Fig. 5: Adolescent THC-exposure-induced alterations in neuronal excitability and synaptic function are prevented by NAC co-treatment. | Translational Psychiatry

Fig. 5: Adolescent THC-exposure-induced alterations in neuronal excitability and synaptic function are prevented by NAC co-treatment.

From: The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent Δ-9-tetrahydrocannabinol exposure in male rats

Fig. 5

a Input resistance, b membrane time constant and c resting membrane potential were not affected by adolescent THC treatment (n: VEH = 29, THC = 27, VEH-NAC = 15; THC-NAC = 20). Two-way ANOVAs: a IP treatment: F(1,87) = 2.031,p = 0.158; oral treatment: F(1,87) = 0.297, p = 0.587; IP*oral treatment: F(1,87) = 0.064, p = 0.8. b IP treatment: F(1,87) = 0.176, p = 0.676; oral treatment: F(1,87) = 6.174, p = 0.015; IP*oral treatment: F(1,87) = 1.252, p = 0.266; pairwise comparisons: THC vs. THC-NAC p = 0.01. c IP treatment: F(1,87) = 1.477, p = 0.227; oral treatment: F(1,87) = 2.586, p = 0.111; IP*oral treatment: F(1,87) = 0.789, p = 0.377. d Spike half-width and e spike threshold also did not differ between groups. Two-way ANOVAs: d IP treatment: F(1,87) = 0.335, p = 0.564; oral treatment: F(1,87) = 3.288, p = 0.073; IP*oral treatment: F(1,87) = 0.704, p = 0.404; e IP treatment: F(1,87) = 0.009, p = 0.926; oral treatment: F(1,87) = 3.075, p = 0.083; IP*oral treatment: F(1,87) = 0.138, p = 0.711. f Spike AHP was augmented by NAC treatment. Two-way ANOVA: IP treatment: F(1,87) = 0.023, p = 0.88; oral treatment: F(1,87) = 10.52, p = 0.002; IP*oral treatment: F(1,87) = 0.107, p = 0.745; pairwise comparisons: VEH vs. VEH-NAC p = 0.05; THC vs. THC-NAC p = 0.01. g Response of representative layer 2/3 mPFC pyramidal neurons obtained from different treatment groups to current step of +230 pA (square pulse illustrated below voltage trace). h Neuronal gain curves indicate a trend toward increase in excitability following THC exposure, although no interactions with treatments were detected. Two-way repeated measures ANOVA: depolarization step: F(5,435) = 244.787, p < 0.001; depolarization step*IP treatment: F(5,435) = 1.817, p = 0.108; depolarization step*oral treatment: F(5,435) = 0.556, p = 0.734; depolarization step*IP*oral treatment: F(5,435) = 1.526, p = 0.180. i Example traces illustrating action potential firing in response to a current ramp (ramping current injection from 0–400 pA in 1.5 s; 0.266 pA/ms). j Average no. of spikes/ramp was significantly increased following THC exposure. Two-way ANOVA: IP treatment: F(1,85) = 5.197, p = 0.025; oral treatment: F(1,85) = 2.251, p = 0.137; IP*oral treatment: F(1,85) = 3.874, p = 0.052; pairwise comparisons: VEH vs. THC p = 0.001; THC vs. THC-NAC p = 0.013. k Percentage of cells with more/less than 10 spikes in a ramp across treatment groups. l sEPSCs frequency was increased in cells from THC-exposed rats (n = 15–21/group). Two-way ANOVA: IP treatment: F(1,67) = 3.039, p = 0.086; oral treatment: F(1,67) = 10.265, p = 0.002; IP*oral treatment: F(1,67) = 6.475, p = 0.013; pairwise comparisons: VEH vs. THC p = 0.002; THC vs. THC-NAC p < 0.001. m Percentage of cells with sEPSC freq< or >2 Hz across different groups (n: VEH = 17, THC = 21, VEH-NAC = 15; THC-NAC = 16). n sEPSCs amplitude was increased in cells from NAC exposed rats, but not affected by THC exposure. Two-way ANOVA: IP treatment: F(1,67) = 0.497, p = 0.483; oral treatment: F(1,67) = 15.118, p < 0.001; IP*oral treatment: F(1,67) = 0.269, p = 0.606; pairwise comparisons: VEH vs. VEH-NAC: p = 0.022; THC vs. THC-NAC: p = 0.002. o Percentage of cells with average sEPSCs amplitude smaller/larger than 10 mV across treatments. p Examples of sEPSCs recorded from adult pyramidal neurons following different adolescent treatments. q Paired-pulse facilitation ratio is not affected by adolescent treatment (n: VEH = 11, THC = 9, VEH-NAC = 15; THC-NAC = 17). Two-way RM ANOVA: stimulation interval: F(3,144) = 6.805,p < 0.001; stimulation interval*IP treatment: F(3,144) = 0.832, p = 0.478; stim interval*oral treatment: F(3,144) = 0.172, p = 0.915; Stim interval*IP*oral treatment: F(3,144) = 1.311, p = 0.273. r Example recordings representing EPSCs evoked by stimulation pulses delivered with 20, 50, 100 and 200 ms interval (from top to bottom). s Schematic depiction of LFP recording with an example raw signal trace and power spectrum analysis (inset). t and u Average normalized power for specific oscillatory bands was affected by adolescent treatments (n: VEH = 8, THC = 8, VEH-NAC = 6; THC-NAC = 7). Two-way ANOVAs for delta: IP treatment: F(1.25) = 2.523, p = 0.125; oral treatment: F(1.25) = 23.012, p < 0.001; IP*oral treatment: F(1.25) = 1.919, p = 0.178; pairwise comparisons: VEH vs. THC: p = 0.035; VEH vs. VEH-NAC: p = 0.026; THC vs. THC-NAC: p < 0.001; theta: IP treatment: F(1.25) = 0.109, p = 0.744; oral treatment: F(1.25) = 15.214, p < 0.001; IP*oral treatment: F(1.25) = 0.533, p = 0.472; pairwise comparisons: VEH vs. VEH-NAC: p = 0.038; THC vs. THC-NAC: p = 0.003; alpha: IP treatment: F(1.25) = 1.428, p = 0.243; oral treatment: F(1.25) = 25.1, p < 0.001; IP*oral treatment: F(1.25) = 0.076, p = 0.785; pairwise comparisons: VEH vs. VEH-NAC: p = 0.003; THC vs. THC-NAC: p < 0.001; beta: IP treatment: F(1.25) = 2.449, p = 0.13; oral treatment: F(1.25) = 14.204, p < 0.001; IP*oral treatment: F(1.25) = 0.083, p = 0.776; pairwise comparisons: VEH vs. VEH-NAC: p = 0.024; THC vs. THC-NAC: p = 0.007; gamma: IP treatment: F(1.25) = 4.432, p = 0.045; oral treatment: F(1.25) = 6.456, p = 0.018; IP*oral treatment: F(1.25) = 4.784, p = 0.038; pairwise comparisons: VEH vs. THC: p = 0.004; THC vs. THC-NAC: p = 0.002. Patch clamp recordings were taken from layer 2/3 mPFC pyramidal neurons obtained from 28 adult male rats (VEH = 7, THC = 8, VEH-NAC = 5; THC-NAC = 8).

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