Addiction is characterised by a persistent loss of behavioural control resulting in insensitivity to negative feedback and abnormal decision-making. Here we investigated the influence of methamphetamine (METH)-paired contextual cues on decision-making in rats. Choice between goal-directed actions was sensitive to outcome devaluation in a saline-paired context but was impaired in the METH-paired context, a deficit that was also found when negative feedback was provided. Reductions in c-Fos-related immunoreactivity were found in dorsomedial but not dorsolateral striatum after exposure to the METH context suggesting this effect reflected a loss specifically in goal-directed control in the METH context. This reduction in c-Fos was localized to non-enkephalin expressing neurons in the DMS, likely dopamine D1-expressing direct pathway neurons, suggesting a relative change in control by the D1-direct vs. D2-indirect pathways originating in the DMS may have been induced by METH context exposure. To test this suggestion we infused the adenosine 2A receptor antagonist ZM241385 into the dorsomedial striatum prior to test to reduce activity in D2 neurons relative to D1 neurons in the hope of reducing the inhibitory output from this region of the striatum. We found that this treatment fully restored sensitivity to negative feedback in a test conducted in the METH-paired context. These results suggest that drug-exposure alters decision-making by down-regulation of the circuitry mediating goal-directed action, an effect that can be ameliorated by acute A2A receptor inhibition in this circuit.
Background: College students are within the high-risk group to experience the full spectrum of alcohol-related psychopathologies, ranging from initial contact with alcohol to the severe problematic drinking. The prevalence, degree of severity, reasons of drinking, among other variables, however, have been inconsistent across studies. Therefore, it is crucial to replicate such studies in different socio-cultural settings to synthesize a broader understanding about alcohol-consuming behavior and formulating intervention strategies. This research aims to describe the pattern of alcohol drinking behavior among college students in Minahasa, Indonesia, and to analyze its correlation with academic performance. Methods: We conducted a questionnaire-based cross-sectional study to investigate the alcohol-consumption pattern and examined its association with the students' academic performance obtained from the campus database. A total-sampling technique was applied to draw the samples. Chi-square and Kendall's tau analyses were employed accordingly to measure the relationship significance. Results: From 417 samples (338 samples were females), 70.98% of them reported never had consumed alcohol of any amount. Male sex and local ethnicity are positively associated with consuming behavior. We found an association between alcohol consumption status with cumulative GPA but not with current GPA. Although alcohol consumers considered GPA as less important, the self-insight about their academic performance is intact. The consumed beverages were mostly beers, followed by traditional liquor and winepalms. Most of them consumed alcohol to "warm-up the body"—a common practice in this area, followed by social reasons. Only small number of them identified themselves as being addicted. Majority of the consumers realized the importance to reduce or quit consuming alcohol. The implications of these findings are then discussed. Conclusions: This study showed that most of the students have never consumed alcohol. However, among the consumers, male sex and local ethnicity are more prone to become alcohol users. The academic performance is also affected, and since most of the consumers consider to reduce their drinking behavior, professional interventions are necessary to facilitate recovery attempts.
ABSTRAK Kata kunci: CRISPR, Cas9, efektivitas, spesifisitas, terapi gen ABSTRACTGene editing has become reasonably easy since the discovery of clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein 9 (Cas9). Most genetic diseases cannot be treated causally, and currently available therapies are mainly symptom-based. To treat the etiology of genetic diseases, a firm gene editing therapy is necessary to be established. This posits Cas9-facilitated gene editing as a prospective modality to become a clinically approved therapy in the future to treat genetic disorders. However, until recently, Cas9-based genome editing is still facing several hurdles, including low specificity, low effectiveness, and difficult delivery. Currently available Cas9 nucleases are able to bind to non-specific DNA sequence and produce non-specific cleavage. The efficiency has been relatively low due to the preference of non-homologous end-joining (NHEJ) over homology-directed repair (HDR) by the host cell. Furthermore, in order to deliver Cas9 into the nucleus, multiple physiological barriers have to be overcome. This review discussed recent developments in tackling these three hurdles, ranging from designing the guide RNA using multiple bioinformatics tools, modifying Cas9 structure, as well as packaging the nuclease-guide RNA complex into viral vectors and nanoparticles. Considering the active research on this area, it is expected that CRISPR/Cas9 can be utilized as a clinical therapy in the near future.
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