Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

by Selleckchem | Dec 29 2023

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30-45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3β (GSK3β), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3β signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

Comments:

The study you're referencing delves into the impact of adolescent exposure to ethanol (alcohol), delta-9-tetrahydrocannabinol (THC), and their combined use on brain plasticity, particularly in the prelimbic region of the medial prefrontal cortex (mPFC) in rats. The findings suggest several significant effects:

1. **THC Exposure Effects:** THC exposure led to reduced body weight gain in rats and decreased their intake of saccharin (used as a control substance) and ethanol.

2. **Long-Term Impact on Neuronal Plasticity:** Exposure to either THC or ethanol alone resulted in a significant reduction in high frequency stimulation (HFS)-induced long-term depression (LTD) in the mPFC. Interestingly, rats exposed to the combination of THC and ethanol showed an absence of LTD.

3. **GABA and GSK3β Signaling Involvement:** The study suggests that lasting adaptations in GABA (gamma-aminobutyric acid) and GSK3β (glycogen synthase kinase 3β) signaling might be contributing factors to the observed effects. Bath application of indiplon (enhancing GABAA receptor function) or AR-A014418 (inhibiting GSK3β) indicated that the effects of ethanol, THC, or their combination might be partially due to alterations in these signaling pathways.

These findings emphasize the potential long-term impact of co-exposure to alcohol and cannabis during adolescence on the mPFC's output and neuronal signaling. The alterations observed in LTD, body weight, and substance intake suggest that the combination of these substances might induce unique effects compared to exposure to each substance alone. The involvement of GABA and GSK3β signaling pathways further adds complexity to understanding the mechanisms behind these lasting adaptations.