Prenatal exposure to NMDA receptor antagonists like ketamine and methoxetamine in pregnant rats leads to psychosis-like behaviors in their offspring, including hyperactivity and reduced prepulse inhibition (PPI), a measure of sensorimotor gating. These effects are linked to increased expression of the arginine vasopressin receptor 1A (Avpr1a) in the striatum, and artificially overexpressing Avpr1a in the striatum also impairs PPI. Additionally, the treatments raise levels of glutamate decarboxylase 67 (GAD67) and GABA in the striatum, indicating that prenatal NMDA receptor blockade disrupts GABAergic neuron function and sensorimotor gating through Avpr1a regulation.
Reducing levels of the GABA-synthesis enzyme GAD67 in the dorsal striatum of mice increased depression-like behavior but decreased anxiety. The reduction also heightened the rewarding effect of ketamine, measured by conditioned place preference, but did not alter the reward behavior triggered by the cannabinoid agonist JWH-018. The findings suggest that lower striatal GAD67 weakens GABAergic signaling, which may make the brain more vulnerable to ketamine's reward effects by enhancing NMDA receptor inhibition.
In mice, 18 abused drugs (including cocaine, methamphetamine, and several synthetic cannabinoids and cathinones) were tested using intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess their reward-seeking potential. Dopamine transporter (DAT) availability in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) significantly correlated with the ICSS threshold after drug treatment. Extracellular dopamine and calcium levels in PC-12 cells also correlated with the ICSS threshold. The findings suggest that drug-induced reward-seeking behavior may be linked to DAT availability-mediated extracellular dopamine levels in the mPFC and NAc.
The psychoactive substance 25I-NBOMe, a phenethylamine analog, is toxic to heart muscle cells and can disrupt normal heart electrical activity in rats. In laboratory tests, the compound reduced the viability of rat heart cells in a dose-dependent manner, with a half-maximal toxic concentration of 70.4 μM. It also lowered the activity of the protein PAK1, which plays a key role in cardiovascular function. When injected into rats at doses of 1.0 and 3.0 mg/kg, 25I-NBOMe prolonged the QTc interval on electrocardiograms, an abnormal pattern linked to risk of dangerous heart rhythms. The findings suggest that 25I-NBOMe's cardiotoxicity involves PAK1-related pathways.