Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial

Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information (Freedman et al. 1983). The typical sensory gating paradigm consists of two identical auditory stimuli that are presented shortly after each other. The main principle is that the response, as measured by scalp EEG, to the second stimulus (S2) will be smaller than the response to the first stimulus (S1). In humans, the P50 (i.e., the response evoked 50 ms after stimulus onset) of the event-related potential (ERP) is believed to be the main component in the sensory gating paradigm. Although the P50 reflects information processing at early stages, it has also been associated with different cognitive functions (Yadon et al. 2009).

Human research has shown indications for disruptions in sensory gating in clinical disorders including attention deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer’s disease (Adler et al. 1982; Ally et al. 2006; Micoulaud-Franchi et al. 2015). However, the whole concept of cognition in humans and the relation to sensory gating is still under investigation. For instance, the P50 has been suggested as a biomarker for the evaluation of drugs that may potentially have a beneficial effect on cognitive functions in schizophrenia (Javitt et al. 2008), but despite the prominent role that P50 abnormalities have played in our understanding of schizophrenia, more data is needed to fully incorporate P50 as clinical correlate (Potter et al. 2006). One advantage of this EEG-related measure is that it can be used for translational purposes (Blokland et al. 2015).

In the last decades, phosphodiesterase (PDE) inhibitors have received an increasing interest as a tool to improve cognitive performance in both animals and man (Reneerkens et al. 2009). As the initial focus of cognition enhancement was directed towards memory function, nowadays the relation between PDEs and cognitive processing is also investigated beyond the memory domain (e.g., Heckman et al. 2016). One cognitive process in which PDE inhibitors might play a role is sensory gating (see Fig. 1).

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Overall, only a limited number of human and animal studies have tested the effects of PDE inhibitors on sensory gating. Redrobe and colleagues (2014), using the relatively new PDE2 inhibitor Lu AF64280, managed to induce an effect on sensory gating, i.e., reduction of an amphetamine-induced gating deficit in DBA2 mice. Two studies by Reneerkens et al. (2013a, b) found no effects of either the PDE2 inhibitor BAY 60-7550 in rats, or the PDE5 inhibitor vardenafil in healthy rats as well as healthy young humans (in the absence of a deficit model). Another class of PDE inhibitors tested in the sensory gating paradigm is PDE10A inhibitors. PDE10A inhibitors are chosen with respect to the search for new antipsychotics in the field of schizophrenia research due to the high and exclusive expression of PDE10A in the striatum (Lakics et al. 2010). However, the effects of PDE10A inhibitors in animal models are mixed. On the one hand, no effects were found for the PDE10A inhibitor PQ-10 in healthy rats (Reneerkens et al. 2013a), an amphetamine-deficit model, or a phencyclidine (PCP) deficit model (Ahnaou et al. 2016). On the other hand, TP-10, another more potent PDE10A inhibitor, reversed impaired sensory gating in the hippocampus using the amphetamine-induced deficit model in rats (Schmidt et al. 2008).

The PDE9 inhibitor PF-4447943 and PF-4449613 reversed an amphetamine-induced sensory gating deficit in mice (Kleiman et al. 2012). Additionally, PF-4447943 was tested in transgenic BACHD rats and Q175 mice (both transgenic animal models for Huntington’s disease exhibiting impaired sensory gating) (Nagy et al. 2015). PF-4447943 dose-dependently improved the gating deficit in the primary auditory cortex and hippocampus of transgenic BACHD rats. Daily administration of PF-04447943 (1 mg/kg) over 7 days resulted in a complete recovery in their auditory gating in two brain regions (i.e., the cortex and hippocampus). In Q175 mice, including wild-type, heterozygote, and homozygote mice, PDE9 inhibition was without any effect. PDE4 inhibitors were tested in a sensory gating paradigm in two separate studies. The first study tested the first-generation PDE4 inhibitor rolipram (Maxwell et al. 2004) and found that rolipram normalized the amphetamine-induced gating deficit in the hippocampus of mice. Another PDE4 inhibitor, RO-20-1724, (Halene and Siegel 2008) also restored gating in the hippocampus of mice using an amphetamine-induced deficit model.

Although there are great similarities between the ERPs of humans and rats, it has been argued that basic components of sensory gating may still differ between both species (e.g., de Bruin et al. 2001). Nevertheless, compared to other cognitive measures, ERPs are one of the most translational tools available to date (Blokland et al. 2015). Therefore, we expect that the effects of PDE inhibitors on sensory gating in animals translate to humans (c.f., Maxwell et al. 2004). Based on the few studies that are available, it appears that PDE4 is a promising PDE subtype in this respect (see Heckman et al. 2015). The PDE4 inhibitor roflumilast was the first oral-obtainable PDE4 inhibitor clinically approved at a daily dose of 500 μg, i.e., to treat chronic obstructive pulmonary disease (COPD). However, some typical side-effects have been observed for PDE4 inhibitors, such as nausea and emesis. Recently, we have shown that roflumilast is a brain penetrant and improves short-term and long-term memory in rodents (Vanmierlo et al. 2016). Importantly, a PET study with the ligand [18F]B9302-107 for roflumilast confirmed that the currently marketed dose for COPD is also a brain penetrant in humans (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf, p. 150–151). On basis of this existing data, we investigated the effects of the PDE4 inhibitor roflumilast on sensory gating in humans. We tested the acute effects in healthy young human volunteers at three different doses in a double-blind placebo-controlled study. We hypothesized roflumilast to enhance sensory gating in healthy young humans without exhibiting an effect on overall auditory processing as indicated by auditory-evoked potentials (AEP).

In the current study, we investigated whether the PDE4 inhibitor roflumilast could enhance sensory gating in healthy young human volunteers without exhibiting an effect on overall auditory processing as indicated by AEP. Results showed that roflumilast significantly improved sensory gating in healthy young human volunteers in a dose-dependent manner. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in COPD. Notably, no emetic side-effects were reported by the participants after administration of this low dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study. Nausea was only occasionally reported at the 300- and 1000-μg dose. This shows a favorable side-effect profile of roflumilast at a dose of 100 μg.

As shortly mentioned before, a clear distinction should be made between effects on AEPs (S1) and effects on sensory gating, even though both are considered “early information processing.” Different PDE families and their inhibitors can distinctively affect AEPs and sensory gating. Furthermore, whether sensory gating is expressed as a ratio score (e.g., S2/S1), difference score (e.g., S1 − S2), proportional score (e.g., S1 − S2/S2), or percentage score (e.g., (S1 − S2/S2)× 100), it always explains S2 in terms of S1. An effect on AEPs after S1 will also change the ratio between S1 and S2 which has to be taken into consideration when interpreting an effect on sensory gating. An effect on S1 indicates an effect on basic information processing. To induce a true effect on sensory gating, S1 should not be affected by the drug. A significant S2 effect (decreasing amplitude) would support drug effects on sensory gating. However, this is not necessary, as long as the relative gating score is showing significant drug effects, i.e., there is a difference on this score between drug conditions. We found that S1 did not differ between the placebo and the 100 μg roflumilast condition. Also, roflumilast did not affect S1 and that the S1-S2 ratio was enhanced after treatment with the 100-μg dose. This indicates that roflumilast specifically enhances P50 gating in young healthy volunteers.

Another point of attention regards the fact that in preclinical studies, an amphetamine-induced deficit was reversed by a PDE4 inhibitor (Maxwell et al. 2004; Halene and Siegel 2008). This might be related to a similar mechanism compared to enhanced unimpaired sensory gating in healthy volunteers. In schizophrenia, the dopamine hypothesis has been revised to postulate that positive symptoms, in particular, arise from hyperactivation of the dopaminergic D2 receptor subtype in mesolimbic brain regions (Brisch et al. 2014). Disruptive effects of amphetamine on sensory gating are suggested to be caused by hyperactive dopamine transmission resembling the dopamine hypothesis in schizophrenia (Smucny et al. 2015). Thus, amphetamine increases the levels of mesolimbic dopamine and this extra dopamine activates the mesolimbic D2 receptors on the inhibitory interneurons in, for instance, the hippocampus. Activation of D2 receptors inhibits the inhibitory interneurons. Excessive dopamine levels will thus lead to excessive throughput and thereby impair normal gating. This hypothesis is supported by the fact that D2 receptor antagonists can prevent the amphetamine-induced deficits in sensory gating (During et al. 2014; Witten et al. 2016). D2 receptor antagonism prevents inhibition of the inhibitory interneurons responsible for sensory gating by amphetamine.

However, it should be noted that in the field of schizophrenia research, dopaminergic drugs (D2 antagonists) generally show no gating-enhancing effects. Also, D2 receptor antagonism has not convincingly shown to affect sensory gating in healthy subjects (either animal or man; e.g., Nagamoto et al. 1996). On the other hand, D2 antagonists do show effects in the amphetamine-deficit model in schizophrenia patients, in healthy humans and animals, and in animal models of schizophrenia (e.g., Light et al. 1999; Siegel et al. 2005; During et al. 2014). This indicates that the effects of D2 antagonist are dependent on the model in which it is tested. Although the current study showed improved sensory gating after PDE4 inhibition, further studies in which roflumilast is tested in different models in humans and animals are indicated to further support its potential clinical effects.

Dopamine is not the only neurotransmitter that can affect sensory gating. Other signaling systems, affecting downstream structures capable of exhibiting gating, can show effects in a sensory gating paradigm (see Fig. 1). Both noradrenergic (e.g., Siegel et al. 2005) and cholinergic (e.g., Adler et al. 2001) drugs have shown to affect sensory gating. Especially, the cholinergic system is of interest as a treatment for gating deficits in schizophrenia, as the inhibitory interneurons contain, next to the dopamine D2 receptors, α7 nicotinic acetylcholine receptors which upon activation stimulate GABA (γ-aminobutyric acid) release (e.g., Young and Geyer 2013; see Fig. 1). Via PDE4 expressed in neurons, modulating the inhibitory interneurons, roflumilast could also modulate sensory gating by targeting these different mechanisms. Thus, the current effects may not be explained in terms of an effect on the dopamine system itself but explained by downstream mechanisms in inhibitory interneurons containing D2 receptors that can be affected by PDE4 inhibition (Fig. 1).

This way, different neurobiological mechanisms may underlie the present effects of roflumilast on sensory gating. In general, effects of PDE inhibitors on sensory gating are believed to be induced by targeting PDEs expressed in inhibitory interneurons of the auditory cortex and the thalamic “gate,” frontal inhibitory output neurons or in the interneurons that locally release inhibitory neurotransmitter in any other brain area capable of eliciting sensory gating like the hippocampus. In other words, in the abovementioned brain areas, S1 excites an excitatory neuron, which in turn excites an inhibitory interneuron as well as an excitatory pyramidal neuron (During et al. 2014; see Fig. 1). Activation of the inhibitory interneuron induces release of the inhibitory neurotransmitter GABA. GABA release then causes fast inhibition of the pyramidal neuron via postsynaptic GABA-A receptors. Additionally, GABA released from the inhibitory interneurons induces slow, persistent inhibition of glutamate release from the first excitatory neuron onto the pyramidal neuron via presynaptic GABA-B receptors (Hershman et al. 1995). This persistent inhibition reduces the activity of the pyramidal neuron for up to 8 s. Consequently, if S2 arrives, the ERP amplitude will be reduced.

Hypothetically, targeting any PDE subtype, e.g., PDE4, expressed in the first excitatory neuron’s projections to the inhibitory interneuron as well as PDEs expressed in the inhibitory interneuron itself could enhance output of both neurons when activated by S1. Consequently, the S2-induced amplitude will be further reduced. Note, however, that PDEs expressed in the first excitatory neuron’s projections directly to the pyramidal neuron must not be enhanced since this would increase the response to S1 and therefore positively affect general auditory information processing. Roflumilast enhances sensory gating without exhibiting an effect on S1. Therefore, the effect of roflumilast is more likely to occur in the inhibitory interneurons themselves. PDE4 is indeed relatively highly expressed in brain areas associated with sensory gating (Lakics et al. 2010).

Additionally, PDE4 inhibitors may function like D2 receptor antagonists although it needs to be determined whether this is directly beneficial for sensory gating (Heckman et al. 2017). Taken together, future studies will have to provide more insight into the mechanism by which PDE4 inhibition enhances sensory gating in healthy and pharmacologically impaired volunteers, and eventually patients. Of note, when comparing results, several translational considerations should be taken into account. For example, the site of measurement (intra-cranial in rodents vs scalp in humans), mental state (anesthetized in rodents vs awake in rodents or humans), treatment duration (acute vs chronic), and route of drug administration (mostly intraperitoneal/subcutaneous in rodents vs mostly oral in humans), but also differences in PDE4 expression and pharmacokinetic properties of the drug.

To our knowledge, this is the first study that showed enhanced sensory gating after PDE4 treatment in healthy human subjects. This may indicate that PDE4 inhibition may be relevant for this specific pre-attentive process. Of note, there is also a wealth of data that PDE4 inhibitors also improve memory functions in various animal models (e.g., Jabaris et al. 2015; Vanmierlo et al. 2016). Taken together, this may suggest that PDE4 inhibition may have widespread effects in the brain leading to improvement of different cognitive processes. On basis of the current data, we conclude that a low dose of roflumilast might be considered as a potential treatment for disorders that are characterized by impaired sensory gating.