Motor Transitions' Peculiarity of Heterozygous DAT Rats When Offspring of an Unconventional KOxWT Mating.

Causal factors of psychiatric diseases are unclear, due to gene × environment interactions. Evaluation of consequences, after a dopamine-transporter (DAT) gene knock-out (DAT-KO), has enhanced our understanding into the pathological dynamics of several brain disorders, such as Attention-Deficit/Hyperactivity and Bipolar-Affective disorders. Recently, our attention has shifted to DAT hypo-functional (heterozygous, HET) rodents: HET dams display less maternal care and HET females display marked hypo-locomotion if cared by HET dams (Mariano et al., 2019). We assessed phenotypes of male DAT-heterozygous rats as a function of their parents: we compared "maternal" origin (MAT-HET, obtained by breeding KO-male rats with WT-female dams) to "mixed" origin (MIX-HET, obtained by classical breeding, both heterozygous parents) of the allele. MAT-HET subjects had significantly longer rhythms of daily locomotor activity than MIX-HET and WT-control subjects. Furthermore, acute methylphenidate (MPH: 0, 1, 2 mg/kg) revealed elevated threshold for locomotor stimulation in MAT-HETs, with no response to the lower dose. Finally, by Porsolt-Test, MAT-HETs showed enhanced escape-seeking (diving) with more transitions towards behavioral despair (floating). When comparing both MAT- and MIX-HET to WT-control rats, decreased levels of DAT and HDAC4 were evident in the ventral-striatum; moreover, with respect to MIX-HET subjects, MAT-HET ones displayed increased DAT density in dorsal-striatum. MAT-HET rats displayed region-specific changes in DAT expression, compared to "classical" MIX-HET subjects: greater DAT availability may elevate threshold for dopamine action. Further behavioral and epigenetic characterizations of MAT-HETs, together with deeper characterization of maternal roles, could help to explore parent-of-origin mechanisms for such a peculiar phenotype.

Prior Activation of 5-HT7 Receptors Modulates the Conditioned Place Preference With Methylphenidate.

The serotonin receptor subtype 7 (5-HT7R) is clearly involved in behavioral functions such as learning/memory, mood regulation and circadian rhythm. Recent discoveries proposed modulatory physiological roles for serotonergic systems in reward-guided behavior. However, the interplay between serotonin (5-HT) and dopamine (DA) in reward-related behavioral adaptations needs to be further assessed. TP-22 is a recently developed arylpiperazine-based 5-HT7R agonist, which is also showing high affinity and selectivity towards D1 receptors. Here, we report that TP-22 displays D1 receptor antagonist activity. Moreover, we describe the first in vivo tests with TP-22: first, a pilot experiment (assessing dosage and timing of action) identified the 0.25 mg/kg i.v. dosage for locomotor stimulation of rats. Then, a conditioned place preference (CPP) test with the DA-releasing psychostimulant drug, methylphenidate (MPH), involved three rat groups: prior i.v. administration of TP-22 (0.25 mg/kg), or vehicle (VEH), 90 min before MPH (5 mg/kg), was intended for modulation of conditioning to the white chamber (saline associated to the black chamber); control group (SAL) was conditioned with saline in both chambers. Prior TP-22 further increased the stimulant effect of MPH on locomotor activity. During the place-conditioning test, drug-free activity of TP-22+MPH subjects remained steadily elevated, while VEH+MPH subjects showed a decline. Finally, after a priming injection of TP-22 in MPH-free conditions, rats showed a high preference for the MPH-associated white chamber, which conversely had vanished in VEH-primed MPH-conditioned subjects. Overall, the interaction between MPH and pre-treatment with TP-22 seems to improve both locomotor stimulation and the conditioning of motivational drives to environmental cues. Together with recent studies, a main modulatory role of 5-HT7R for the processing of rewards can be suggested. In the present study, TP-22 proved to be a useful psychoactive tool to better elucidate the role of 5-HT7R and its interplay with DA in reward-related behavior.