Route of administration is well-known to impact factors ranging from absorption and distribution, up through the subjective effects of active ingredients. Different routes of administration confer specific advantages, such as more rapid absorption resulting from intravenous injection, or increased convenience with oral administration, but a combination of both rapid and convenient delivery is highly desirable. QuickStrip™ was designed as a rapidly dissolving thin film matrix that contains active ingredients, which may be promising for rapid and convenient delivery via the oral mucosa. To assess the delivery of QuickStrip™, we administered the well-characterized active ingredient caffeine to mice and compared QuickStrip™ to standard oral gavage delivery at an equivalent dose of 20 mg kg-1. Using HPLC assessment of serum concentrations of caffeine, we found that QuickStrip™ delivery resulted in higher serum levels of caffeine at 1, 10, and 30 min following administration compared to gavage. QuickStrip™ also produced greater bioavailability compared to gavage, as demonstrated by area under the curve analysis. Caffeine delivered by QuickStrip™ produced robust behavioral activation of locomotion, consistent with gavage caffeine. Electroencephalographic (EEG) assessment of central nervous system effects demonstrated that both gavage and QuickStrip™ caffeine produced suppression of delta and theta, consistent with prior literature on the effects of caffeine. In addition, QuickStrip™ produced a more rapid onset of EEG suppression, supporting the more rapid absorption demonstrated in the serum studies. Collectively, these studies suggest that QuickStrip™ may provide a balance between convenience and rapid onset, offering new options for delivery of therapeutics.

Perception, emotion, and mood are powerfully modulated by serotonin receptor (5-HTR) agonists including hallucinogens. The 5-HT2AR subtype has been shown to be central to hallucinogen action, yet the precise mechanisms mediating the response to 5-HT2AR activation remain unclear. Hallucinogens induce the head twitch response (HTR) in rodents, which is the most commonly used behavioral readout of hallucinogen pharmacology. While the HTR provides a key behavioral signature, less is known about the meso level changes that are induced by 5-HT2AR activation. In response to administration of the potent and highly selective 5-HT2AR agonist 25I-NBOH in mice, we observe a disorganization of behavior which includes frequent episodes of behavioral arrest that consistently precede the HTR by a precise interval. By combining behavioral analysis with electroencephalogram (EEG) recordings we describe a characteristic pattern composed of two distinctive EEG waveforms, Phase 1 and Phase 2, that map onto behavioral arrest and the HTR respectively, with the same temporal separation. Phase 1, which underlies behavioral arrest, is a 3.5–4.5 Hz waveform, while Phase 2 is slower at 2.5–3.2 Hz. Nicotine pretreatment, considered an integral component of ritualistic hallucinogen practices, attenuates 25I-NBOH induced HTR and Phase 2 waveforms, yet increases behavioral arrest and Phase 1 waveforms. Our results suggest that in addition to the HTR, behavioral arrest and characteristic meso level slow waveforms are key hallmarks of the response to 5-HT2AR activation. Increased understanding of the response to serotonergic hallucinogens may provide mechanistic insights into perception and hallucinations, as well as regulation of mood.

Network communication in the CNS relies upon multiple neuronal and glial signaling pathways. In addition to synaptic transmission, other organelles such as mitochondria play roles in cellular signaling. One highly conserved mitochondrial signaling mechanism involves the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane. Originally, TSPO was identified as a binding site for benzodiazepines in the periphery. It was later discovered that TSPO is found in mitochondria, including in CNS cells. TSPO is implicated in multiple cellular processes, including the translocation of cholesterol and steroidogenesis, porphyrin transport, cellular responses to stress, inflammation, and tumor progression. Yet the impacts of modulating TSPO signaling on network activity and behavioral performance have not been characterized. In the present study, we assessed the effects of TSPO modulators PK11195, Ro5-4864, and XBD-173 via electroencephalography (EEG) and the open field test (OFT) at low to moderate doses. Cortical EEG recordings revealed increased power in the δ and θ frequency bands after administration of each of the three modulators, as well as compound- and dose-specific changes in α and γ. Behaviorally, these compounds reduced locomotor activity in the OFT in a dose-dependent manner, with XBD-173 having the subtlest behavioral effects while still strongly modulating the EEG. These findings indicate that TSPO modulators, despite their diversity, exert similar effects on the EEG while displaying a range of sedative/hypnotic effects at moderate to high doses. These findings bring us one step closer to understanding the functions of TSPO in the brain and as a target in CNS disease.