Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, providing a contrast to the gross deficits in Dlg2 homozygous models (Winkler, et al., 2018; Yoo et al., 2020a) which do not so specifically model the single chromosome DLG2 deletion in carriers of risk-associated copy number variants.

Dopamine D1 receptor-expressing neurons activity is essential for locomotor and sensitizing effects of a single injection of cocaine

D1 dopamine receptors play an important role in the effects of cocaine. Here we investigated the role of neurons which express these receptors (D1-neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug. We inhibited D1-neurons using double transgenic mice conditionally expressing the inhibitory Gi-coupleddesigner receptor exclusively activated by designer drugs(Gi-DREADD) in D1-neurons. Chemogenetic inhibition of D1-neurons by a low dose of clozapine (0.1 mg/kg) decreased the induction of Fos in striatal neurons. It diminished the basal locomotor activity and acute hyper-locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in non-transgenic mice. Inhibition of D1-neurons during the first cocaine administration reduced the sensitization of the locomotor response in response to a second cocaine administration ten days later. At day 11, inhibition of D1-neurons by clozapine stimulation of Gi-DREADD, prevented the expression of the sensitized locomotor response, whereas at day 12, in the absence of clozapine and D1-neurons inhibition, all mice displayed a sensitized response to cocaine. These results show that chemogenetic inhibition of D1-neurons decreases spontaneous and cocaine-induced locomotor activity. It blunts the induction and prevents the expression of sensitization in a two-injection protocol of sensitization but does not alter established sensitization. Our study further supports the central role of D1-neurons in mediating the acute locomotor effects of cocaine and its sensitization.

Constitutive deletion of translin (Tsn) enhances locomotor response to amphetamine: role of developmental effects

The translin/trax microRNA-degrading enzyme mediates activity-induced changes in translation that underlie several long-lasting forms of cellular plasticity. As translin and trax are expressed in dopaminergic and striatal neurons, we investigated whether deletion of Tsn blocks amphetamine sensitization, a long-lasting, translation-dependent form of behavioral plasticity.Although we had hypothesized that constitutive Tsn deletion would impair amphetamine sensitization, we found, instead, that it enhances the hyperlocomotion produced by the initial dose of amphetamine. Since these mice display elevated adiposity, which alters pharmacokinetics of many drugs, we measured brain levels of amphetamine in Tsn knockout mice and found that these are elevated. As conditional Tsn deletion in adulthood does not impact adiposity, we monitored the locomotor response to amphetamine following this manipulation. Acute and sensitized responses to amphetamine are not altered in these mice, indicating that the enhanced amphetamine response displayed by constitutive Tsn knockout mice is due to Tsn absence during development.

Pre-exposure of adolescent mice to morphine results in stronger sensitization and reinstatement of conditioned place preference than pre-exposure to hydrocodone

Background: Opioids are commonly prescribed to treat moderate-to-severe pain. However, their use can trigger the development of opioid use disorder. A major problem in treating opioid use disorder remains the high rate of relapse. Aim: The purpose of this study was to determine whether there are differences among opioids in their ability to trigger relapse after pre-exposure during adolescence. Methods: On postnatal day 33, mice were examined for the acute locomotor response to saline, morphine, or hydrocodone (5 mg/kg). They were administered with the corresponding opioid or saline during postnatal days 34–38 (20 mg/kg) and 40–44 (40 mg/kg). On postnatal day 45, they were recorded for the development of locomotor sensitization (5 mg/kg). Starting on postnatal day 55, mice were examined for the acquisition (1, 5, 10, 20, and 40 mg/kg), extinction, and drug-induced reinstatement (1, 2.5, and 5 mg/kg) of conditioned place preference. Results: There were no significant differences in the acute locomotor response to morphine and hydrocodone. Morphine induced significantly stronger locomotor sensitization as compared to hydrocodone. Pre-exposure to morphine, but not hydrocodone, sensitized the acquisition of conditioned place preference. There were no significant differences in extinction rates. Mice pre-exposed to morphine reinstate conditioned place preference after priming with a 1 mg/kg dose. In contrast, higher priming doses were required for reinstatement in all other experimental groups. Conclusions: Adolescent mice administered with morphine develop greater sensitization to its effects and subsequently reinstate conditioned place preference more readily than mice administered with hydrocodone. This suggests higher risk for relapse after pre-exposure to morphine during adolescence as compared to hydrocodone.