Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; nZ13, or 400 mg/kg; nZ11) or vehicle (Veh) (nZ11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (R a ) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal R a with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

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METH-or MK-801-induced hyperactivity in rats and MK-801-induced PPI deficits in mice. TAK-063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response induced by HAL or OLA in rats. Discussion: PDE10A inhibitors and HAL showed similar patterns of gene regulation in indirect pathway MSNs in mice. Combined treatment with TAK-063 and either HAL or OLA at subeffective doses produced significant antipsychotic-like effects but no augmentation of the plasma prolactin level and cataleptic response. Although further preclinical and clinical studies will be needed, TAK-063 may provide a novel mechanism as a PDE10A inhibitor for use as combination therapy in schizophrenia. Background: Cannabis use can induce acute and long-lasting psychosis and cognitive dysfunction. Some evidence suggests that the acute behavioral and neurocognitive effects of the main active ingredient in cannabis, (−)-trans-Δ9-tetrahydrocannabinol (∆9-THC), might be modulated by previous cannabis exposure. However, this has not been investigated either using a control group of non-users, or following abstinence in modest cannabis users, who represent the majority of recreational users. Methods: Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, ∆9-THC challenge study. S224Results: Compared to non-users (N=12; <5 lifetime cannabis joints smoked), abstinent modest cannabis users (N=12; 24.5 ± 9 lifetime cannabis joints smoked) showed worse performance and stronger right hemispheric activation during cognitive processing, independent of the acute challenge (all P≤0.047). Acute ∆9-THC administration produced transient anxiety and psychotomimetic symptoms (all P≤0.02), the latter being greater in non-users compared to users (P=0.040). Non-users under placebo (control group) activated specific brain areas to perform the tasks, while deactivating others. An opposite pattern was found under acute (∆9-THC challenge in non-users) as well as residual (cannabis users under placebo) effect of ∆9-THC. Under ∆9-THC, cannabis users showed brain activity patterns intermediate between those in non-users under placebo (control group), and non-users under ∆9-THC (acute effect) and cannabis users under placebo (residual effect). In non-users, the more severe the ∆9-THC-induced psychotomimetic symptoms and cognitive impairments, the more pronounced was the neurophysiological alteration (all P≤0.036). Discussion: Previous modest cannabis use blunts the acute behavioral and neurophysiological effects of ∆9-THC, which are more marked in people who have never used cannabis.