Introduction
Schizophrenia is a heterogenous psychotic disorder that remains incurable. There are roughly over 21 million people living with schizophrenia, a prevalence that has been increasing over the last two decades (Charlson et al., 2018). Schizophrenia has multiple symptom presentations that typically emerge in late adolescence and early adulthood. These include positive (e.g., psychosis and delusions), negative (e.g., anhedonia and flat affect), and cognitive (e.g., memory deficits) symptoms (Marder & Galderisi, 2017; Marzouk et al., 2020; Bowie & Harvey, 2006). Current treatment comes with unpleasant extrapyramidal side effects and may not provide long term relief (Lally & MacCabe, 2015). Negative symptoms are more strongly correlated with poorer baseline functioning (Rabinowitz et al., 2012; Leifker, Bowie, & Harvey, 2009), and appear to be resistant against current antipsychotic treatment (Hanson et al., 2010; Lin, Tsai, & Lane, 2014). Thus, new alternative treatments are needed that are better tolerated and continue to provide relief.
Glutamate influences the development of schizophrenia through the N-methyl-D-aspartate receptor (NMDAR) system. NMDAR antagonists are frequently used as models of schizophrenia in animal research, and symptoms induced in rodents are comparable to clinical schizophrenia (Krystal et al., 1994; Javitt & Zukin, 1991). Dizocilpine (MK-801) is an NMDAR antagonist often used to model schizophrenia and has been shown to induce a number of behaviors in rodents that are indicative of schizophrenia-like behavior such as increased locomotor activity, changes in locomotor activity in response to stress, pre-pulse inhibition deficits, impaired spatial memory, and social withdrawal (Bubeníková-Valešová et al., 2008), and similar behaviors are seen in humans (Seillier & Giuffrida, 2009; Bubeníková-Valešová et al., 2008).
The neuro-modulatory serotonergic and endocannabinoid systems have been implicated in psychotic illness as potential therapeutic pathways (Davies & Bhattacharyya, 2019; Yang & Tsai, 2017). Serotonin is implicated in schizophrenia because it is a primary regulator of dopamine and second-generation antipsychotics antagonize 5-hydroxytryptamine receptor 2A (5-HT2AR) to provide relief for negative symptoms more so than first-generation antipsychotics (Kim, 2021; Ohno, 2011). Indeed, drugs that are 5-hydroxytryptamine receptor 1A (5-HT1AR) agonist provide relief for positive and negative symptoms without extrapyramidal side effects (Lobo et al., 2022). Moreover, increased 5-HT1AR receptor density is seen in schizophrenic patients, and may be sensitized due to overstimulating serotonin 5-HT2A receptors (Kim, 2021). Dopaminergic and serotoninergic neurons can communicate with the endocannabinoid system to regulate excitability within the brain via glutamate and γ-aminobutyric acid (GABA; Peters, Cheer, & Tonini, 2021), therefore there are complex crosstalk relationships in the regulation of glutamate activity. Agonizing cannabinoid receptor type 1 (CB1R) results in increased glutamate and dopamine and increases locomotive activity consistent in schizophrenic-like behavior (Polissidis et al., 2013). Conversely, antagonizing CB1R results in symptom relief (Ballmaier et al., 2007).
This study tested deficits induced by MK-801 in mice and investigate if cannabidiolic acid (CBDA) methyl ester (HU-580) would provide therapeutic relief. HU-580 is a more stable CBDA analogue that is shown to be a strong agonist of 5-HT1AR and an antagonist of CB1R (Pertwee et al., 2018; Navarro et al., 2020). We have ascertained that exposure to MK-801 would induce schizophrenic-like behaviors and pathophysiology that would be attenuated by HU-580.