Buprenorphine and methadone differentially alter early brain development in human cortical organoids.

Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a µ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are µ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications.

A Test of the Kin Selection Hypothesis for Female Gynephilia in Thailand.

Female gynephilia (i.e., sexual attraction to adult females) is considered an evolutionary paradox because it reduces direct reproduction, yet it is influenced by genetic factors and has persisted over time and across different cultures. The Kin Selection Hypothesis proposes that same-sex attracted individuals offset their lowered direct reproduction by engaging in kin-directed altruism that increases the reproduction of close genetic relatives, thereby enhancing inclusive fitness. Previous research on male same-sex attraction found evidence to support this hypothesis in some cultures. The present study employed a Thai sample to compare altruistic tendencies towards kin and non-kin children in heterosexual women (n = 285), lesbian women (n = 59), toms (i.e., masculine gynephilic females who take on a nonbinary gender identity; n = 181), and dees (i.e., feminine gynephilic females who are attracted to toms; n = 154). The Kin Selection Hypothesis of same-sex attraction predicts that gynephilic groups would show increased kin-directed altruism compared with heterosexual women, but we did not find evidence supporting this prediction. Instead, the tendency to invest more towards kin than non-kin children was more exaggerated in heterosexual women than lesbian women. Also, heterosexual women showed greater dissociation between kin and non-kin altruistic tendencies compared with toms and dees, which may suggest the former's cognition is better attuned for kin-directed altruism. Thus, the present findings were contrary to the Kin Selection Hypothesis for female gynephilia. Alternative explanations regarding the maintenance of genetic factors predisposing individuals to female gynephilia are discussed and require further investigation.