34 of second messenger systems. Because GABA1 plays a critical role in controlling the excitability of neurons, cortico-striatal GABAergic neurons is implicated in the pathogenesis of several of the pertinent conditions discussed here, i.e. OCD2 (Richter et al. 2012), ASD3 (Fatemi, Folsom, et al. 2009; Fatemi, Reutiman, et al. 2009) and MDD4 (Prevot and Sibille 2021).
35 et al. 2015; Katzman et al. 2014; Szechtman et al. 2020; Geller et al. 2003) and ASD1 (Eissa et al. 2018;
Soorya, Kiarashi, and Hollander 2008; Lacivita et al. 2017), SSRIs2 act on the limbic system to improve mood in patients with depression (Warren, Pringle, and Harmer 2015; Hensler 2006). Yet, for all these conditions, treatment resistance invariably remains a clinical challenge (Williams et al. 2013; Kolevzon, Mathewson, and Hollander 2006; Fineberg et al. 2015; Bedford, Hunsche, and Kerns 2020), in which case augmentation strategies are followed.
While different augmentation approaches can be followed, modulation of dopaminergic signalling is one of the foremost. To this end, low-dose anti-dopaminergic drugs, e.g. risperidone, olanzapine and quetiapine, are usually added to current SRI/SSRI regimens in OCD3 and ASD, but less so for patients with MDD4, except if there is a need for neuroleptic intervention (Erzegovesi et al. 2005; Misri and Milis 2004; Fineberg et al. 2015; Dold et al. 2015; Kumar et al. 2012; Carvalho et al. 2007). To the contrary, patients with MDD normally benefit from pro-dopaminergic intervention, e.g. the dopamine and norepinephrine reuptake inhibitor, bupropion and the dopaminergic agonists, bromocriptine and pergolide (Sherdell, Waugh, and Gotlib 2012; Forbes et al. 2009; Tremblay et al. 2002; Papakostas 2006).
While the primary objective of treatment in OCD and ASD is to engender control over a highly dysregulated CSTC5 circuit pathway (by blocking D2 receptor activation), the focus of dopaminergic intervention in MDD is to bolster phasic dopamine release in both the CSTC pathways and the limbic system (Tremblay et al. 2002; Pruessner et al. 2004; Thase et al. 2007; Moreines et al. 2017), thereby increasing the motivational valence of rewarding outcomes (Salamone et al. 2003; Berridge and Robinson 1998; Yadid and Friedman 2008).
Since CF6 may variably be affected in different phenotypes of these disorders, and since both CF and CR7 are related to the functioning of the dopamine- and serotonin-regulated CSTC pathways, it would be important to ask how said treatments of the disorders referred to above, influence CF and CR. In fact, it is possible that in patients with no perturbations in the balance between CF and CR, such abnormalities could be elicited by altering CSTC function, while in others already suffering from deficits in CF, could show improvement. Indeed, this possibility has been highlighted in clinical investigations before. Briefly, with respect to the dopaminergic system as example, the relationship between cognitive task execution (used to measure CF) and dopamine modulation is exceedingly complex, due to paradoxical observations of improvement as well as impairment in said tasks through the administration of the same
1 autism spectrum disorders
2 selective serotonin reuptake inhibitors
3 obsessive-compulsive disorder
4 major depression disorder
5 cortical-striatal-thalamic-cortical
6 cognitive flexibility
7 cognitive rigidity
36 drug (Cools and D'Esposito 2011; Cools et al. 2001; Mehta et al. 2004). The findings of these psychopharmacological studies indicate that the effect of the dopaminergic drug is dependent on the baseline performance levels of the individual performing the task (Kimberg, D'Esposito, and Farah 1997;
Kimberg and D’Esposito 2003; Gibbs and D’Esposito 2005). For example, administration of bromocriptine to healthy volunteers improved performance in a working memory task of subjects with a lower baseline (before treatment) working memory capacity. However, it worsened the performance of subjects with a higher pre-treatment capacity (Kimberg, D'Esposito, and Farah 1997). Since this phenomenon was observed, it was repeatedly identified in numerous studies using different dopamine- modulating agents and applying various methods that assess cognitive task execution (measures of CF1) (Frank and O'Reilly 2006; Cools et al. 2007; Cools et al. 2009; Sawamoto et al. 2008). As such, it was shown that low levels of performance in light of psychopathology could be remedied by agonistic drug therapy, while the same drug could worsen already optimal performance (Cools and D'Esposito 2011).
At a simpler level, bolstered dopaminergic signalling can induce rigid and repetitive behaviours that may be reminiscent of compulsive-like behaviours in animals (Cinque et al. 2018; Szechtman, Sulis, and Eilam 1998) and humans, presumably in part by modulating CSTC2 circuit activity (Hassan et al. 2011).
Touching on glutamatergic and GABAergic signalling, results are promising, though not yet sufficient to influence currently accepted treatment approaches. Still, altered glutamate and GABA3 concentrations and signalling intensities have been shown in OCD4 (Pittenger, Bloch, and Williams 2011; Winter et al.
2018), MDD5 (Sanacora, Treccani, and Popoli 2012; Abdallah et al. 2014; Prevot and Sibille 2021) and ASD6 (Horder et al. 2018; Pizzarelli and Cherubini 2011). One of the most investigated glutamatergic modulators, e.g. the NMDA7 receptor antagonist, ketamine, not only shows promise as a rapid-acting antidepressant (Ionescu and Papakostas 2016), but has also been trialled in OCD and ASD. This makes sense, given a proposed role for heightened glutamatergic activation of the CSTC pathways in these conditions (Chakrabarty et al. 2005; Rolls 2012; Duman, Sanacora, and Krystal 2019; Rubenstein and Merzenich 2003). Even though the exact manner in which the drug influences psychobiological processes is still unknown, the general consensus is that ketamine modulates excitatory synapses within affected brain regions, thereby resulting in stabilisation of excessive excitatory signalling, neuroprotection and improved symptomology (Zanos et al. 2018; Li et al. 2010; Autry et al. 2011). It is also believed that ketamine acts via both NMDA receptor-dependent and independent mechanisms
1 cognitive flexibility
2 cortical-striatal-thalamic-cortical
3 gamma-aminobutyric acid
4 obsessive-compulsive disorder
5 major depression disorder
6 autism spectrum disorders
7 N-methyl-D-aspartate
37 (Kadriu et al. 2019; Zanos et al. 2018), which also increases GABAergic signalling and reduces glutamate release. Importantly, these mechanisms potentially share some overlap with the actions of LEV1, which will be investigated in this work (see paragraph 2.4; Zanos et al. (2018); Kadriu et al. (2019)).
Results for GABAergic compounds are less robust. Benzodiazepines allosterically modulate GABAA
receptors, increasing binding of GABA2 to the complex(Möhler, Fritschy, and Rudolph 2002). While demonstrating acute treatment potential, these agents show little promise in the long-term treatment of conditions characterised by abnormal GABAergic functioning, e.g. OCD3, ASD4 and MDD5 due to their noteworthy side-effect profile and high potential for abuse (Möhler, Fritschy, and Rudolph 2002; Petty et al. 1995; Duman, Sanacora, and Krystal 2019; Pehrson and Sanchez 2015). Recently, GABAergic compounds with more acceptable side-effect profiles, including the neuroactive steroids (specifically allopregnanolone and its analogues, brexanolone and SAGE-217, which are also positive allosteric modulators of the GABAA receptor complex), reached the market (Duman, Sanacora, and Krystal 2019;
Fogaça and Duman 2019; MacKenzie and Maguire 2013). The major mechanism of action of these agents is related to restoring the GABA-mediated excitatory-inhibitory imbalance in the CSTC6-circuit (Prevot and Sibille 2021; Ren et al. 2016; Rodriguez et al. 2013; Peyrovian et al. 2020).