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.

Enhanced heroin analgesic effect in male offspring of sires who self-administered heroin.

Introduction: A growing body of evidence suggests that parental substance abuse, even prior to conception, may induce phenotypic changes in offspring. Parental opioid exposure has been shown to affect developmental processes, induce memory deficits, and lead to psycho-emotional disorders in offspring. However, how parental, especially paternal, chronic drug exposure affects offspring remains unexplored. Methods: Adult male rats were subjected to 31 days of heroin self-administration followed by mating with naïve females. Litter size and body weight of F1 offspring were recorded. Object-based attention tests, cocaine self-administration tests, and hot plate tests were used to test for potential effects of chronic paternal heroin seeking on cognition, reward, or analgesic sensitivity in the offspring. Results: Body weight and litter size of the heroin F1 generation were not altered compared to the saline F1 generation. Furthermore, paternal chronic heroin self-administration experience had no significant effect on object-based attention tests or cocaine self-administration behavior in either sex. However, in the hot plate test, although no difference in basal latency was found between the two groups in either sex, a significant increase in the analgesic effect of heroin was observed in the male heroin F1 generation. Conclusions: Taken together, these data provide evidence that paternal chronic heroin self-administration experience could sex-dimorphically increase the analgesic effect of heroin in male offspring, but had no significant effect on response to cocaine reinforcement or attentional behavior.

Persistent increase of accumbens cocaine ensemble excitability induced by IRK downregulation after withdrawal mediates the incubation of cocaine craving.

The incubation phenomenon, cue-induced drug craving progressively increasing over prolonged withdrawal, accounts for persistent relapse, leading to a dilemma in the treatment of cocaine addiction. The role of neuronal ensembles activated by initial cocaine experience in the incubation phenomenon was unclear. In this study, with cocaine self-administration (SA) models, we found that neuronal ensembles in the nucleus accumbens shell (NAcSh) showed increasing activation induced by cue-induced drug-seeking after 30-day withdrawal. Inhibition or activation of NAcSh cocaine-ensembles suppressed or promoted craving for cocaine, demonstrating a critical role of NAcSh cocaine-ensembles in incubation for cocaine craving. NAcSh cocaine-ensembles showed a specific increase of membrane excitability and a decrease of inward rectifying channels Kir2.1 currents after 30-day withdrawal. Overexpression of Kir2.1 in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed cue-induced drug-seeking after 30-day withdrawal. Expression of dominant-negative Kir2.1 in NAcSh cocaine-ensembles enhanced neuronal membrane excitability and accelerated incubation of cocaine craving. Our results provide a cellular mechanism that the downregulation of Kir2.1 functions in NAcSh cocaine-ensembles induced by prolonged withdrawal mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving.

Diatomite Composited with a Zeolitic Imidazolate Framework for Removing Phosphate from Water.

Adsorption technology based on various adsorbents has been widely applied in wastewater treatment containing phosphate. A novel diatomite adsorbent composited with ZIF-8 (CZD) was developed for removing phosphate from water in this work. The chitosan was used to pre-modify the diatomite so that ZIF-8 could be anchored on the surface of the diatomite solidly and uniformly. The diatomite composited with ZIF-8 was then used to remove phosphate in water by an adsorption process, the process variables such as adsorption time, temperature, pH, and competitive ions were investigated. The electrostatic attraction was the primary mechanism of phosphate removal. The adsorption reached equilibrium within 90 min, and its sorption capacity increased when adsorption time and temperature increased. Especially, CZD had a rapid adsorption rate and 85% of the phosphate in the solution can be adsorbed within the first 10 min. The maximum phosphate adsorption capacities of the modified diatomite reached 13.46, 13.55, and 13.95 mg/g at 25, 35, and 45 °C, respectively. The removal efficiencies of CZD for phosphate were more than 98% and even came up to 100% at 45 °C. The adsorption isotherms fit well with the Langmuir isotherm model. The Freundlich isotherm and Temkin isotherm showed that the adsorption process is physical in nature. The kinetic data of the adsorption process were fitted by the pseudo-second-order kinetics. Thermodynamic parameters indicated that the adsorption process was endothermic. This adsorbent provided an alternative for phosphate removal on account of the high adsorption efficiency in a short time. Therefore, CZD could be a promising and eco-friendly phosphate adsorbent for wastewater treatment.

Diatomite Modified with an Alkyl Ketene Dimer for Hydrophobicity of Cellulosic Paper.

Multifunctionalization of papermaking chemicals is one of the main developing strategies. Fillers and internal sizing agents are often mutually restricted in practice. Therefore, it is feasible to prepare a new papermaking chemical by combining the functions of both. A process of diatomite modified with an alkyl ketene dimer (AKD) was developed in this study. The modified diatomite (AD) can concurrently play the role of a mineral filler and sizing agent in the papermaking process. With the equal dosage of AKD, the AD showed better sizing and retention performance than the commercial AKD emulsion in the case of cationic polyacrylamide (CPAM) and the CPAM/bentonite retention system. The sizing mechanism of the AD can be interpreted to be due to numerous hydrophobic sites and the microsurface structure of the paper sheet caused by the AD. Since ketones were not detected in Fourier-transform infrared spectra of the paper sheet filled by the AD, the chemical reaction may not be indispensable for its sizing performance. What is more, an interesting "sticky" hydrophobicity phenomenon was observed when filling with AD. The approach in this study to prepare the "sticky" hydrophobic paper sheet can find its applications in some nontraditional application fields of cellulosic paper.