THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia

Abstract

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach.

Keywords: THC; electrophysiology; endocannabinoids; prefrontal cortex; schizophrenia; ventral hippocampus.

Figure 1

Experimental timeline for surgery, subchronic injections, and recordings (A) as well as the timeline of each experimental recording session (B). The vehicle and URB597 experiments were performed in a counterbalanced order, with the THC experiment always occurring last to minimize potential confounds associated with THC-induced CB1 receptor desensitization.

Figure 2

Schematic demonstrating the electrode track placements throughout the medial prefrontal cortex (A) and ventral hippocampus (B). Target areas are outlined in grey. Histology was performed with reference to a stereotaxic atlas (Paxinos and Watson, 1986).

Figure 3. Single unit activity in the PFC

Before-after plots of the average mPFC firing rate per animal at baseline and 120 minutes after acute treatment of vehicle (A), URB597 (B), or THC (C). Group means are in foreground (black) while individual animal means are in the background (grey). URB597 increases the average firing rate of mPFC cells in PCP but not saline treated animals (B). THC decreases the average firing rate of mPFC cells in saline but not PCP treated animals (C). Frequency histograms (D-G) were fit by Gaussian models and effects of URB597 or THC can be seen as shifts in the distribution. * represents significant difference from baseline (two-way RM ANOVA p<0.05)

Figure 4. Single unit activity in the vHipp

Before-after plots of the average vHipp firing rate per animal at baseline and 120 minutes after acute treatment of vehicle (A), URB597 (B), or THC (C). Group means are in foreground (black) while individual animal means are in the background (grey). No significant changes in firing rate were evoked by vehicle, URB597, or THC. Nevertheless, URB597 appeared to increase firing rate in both groups (main effect of URB – p<0.06) while THC evokes a significant interaction that suggests a decreased firing rate in saline rats and the opposite response in PCP treated rats. Frequency histograms (D-G) were fit by Gaussian models and effects of URB597 or THC can be seen as shifts in the distribution.

Figure 5. Coordinated activity in the mPFC

Analysis of power spectral density within the mPFC demonstrates a significant increase in low gamma power (30-55 Hz) in response to URB597 whereas no effects of THC were observed. † depicts main effect of URB597 (two-way RM ANOVA).

Figure 6. Coordinated activity in the vHipp

Analysis of power spectral density within the vHipp demonstrates a significant decrease in delta rhythms in response to URB597 whereas no effects of THC were observed. † depicts main effect of URB597 (two-way RM ANOVA).

Figure 7. Hippocampal – prefrontal coherence

Coherence between the vHipp and mPFC is differentially altered by URB597 and THC. Specifically, delta coherence is decreased by URB597 but increased by THC administration. No other effects were observed for either URB597 in THC in any other frequency band. † depicts main effect of drug (two-way RM ANOVA).