Biology subjects

Di Giovanni, G.

Publications and source records attributed to Di Giovanni, G..

4 recordsLinked to original sources

bioRxiv2026

Biphasic Modulation of Absence Seizures by Lisuride in GAERS: Dissecting the Role of 5-HT2A Receptors

BackgroundSerotonergic signaling plays an important role in the modulation of absence seizures (ASs), and activation of serotonin 2A receptors (5-HT2ARs) with TCB-2 suppresses spontaneous absence seizures (ASs) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Lisuride is a pharmacologically complex serotonergic and dopaminergic ligand with low 5-HT2AR signaling efficacy and a receptor profile distinct from that of TCB-2. We therefore investigated its effects on spontaneous ASs and the contribution of 5-HT2ARs to its actions. MethodsThe effects of systemic lisuride (0.1 and 0.5 mg/kg) on spontaneous ASs were examined in freely moving GAERS over 120 min by quantifying time spent in seizure, mean seizure duration and seizure number. The contribution of 5-HT2ARs was investigated by administering lisuride (0.5 mg/kg) following pretreatment with the selective 5-HT2AR antagonist MDL11,939 (0.5 mg/kg). ResultsLisuride produced marked dose- and time-dependent effects on ASs. At 0.1 mg/kg, lisuride elicited modest pro-absence effect. In contrast, 0.5 mg/kg produced a pronounced biphasic response, with a marked reduction in seizure activity during the first 40 min, followed by rebound increase during the second hour. The early suppression involved reductions in both seizure number and duration, whereas the delayed pro-absence effect was predominantly associated with prolonged ASs. MDL11,939 did not prevent the early seizure suppression but blocked the increase in seizure duration while producing a transient increase in seizure number. ConclusionsLisuride is a dose- and time-dependent bidirectional modulator of ASs in GAERS. The persistence of the profound early anti-absence effect during 5-HT2AR blockade indicates that this response does not require 5-HT2AR activation, whereas the modification of the delayed response by MDL11,939 supports a 5-HT2AR-dependent component in the later phase. These findings distinguish lisuride pharmacologically from TCB-2 and suggest that its biphasic effects arise from the dynamic engagement of multiple receptor mechanisms, potentially including dopaminergic signaling.

neuroscience↗

bioRxiv2026

Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures

Absence epilepsy is a generalized non-convulsive epilepsy characterized by recurrent absence seizures (ASs) and enhanced GABAA receptor-mediated tonic inhibition of thalamocortical (TC) neurons has been shown to lead to ASs. Serotonergic signalling is an important modulator of these seizures, yet the contribution of specific 5-HT receptor subtypes remains incompletely understood. Here, we investigated whether endogenous serotonergic signalling through 5-HT2A receptors (5-HT2ARs) contributes to pathological tonic inhibition and ASs expression. Patch-clamp recordings were obtained from ventrobasal (VB) TC neurons of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control (NEC) rats. The selective 5-HT2AR antagonist MDL11,939 had no effect on tonic GABA-A currents in NEC TC neurons but significantly reduced the enhanced tonic current in GAERS neurons, revealing a disease-dependent contribution of endogenous 5-HT2AR signalling. MDL11,939 administered bilaterally into the VB of freely moving GAERS by reverse microdialysis did not alter ASs. This dissociation between the modulation of a disease-associated cellular mechanism and seizure outcome suggests that the previously reported reduction of ASs by systemic 5-HT2AR blockade may involve mechanisms outside the VB.

neuroscience↗

bioRxiv2022

Alcohol and Cannabinoid Binges and Daily Exposure to Nicotine in Adolescent/Young Adult Rats induce Sex-Dependent Long-Term Learning and Motivation Alterations

Adolescence is a critical developmental period, concerning anatomical, neurochemical and behavioral changes. Moreover, adolescents are more sensitive to the long-term deleterious effects of drug abuse. Binge-like consumption of alcohol and marijuana, along with tobacco smoking, is a dangerous pattern often observed in adolescents during weekends. Nevertheless, the long-term effect of their adolescent co-exposure has not been experimentally investigated yet. Long-Evans adolescent male (n = 20) and female (n = 20) rats from postnatal day 30 (P30) until P60 were daily treated with nicotine (0.3 mg/kg, i.p.), and, on two consecutive binging days per week (for a total of eight times), received an intragastric ethanol solution (3 g/kg) and an intraperitoneal (i.p.) dose of cannabinoid 1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). These rats were tested after treatment discontinuation at >P90 for associative food-rewarded operant learning in the two-lever conditioning chambers for six consecutive days on a fixed ratio 1 (FR1) schedule followed by another six days of daily FR2 schedule testing, after 45 days rest. We found the main effects of sex x treatment interactions in FR1 but not in FR2 experiments. Treated females show attenuated operant responses for food pellets during all FR1 and the FR2 schedule, whilst the treated males show an impairment in FR2 but not in the FR1 schedule. Moreover, the treated females percentage of learners was significantly lower than female controls in FR1 while treated males and females were lower than controls in FR2. Our findings suggest that intermittent adolescent abuse of common drugs, such as alcohol and marijuana, and chronic tobacco exposure can cause significant long-term effects on motivation for natural reinforcers later in adulthood in both sexes. Females appear to be more sensitive to the deleterious effects of adolescent polydrug abuse with both sexes having an increased likelihood of developing lifelong brain alterations.

animal behavior and cognition↗

bioRxiv2022

Cannabinoid 1/2 Receptor Activation Induces Strain-Dependent Behavioral and Neurochemical Changes in GAERS and NEC rats

Childhood absence epilepsy (CAE) is characterized by absence seizures which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with ASs are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities. Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg, i.p.) has a strain-dependent effect on anxiety-like and motor behavior and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal-Pattern analysis, we found that WIN 55,212-2 did not affect the emotional status of GAERS but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS are more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats. These data support the view of a strain-dependent alteration of the endocannabinoid system by adding evidence of lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats.

neuroscience↗