Zatrzymać sztuczne raje. O temporalizacji doświadczenia psychodelicznego w pismach Witkacego i Huxleya

The article deals with the problem of verbalizing drug experience and the resulting problem of determining passage of time. I study Aldous Huxley’s and Stanislaw Ignacy Witkiewicz’s trip-reports written during psychedelic experience. Both writers have trouble with defining passage of time, and although they took the same drug, their psychedelic experience took completely different courses. In Huxley’s subjective perception time seems to “freeze”, while Witkacy’s psychedelic experience seems to be quick and dynamic.

Plasticity in the Hippocampus, Neurogenesis and Drugs of Abuse

Synaptic plasticity in the hippocampus assists with consolidation and storage of long-lasting memories. Decades of research has provided substantial information on the cellular and molecular mechanisms underlying synaptic plasticity in the hippocampus, and this review discusses these mechanisms in brief. Addiction is a chronic relapsing disorder with loss of control over drug taking and drug seeking that is caused by long-lasting memories of drug experience. Relapse to drug use is caused by exposure to context and cues associated with the drug experience, and is a major clinical problem that contributes to the persistence of addiction. This review also briefly discusses some evidence that drugs of abuse alter plasticity in the hippocampus, and that development of novel treatment strategies that reverse or prevent drug-induced synaptic alterations in the hippocampus may reduce relapse behaviors associated with addiction.

Distinct populations of cortical pyramidal neurons mediate drug reward and aversion

Processing within the anterior cingulate cortex (ACC) is crucial for the patterning of appropriate behavior, and ACC dysfunction following chronic drug use is thought to play a major role in drug addiction. However, cortical pyramidal projection neurons can be subdivided into two major types (intratelencephalic (IT) and pyramidal tract (PT)), with distinct inputs and projection targets, molecular and receptor profiles, morphologies and electrophysiological properties. Yet, how each of these cell populations modulate behavior related to addiction is unknown. We demonstrate that PT neurons regulate the positive features of a drug experience whereas IT neurons regulate the negative features. These findings support a revised theory of cortical function in addiction, with distinct cells and circuits mediating reward and aversion.

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

The orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD). Suvorexant (Belsomra™) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain

Stress affects dopamine-dependent behaviors in part through the actions of corticotropin releasing factor (CRF) in the ventral tegmental area (VTA). For example, acute stress engages CRF signaling in the VTA to suppress the motivation to work for food rewards and promote drug seeking behavior. These diverging behavioral effects in food- and drug-based tasks could indicate that CRF modulates goal-directed actions in a reinforcer-specific manner. Alternatively, prior drug experience could functionally alter how CRF in the VTA regulates dopamine-dependent behavior. To address these possibilities, we examined how intra-VTA injections of CRF influenced cocaine intake and whether prior drug experience alters how CRF modulates the motivation for food rewards. Our results demonstrate that intra-VTA injections of CRF had no effect on drug intake when self-administering cocaine under a progressive ratio reinforcement schedule. We also found that a prior history of either contingent or non-contingent cocaine infusions abolished the capacity for CRF to reduce the motivation for food rewards. Furthermore, voltammetry recordings in the nucleus accumbens illustrate that CRF in the VTA had no effect on cocaine-evoked dopamine release. These results collectively illustrate that exposure to abused substances functionally alters how neuropeptides act within the VTA to influence motivated behavior.

CDEK: Clinical Drug Experience Knowledgebase

The Clinical Drug Experience Knowledgebase (CDEK) is a database and web platform of active pharmaceutical ingredients with evidence of clinical testing as well as the organizations involved in their research and development. CDEK was curated by disambiguating intervention and organization names from ClinicalTrials.gov and cross-referencing these entries with other prominent drug databases. Approximately 43% of active pharmaceutical ingredients in the CDEK database were sourced from ClinicalTrials.gov and cannot be found in any other prominent compound-oriented database. The contents of CDEK are structured around three pillars: active pharmaceutical ingredients (n = 22 292), clinical trials (n = 127 223) and organizations (n = 24 728). The envisioned use of the CDEK is to support the investigation of many aspects of drug development, including discovery, repurposing opportunities, chemo- and bio-informatics, clinical and translational research and regulatory sciences.