Transcriptomic effects of paternal cocaine-seeking on the reward circuitry of male offspring.

It has been previously established that paternal development of a strong incentive motivation for cocaine can predispose offspring to develop high cocaine-seeking behavior, as opposed to sole exposure to the drug that results in drug resistance in offspring. However, the adaptive changes of the reward circuitry have not been fully elucidated. To infer the key nuclei and possible hub genes that determine susceptibility to addiction in offspring, rats were randomly assigned to three groups, cocaine self-administration (CSA), yoked administration (Yoke), and saline self-administration (SSA), and used to generate F1. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naïve conditions and after cocaine self-administration. Pairwise differentially expressed gene analysis revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine exposure, while the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) exhibited changes that were more closely associated with the paternal voluntary cocaine-seeking behavior. Consistently, these nuclei showed decreased dopamine levels, elevated neuronal activation, and elevated between-nuclei correlations, indicating dopamine-centered rewiring of the midbrain circuit in the CSA offspring. To determine if possible regulatory cascades exist that drive the expression changes, we constructed co-expression networks induced by paternal drug addiction and identified three key clusters, primarily driven by transcriptional factors such as MYT1L, POU3F4, and NEUROD6, leading to changes of genes regulating axonogenesis, synapse organization, and membrane potential, respectively. Collectively, our data highlight vulnerable neurocircuitry and novel regulatory candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.

Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Effect of Integrated Psychobehavioral Care on Emotional-Behavioral Responses, Cognitive Changes in Outpatients with Schizophrenia Followed Up: Based on a Prospective Randomized Controlled Study.

Background: In recent years, influenced by the continuous improvement and development of the medical service model and the increasing demands of modern people for the quality of clinical care, the clinical treatment of schizophrenic groups has also received widespread attention and importance from all sectors of society. Psychobehavioral care is administered to patients during active antipsychotic treatment, which can maximize the patient's cooperation with clinical work and thus play an auxiliary role in treatment. Aims: To investigate the impact of emotional-behavioral responses, cognitive changes in outpatient follow-up of schizophrenic patients with integrated psychobehavioral care. Materials and Methods: One hundred cases of schizophrenia patients with outpatient follow-up in our hospital from March 2017 to March 2019 were selected as prospective study subjects and divided into a comparison group and an observation group of 50 cases each according to a random number table. Among them, the comparison group implemented conventional psychobehavioral care, and the observation group implemented integrated psychobehavioral care. The differences in compliance behavior, negative emotions, cognitive behavioral changes, and pain scores before and after care of schizophrenia patients in the outpatient follow-up were compared between the two groups. Results: After care, the compliance behavior, negative emotions, cognitive behavioral changes, and pain scores of schizophrenia patients in both groups with outpatient follow-up were significantly improved and significantly higher in the observation group than in the comparison group, and statistics showed that this difference was statistically significant (P < 0.05). Conclusion: Integrated psychobehavioral care combined with conventional psychobehavioral care can effectively enhance the compliance behavior of outpatient follow-up schizophrenia patients, improve the negative emotions and pain of patients, and facilitate the active treatment of patients to improve their prognosis. It has some reference value for outpatient follow-up schizophrenia patient care.