Considerations on the neurobehavioral assessment (modified Irwin test) in non-human primates

Theophylline, a methylxanthine-class bronchodilator that has anti-inflammatory properties, is clinically used to manage chronic respiratory disorders such as asthma and chronic obstructive pulmonary disease. Although theophylline demonstrates therapeutic efficacy, it has a narrow therapeutic index and central nervous system (CNS) activity, which requires a detailed safety assessment. This study investigated the acute neurobehavioral and thermophysiological effects of orally administered theophylline in male Institute of Cancer Research (ICR) mice using the modified Irwin test. Single doses of 10, 30, or 100 mg/kg of theophylline were administered, followed by structured behavioral observations at 0, 1, 2, 4, 6, and 24 h post-dosing. Administration at concentrations of 30 and 100 mg/kg induced transient hyperthermia, increased spontaneous locomotion, and reversible motor coordination deficits between 1 and 6 h, with full recovery by 24 h. Tail elevation was observed only at concentrations of 30 mg/kg, whereas partial eyelid closure occurred exclusively in mice receiving 100 mg/kg administered doses. However, doses of 10 mg/kg did not produce measurable changes in any of these parameters. No notable alterations were detected in the abdominal tone, tremors, convulsions, respiration, righting reflex, salivation, lacrimation, skin color, or exophthalmos, thereby indicating the absence of systemic or generalized CNS toxicity. The modified Irwin test captured the subtle, regionally selective neurofunctional responses induced by theophylline, thus emphasizing its relevance in CNS safety pharmacology and supporting continued mechanistic investigations under clinically relevant exposure conditions.

The standardized functional observational battery: Its intrinsic value remains in the instrument of measure: The rat

Pharmacological safety of single oral pentoxifylline administration in mice using a modified Irwin test

There are a number of reasons for assessing the neurobehavior of neonatal nonhuman primates. A central premise is that neurobehavior—characterized by rapid neuromotor development, increasing state regulation, and an emerging attentional system (Als, 1986)—is presumed to be linked to the growth of neural systems in the brain. Although the state of knowledge regarding brain-behavior relations in early development is rudimentary, new knowledge is emerging regarding the relation between early brain functioning and behavior (Nelson et al., 2002). For instance, there is evidence that in large areas of the cerebral cortex in rhesus macaques, synapses grow and are pruned in approximately parallel cycles that seem to be closely related to broad cognitive changes (Goldman-Rakic, 1987; Rakic et al., 1986). Thus, the study of neurobehavioral development during the neonatal period of life may provide some insight into the development of neural networks that support behavioral systems and may provide meaningful inferences related to central nervous system (CNS) integrity relevant to certain human disorders.

Data strength assessment of the social-housed modified Irwin test when performed concurrently with a CNS tetrad evaluation

IntroductionGeneralized anxiety disorder (GAD) is a chronic and disabling disorder with an estimated lifetime prevalence of up to 7.8% in the US. MM120 (lysergide D-tartrate), a tartrate salt of D-lysergic acid diethylamide (LSD), is currently under development as a potential treatment for GAD. The mechanism of action (MOA) by which MM120 may elicit profound lasting psychological changes is not fully understood. Studies suggest that it has significant effects on functional brain activity across several networks, likely a result of serotonergic agonism mediated by 5HT2A activity and subsequent changes in neural network connectivity.ObjectivesA series of Good Laboratory Practice (GLP) compliant studies were conducted to evaluate abuse potential of MM120.MethodsIn vitro assessments of MM120, and its main metabolite 2-oxo-3-hydroxy LSD, receptor binding activity were performed using Eurofins CEREP BioPrint. To examine single dosing effects, MM120 was administered by oral gavage to male Sprague Dawley rats (n=6/group) at doses of 0 (vehicle only), 0.5, 2.0, and 6.0 mg/kg. A Modified Irwin test evaluated shorter acting drug effects at 15, 60, 120, and 240 minutes post-dosing compared to pre-dose baseline, with long-term, single dose neurological effects studied in a functional observation battery (FOB) on the day of dosing and 24 hours post dose. To compare potential chronic MM120 effects, male and female Sprague Dawley rats were dosed daily for four weeks via oral gavage at 0 (vehicle only), 0.5, 2.0, and 6.0 mg/kg (n=10-15/sex/group) followed by a 4-week recovery phase. FOB was performed pre-dose, dosing day 27, and day 25 of recovery phase. Additional assessments included toxicological and toxicokinetic evaluations.ResultsReceptor binding assay confirmed MM120’s MOA is mediated by the serotonin system and hallucinogenic effects are driven by agonism at 5-HT2A and 5-HT2C receptors. MM120 demonstrated agonist activity at 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5HT7 receptors and only nanomolar affinity at D2 dopaminergic receptors. Single dose MM120 at 0.5 mg/kg, had no effects on behavioral or physiological states. Following 6 mg/kg MM120, vocalization was recorded in 1/6 rats 2-4 h post dose, and incidences of mild piloerection were recorded in 3/6 rats from 4 to 24 h post dose. In the chronic study, there were no MM120-related changes in basic or fine movements, total ambulation, total rears, or total distance traveled.ConclusionsBinding studies suggest no indication for elements of abuse for MM120 even with binding at serotonergic and, to a smaller degree, dopaminergic receptors. in vivo studies with MM120 evaluated supratherapeutic doses and demonstrated no evidence of physical dependence or withdrawal after sustained, daily administration for four weeks.Disclosure of InterestJ. Tripp Employee of: Mind Medicine, Inc., G. Smagin Employee of: Mind Medicine, Inc.