposto, o presente trabalho teve como objetivo estudar os processos de sensibilização e dessensibilização aos antígenos salivares de A. aegypti, seu impacto no fitness biológico do mosquito (ingestão de sangue, oviposição e escolha do hospedeiro) e potenciais moléculas envolvidas nesse processo. Inicialmente, padronizamos um modelo de exposição natural, no qual camundongos BALB/c fêmeas foram expostos 10 vezes às picadas de 30 mosquitos A. aegyptifêmeas, com um intervalo de 15 dias entre cada exposição. Avaliamos o perfil de anticorpos séricos entre cada exposição e observamos uma mudança no padrão de anticorpos ao longo do tempo, inicialmente com forte componente Th2 (IgE total e IgG1 específica) e mais tardiamente, a presença de um componente Th1 (IgG2a específica). Além disso, o soro de animais expostos 4 vezes aos mosquitos apresentou atividade anafilática dependente de IgE superior ao soro de animais naive e de animais expostos 10 vezes ao mosquito. O perfil de citocinas presentes em culturas de células totais de baço mostrou forte produção de IL-4 e IL-5 antígeno-específicas, que foi semelhante entre os grupos expostos 4 ou 10 vezes aos mosquitos. A avaliação da migração celular na orelha induzida pelas picadas do mosquito mostrou que, comparado com as células residentes da orelha de animais naive, todos os tipos celulares fenotipados estavam presentes maior quantidade em tanto em animais expostos 4 vezes quanto expostos 10 vezes aos mosquitos, com destaque para os eosinófilos (aumentados ~2000 e ~1000 vezes, respectivamente). Entretanto, o número total de eosinófilos e de linfócitos B se mostrou reduzido, enquanto o número de neutrófilos estava aumentado, nos animais expostos 10 vezes quando comparados aos animais expostos 4 vezes. Do ponto de vista do vetor, não observamos grandes alterações no volume de sangue ingerido durante o repasto sanguíneo, embora haja uma tendência de maior aquisição de sangue em animais expostos 7 vezes ao mosquito. Por outro lado, a oviposição foi gradativamente diminuída entre a segunda e a sétima exposição quando comparada com a primeira exposição, voltando aos níveis originais à partir da oitava exposição. Um modelo de inflamação peritoneal aguda induzido pela inoculação do extrato da glândula salivar (EGS) de fêmeas do mosquito A. aegypti, revelou um aumento de eosinófilos, semelhante ao observado no modelo crônico de inflamação na orelha. Esse modelo foi usado para estudar o papel de moléculas do hospedeiro potencialmente envolvidas na migração eosinofílica em resposta aos antígenos salivares, revelando a importância da IL-5 e dos leucotrienos nesse processo. Assim, podemos concluir que a saliva do mosquito A. aegypti provoca uma forte resposta alérgica em camundongos, que apesar de não alterar o volume de sangue ingerido pelos mosquitos, é capaz de afetar sua oviposição. A exposição crônica induz um processo de dessensibilização, com aumento de anticorpos de perfil Th1 e diminuição da migração de eosinófilos no sítio da picada, mas que se refletiu em maior oviposição por parte dos mosquitos. Finalmente, IL-5 e leucotrienos são mediadores que parecem estar envolvidos na inflamação eosinofílica em resposta aos componentes salivares do mosquito. / Females of Aedes aegypti species are vectors of important diseases such as dengue, Yellow Fever, Chikungunya Fever and Zika. The blood meal is essential and necessary for the maturation of eggs in female mosquitoes. During this process, hematophagous mosquitoes need to cope with challenges imposed by the vertebrate host, such as the hemostasis and the immune system barriers. Classical studies have shown that exposure to mosquito saliva is able to sensitize humans, although most individuals show desensitization to salivary proteins throughout their lives. Recent results from our group suggest that the process of sensitization and desensitization can be reproduced in a murine model. Thus, the aim of the present work was to study the sensitization and desensitization processes to A. aegypti salivary antigens, their impact on the biological fitness of the mosquito (blood ingestion, oviposition and host choice) and potential molecules involved in this process. Initially, we standardized a model of natural exposure in which female BALB/c mice were exposed 10 times to the bites of 30 female A. aegypti mosquitoes, with a 15-day interval between each exposure. We evaluated the serum antibody profile between each exposure and observed a change in antibody pattern over time, initially with a strong Th2 component (total IgE and specific IgG1) and later, the presence of a Th1 (specific IgG2a) component. In addition, the serum of animals exposed 4 times to the mosquitoes showed stronger IgE-dependent anaphylactic activity than the serum of naive animals and animals exposed 10 times to the mosquitoes. The cytokine profile in spleen cell cultures showed strong antigen-specific production of IL-4 and IL-5, similar between the groups exposed 4 or 10 times to the mosquitoes. The evaluation of cell migration into the ear induced by mosquito bites showed that, compared to the resident cells of the ear of naive animals, all phenotyped cell types were present in larger amounts in both animals exposed, 4 times and 10 times, to mosquitoes, specially eosinophils (increased ~2000 and ~1000 times, respectively). However, the total number of eosinophils and B lymphocytes was reduced, while the number of neutrophils was increased, in animals exposed 10 times when compared to animals exposed 4 times. From the vector perspective, we did not observe significant changes in the volume of blood taken during the blood feeding, although there is a tendency of greater blood acquisition in animals exposed 7 times to the mosquitoes. On the other hand, the oviposition was gradually diminished between the second and the seventh exposure when compared to the first exposure, returning to the original levels from the eighth exposure. A model of acute peritoneal inflammation induced by the inoculation of female A. aegypti salivary gland extract (SGE) revealed an increase in eosinophils, similar to that observed in the chronic model of inflammation in the ear. This model was used to study the role of host molecules potentially involved in eosinophil migration in response to salivary antigens, revealing the importance of IL-5 and leukotrienes in this process. Thus, we can conclude that the saliva of the A. aegypti mosquito causes a strong allergic response in mice that it does not alter the volume of blood ingested by mosquitoes, but it is able to affect their oviposition. Chronic exposure induced a desensitization process, with increased antibodies of Th1 profile and decreased eosinophil migration to the bite site, but that resulted in greater oviposition by the mosquitoes. Finally, IL-5 and leukotrienes are mediators that seem to be involved in eosinophilic inflammation in response to the salivary components of the mosquito.

A migrânea e a cefaléia tensional são cefaléias primárias que surgem de estruturas não-mastigatórias, porém, a presença de sintomas de DTM, como a dor, pode influenciar de modo excitatório tais condições e vice-versa, influenciando no resultado final do tratamento. Esta pesquisa tem o objetivo principal de avaliar o impacto da presença de cefaléias primárias no tratamento das Disfunções Temporomandibulares (DTMs), e testa a hipótese nula de que a presença de cefaléias primárias não interfere com o resultado do tratamento. Como objetivos secundários, de avaliar se existe diferença na presença de dor miofascial nos músculos mastigatórios e cervicais, se existe diferença entre a variação da dor medida pela Escala Analógica Visual (EAV) em relação ao gênero, estresse e hábitos parafuncionais, e se essa diferença também se apresenta entra as variáveis oclusão, tempo de dor, número de queixas e número de tratamentos indicados. Para isso foram selecionados 546 prontuários clínicos de pacientes, sendo 313 com DTM e 233 com DTM e cefaléias, e analisados segundo a EAV ao início e fim do tratamento para DTM, bem como a variação entre a dor inicial e final entre os grupos. Testes de Mann-Whitney, Correlação de Spearman e Qui-quadrado analisaram os dados, com 5% de significância. A presença de cefaléias primárias interferiu negativamente no índice de sucesso do tratamento da DTM (p<0,05) (redução de 38,70 e de 24,66 na EAV para os grupos de DTM e DTM associada a cefaleia, respectivamente). A presença de dor miofascial nas musculaturas mastigatória e cervical foi semelhante entre os grupos. A variação entre a dor inicial e final não foi afetada pela diferença entre os gêneros, assim como pelo auto-relato da presença de hábitos parafuncionais e de estresse. Da mesma forma, a presença de má-oclusão, o tempo de experiência de dor, o número de queixas relatadas e o número de tratamentos indicados pelo profissional não influenciaram os resultados finais. Conclui-se que presença de cefaléias primárias parece interferir negativamente na melhora do quadro sintomático de pacientes tratados para DTM. / Migraine and tension-type headaches are primary headaches that arise from non-masticatory structures, however, the presence of TMD symptoms, like pain, may have a excitatory effect in these conditions and vice versa, influencing the outcome of treatment. This research has the main objective of evaluating the impact of the presence of primary headache in the treatment of Temoromandibulares Disorders (TMD), and tests the null hypothesis that the presence of primary headache does not interfere with treatment outcome. As secondary objectives, to evaluate whether there are differences in the presence of myofascial pain in the masticatory and cervical muscles, if there is a difference between the change in pain measured by visual analog scale (VAS) in relation to gender, stress, and parafunctional habits. The influence of malocclusion, duration of pain, number of complaints and number of treatments given were also evaluated. For this reason, 546 medical records of patients, 313 and 233 with TMD TMD and headaches were selected, and analyzed using a VAS at the beginning and end of treatment for TMD, as well as the variation between the initial and final pain between the groups. Mann-Whitney, Spearman correlation and chi-square test analyzed the data with 5% significance level. The presence of primary headaches interfered negatively with the rate of successful treatment of TMD (p <0,05) (reduction of 38.70 and 24,66 in the VAS for groups of TMD and headache associated with TMD, respectively). The presence of myofascial pain in the masticatory and cervical muscles was similar between groups. The variation between the initial and final pain was not affected by gender differences, as well as by self-report the presence of parafunctional habits and stress. Likewise, the presence of malocclusion, time of pain experience, the number of complaints reported and the number of treatments given by the professional did not influence the final results. It is concluded that the presence of primary headache seems to have a negative effect on symptomatic improvement in patients treated for TMD.

During welding, the regions adjacent the welds, which can reach high temperatures cause microstructural changes in austenitic steels, thereby increasing the susceptibility to intergranular corrosion, due to the reduction of chromium in adjacent zones over the grain boundaries, rich in precipitates chromium carbides (Cr23C6). A study of the influence of heat input on the sensitization is of great value and interest in various activities, such as in chemical, petroleum, petrochemical, marine, automobile, etc.. Thus, we studied the effect of the amount of heat (energy welding) on the amplitude of the sensitized area, welding of steel free from carbide. For this, we used together with optical microscopy, the technique of polarization PotenciocinÃtica Cyclic Electrochemical Reactivation (PERC), the determination and classification of regions sensitizadas and their resulting structures. / Durante a soldagem, as regiÃes adjacentes Ãs soldas, alcanÃam elevadas temperaturas que podem ocasionar mudanÃas microestruturais nos aÃos austenÃticos, aumentando assim a susceptibilidade à corrosÃo intergranular, em virtude da diminuiÃÃo de cromo em zonas adjacentes ao longo dos contornos de grÃo, ricas em precipitados de carbonetos de cromo (Cr23C6). Um estudo da influÃncia da energia de soldagem sobre a sensitizaÃÃo à de grande valia e interesse nas mais variadas atividades, como por exemplo, nas indÃstrias quÃmicas, petrolÃferas, petroquÃmicas, navais, automobilÃsticas, etc. Desta forma, estudou-se a influÃncia da quantidade de calor (energia da soldagem) sobre a amplitude da regiÃo sensitizada, na soldagem de aÃos livres de carbonetos. Para isto, utilizou-se juntamente com a microscopia Ãtica, a tÃcnica de PolarizaÃÃo EletroquÃmica de ReativaÃÃo PotenciocinÃtica CÃclica (PERC), na determinaÃÃo e classificaÃÃo das regiÃes sensitizadas e suas estruturas resultantes.

Our laboratory has reported neonatal quinpirole (D2/D3 agonist) treatment to rats increases dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. This model appears to have clinical relevance to schizophrenia, and smoking is common in this population. Male and female Sprague-dawley rats were neonatally treated with quinpirole from postnatal (P) days 1–21. After habituation from P30 to 32, animals were administered saline or nicotine (0.3, 0.5, or 0.7mg/kg free base) every other day from P33 to 49 and locomotor activity was assessed. Generally, animals neonatally treated with quinpirole and administered nicotine during adolescence demonstrated increased behavioral activity and/or sensitization compared to animals neonatally given saline and sensitized to nicotine as well as controls. However, animals neonatally treated with quinpirole and given the 0.7mg/kg dose of nicotine demonstrated elevated activity throughout testing but did not show sensitization, and only mild sex differences were reported. Therefore, microdialysis was performed on male rats sensitized to the 0.5mg/kg dose of nicotine, and results revealed that neonatal quinpirole sensitized dopamine overflow in response to nicotine to 500% above animals neonatally given saline and sensitized to nicotine at peak levels. In addition, neonatal quinpirole increased the accumbal BDNF in response to nicotine compared to all other groups, and nicotine alone also produced significant increases in striatal and accumbal BDNF. This study reveals that neonatal quinpirole enhanced adolescent nicotine sensitization, accumbal dopamine overflow, and BDNF protein in response to nicotine, which may be related to changes in the brain's reward system.

In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth we

Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, and then behaviorally and biochemically characterized over the next 15–20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes, as well as functional links between the biologic template of the animal model and ability of pharmacotherapeutics to modulate or reverse biologic and behavioral modalities toward normality. Another such animal model, featuring knockout of trace amine-associated receptor 1 (TAAR1), demonstrates D2RSS with an increase in the proportion of D2R in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D2RSS with substance use disorder. The aspect of adenosine A2A-D2heteroreceptor complexes in substance use disorder is highlighted, and the association of adenosine A2Areceptor antagonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face, construct, and predictive validity, and distinct advantages over earlier models. While the review summarizes elements of D2RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D2RSS in schizophrenia and related clinical entities.