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.