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. 2016 May 4;36(18):5160-9.
doi: 10.1523/JNEUROSCI.3387-15.2016.

Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway Through a Novel mTOR/p70S6 Kinase Signaling Pathway

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Free PMC article

Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway Through a Novel mTOR/p70S6 Kinase Signaling Pathway

Justine Renard et al. J Neurosci. .
Free PMC article

Abstract

Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined with in vivo single-unit neuronal electrophysiology recordings in the ventral tegmental area, and molecular analyses to characterize the actions of CBD directly in the nucleus accumbens shell (NASh), a brain region that is the current target of most effective antipsychotics. We demonstrate that Intra-NASh CBD attenuates AMPH-induced sensitization, both in terms of DAergic neuronal activity measured in the ventral tegmental area and psychotomimetic behavioral analyses. We further report that CBD controls downstream phosphorylation of the mTOR/p70S6 kinase signaling pathways directly within the NASh. Our findings demonstrate a novel mechanism for the putative antipsychotic-like properties of CBD in the mesolimbic circuitry. We identify the molecular signaling pathways through which CBD may functionally reduce schizophrenia-like neuropsychopathology.

Significance statement: The cannabis-derived phytochemical, cannabidiol (CBD), has been shown to have pharmacotherapeutic efficacy for the treatment of schizophrenia. However, the mechanisms by which CBD may produce antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses and in vivo neuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway.

Keywords: cannabidiol; dopamine; mesolimbic system; nucleus accumbens; schizophrenia; ventral tegmental area.

Figures

Figure 1.
Figure 1.
Effects of Intra-NASh VEH versus CBD (100 ng/0.5 μl) pretreatment on AMPH-induced hyperlocomotion. A, Schematic representations of microinfusion locations in the NASh of AMPH-sensitized rats. Black circles represent CBD (100 ng). Gray circle represents VEH. B, Microphotograph of a representative Intra-NASh injector placement. C, Exposure to AMPH (5 d, 5 mg/kg) followed by an 11 day sensitization period caused a typical pattern of AMPH-induced psychomotor sensitization in Intra-NASh VEH-pretreated rats. D, Ambulatory activity assessed in 5 min epochs over the 60 min recording session and total ambulatory activity. Intra-NASh CBD pretreatment significantly decreases the AMPH-induced locomotor activity observed in Intra-NASh VEH-pretreated rats. E, Intra-NASh CBD pretreatment significantly decreases AMPH-induced rearing observed in Intra-NASh VEH-pretreated rats. F, Intra-NASh CBD pretreatment significantly decreases AMPH-induced stereotypy observed in Intra-NASh VEH-pretreated rats. VEH/ Intra-NASh VEH, n = 9; VEH/Intra-NASh CBD, n = 10; AMPH/Intra-NASh CBD, n = 10; AMPH/Intra-Nash VEH, n = 8. **p < 0.01 (one-way ANOVA). *p < 0.05 (one-way ANOVA). ns, Not significant. Error bars indicate SEM. ac, Anterior commissure; NACore, core subdivision of the nucleus accumbens; VP, ventral pallidum.
Figure 2.
Figure 2.
Effects of chronic Intra-NASh VEH or CBD (100 ng/0.5 μl) pretreatment on NAc expression levels of members of the Wnt (GSK-3, Akt, β-catenin) and mTORC1 (mTOR, p70S6K) signal transduction pathway in AMPH-sensitized rats. A, Representative Western blot for phosphorylated and total GSK-3α and GSK-3β expression in the NAc (left). Densitometry analysis revealed a decrease in both phosphorylated GSK-3β and the ratio of phosphorylated to total GSK-3β in Intra-NASh CBD compared with Intra-NASh VEH AMPH-sensitized rats. No significant changes in total GSK-3β, and other levels of GSK-3α are observed. B, Representative Western blot for phosphorylated and total Akt expression in the NAc (left). Densitometry analysis revealed a decrease in both phosphorylated Akt and the ratio of phosphorylated to total Akt in Intra-NASh CBD- compared with Intra-NASh VEH AMPH-sensitized rats. No significant changes in total Akt are observed. C, Representative Western blot for β-catenin expression in the NAc (left). No significant changes in β-catenin expression are observed between Intra-NASh VEH- and CBD-AMPH-sensitized rats. D, Representative Western blot for phosphorylated and total mTOR expression in the NAc (left). Densitometry analysis revealed an increase in both phosphorylated mTOR and the ratio of phosphorylated to total mTOR in Intra-NASh CBD- compared with Intra-NASh VEH AMPH-sensitized rats. No significant changes in total mTOR are observed. E, Representative Western blot for phosphorylated and total p70S6K expression in the NAc (left). Densitometry analysis revealed an increase in both phosphorylated p70S6K and the ratio of phosphorylated to total p70S6K in Intra-NASh CBD- compared with Intra-NASh VEH AMPH-sensitized rats. No significant changes in total p70S6K are observed. **p < 0.01 (t test). *p < 0.05 (t test). Error bars indicate SEM.
Figure 3.
Figure 3.
Effects of Intra-NASh VEH, -CBD, -CBD+Torin2 or -CBD+PF 4708671 (PF) pretreatment on AMPH-induced psychomotor sensitization. A, Intra-NASh CBD pretreatment significantly decreases AMPH-induced locomotor activity observed in Intra-NASh VEH-pretreated rats. Intra-NASh CBD cotreatment with either Torin2 or PF significantly reverses CBD-induced decreases in hyperactivity. B, Intra-NASh CBD pretreatment significantly decreases AMPH-induced rearing observed in Intra-NASh VEH-pretreated rats. Intra-NASh CBD cotreatment with Torin2 significantly reverses CBD-induced attenuation in rearing, whereas Intra-NASh CBD cotreatment with PF has no effect. C, Intra-NASh CBD pretreatment significantly decreases AMPH-induced stereotypies observed in Intra-NASh VEH-pretreated rats. Intra-NASh CBD cotreatment with either Torin2 or PF significantly reverses CBD-induced decrease in stereotypy levels. Intra-NASh CBD, n = 10; Intra-Nash VEH, n = 8; Intra-NASh Torin2+CBD, n = 8; Intra-NASh PF+CBD, n = 8. The Intra-Nash CBD and VEH groups are the same as those shown in Figure 1. **p < 0.01 (one-way ANOVA). *p < 0.05 (one-way ANOVA). Error bars indicate SEM.
Figure 4.
Figure 4.
Effects of Intra-NASh VEH, -CBD, -CBD+Torin2 or - CBD+PF 4708671 (PF) pretreatment on AMPH-induced PPI deficit. Exposure to AMPH (5 d, 5 mg/kg) followed by an 11 day sensitization period caused PPI deficit in Intra-NASh VEH-pretreated rats. Intra-NASh CBD pretreatment significantly decreases the AMPH-induced PPI deficit observed in Intra-NASh VEH-pretreated rats. Intra-NASh CBD cotreatment with either Torin2 or PF significantly reverses CBD-induced increases in PPI. VEH/Intra-NASh VEH (VEH/VEH), n = 8; VEH/Intra-NASh CBD (VEH/CBD), n = 9; AMPH/Intra-NASh VEH (AMPH/VEH), n = 9; AMPH/Intra-NASh CBD (AMPH/CBD), n = 9; AMPH/Intra-NASh Torin2+CBD (AMPH/Torin2+CBD), n = 10; and AMPH/Intra-NASh PF +CBD (AMPH/PF+CBD), n = 10. **p < 0.01 (two-way repeated-measures ANOVA). *p < 0.05 (two-way repeated-measures ANOVA). Error bars indicate SEM.
Figure 5.
Figure 5.
Effects of Intra-NASh VEH versus CBD on VTA DA neuronal activity following AMPH challenge. A, Histological localization of microinfusion sites in the NASh and recording sites in the VTA for each treatment condition performed during electrophysiological recordings. Black circles represent CBD (100 ng). Gray circle represents VEH. A total of n = 19 VTA DA neurons were sampled: Intra-NASh VEH group, n = 10 cells in 8 rats; Intra-NASh CBD (100 ng/0.5 μl) group, n = 9 cells in 6 rats. B, Microphotograph of a representative VTA neuronal recording placement. C, Time-dependent consequences of Intra-NASh VEH and CBD (100 ng/0.5 μl) treatments on VTA DA neuronal firing frequency following the challenge dose of systemic AMPH (1 mg/kg). D, Time-dependent consequences of Intra-NASh VEH and CBD (100 ng/0.5 μl) treatments on VTA DA spikes firing in burst mode following AMPH challenge. E, Representative histogram showing the increase response activity of one DA neuron following the microinfusion of Intra-NASh VEH and systemic AMPH (top) or Intra-NASh CBD and systemic AMPH (bottom). Inset, Action potential waveform of the selected neuron. F, Activity patterns observed 20 min after the microinfusions of either Intra-NASh VEH (top) or CBD (bottom) and systemic AMPH. **p < 0.01 (two-way repeated-measures ANOVA). *p < 0.05 (two-way repeated-measures ANOVA). Error bars indicate SEM.

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