Chronic ∆-9-tetrahydrocannabinol administration delays acquisition of schedule-induced drinking in rats and retains long-lasting effects

Abstract

Rationale Schedule-induced drinking (SID) is a behavioural phenomenon characterized by an excessive and repetitive drinking pattern with a distinctive temporal distribution that has been proposed as a robust and replicable animal model of compulsivity. Despite cannabis currently being the most widely consumed illicit drug, with growing interest in its clinical applications, little is known about the effects of ∆-9-tetrahydrocannabinol (THC) on SID. Objectives The effects of chronic and acute THC administration on SID acquisition, maintenance and extinction were studied, as were the effects of such administrations on the distinctive temporal distribution pattern of SID. Methods THC (5 mg/kg i.p.), or the corresponding vehicle, was administered to adult Wistar rats for 14 days in a row. Subsequently, THC effects on SID acquisition were tested during 21 sessions using a 1-h fixed-time 60-s food delivery schedule. Acute effects of THC were also evaluated after SID development. Finally, two extinction sessions were conducted to assess behavioural persistence. Results The results showed that previous chronic THC treatment delayed SID acquisition and altered the distinctive behavioural temporal distribution pattern during sessions. Moreover, acute THC administration after SID development decreased SID performance in animals chronically pre-treated with the drug. No great persistence effects were observed during extinction in animals pre-treated with THC. Conclusions These results suggest that chronic THC affects SID development, confirming that it can disrupt learning, possibly causing alterations in time estimation, and also leads to animals being sensitized when they are re-exposed to the drug after long periods without drug exposure.

Repeated Δ-9-Tetrahydrocannabinol administration dose dependently increases stablished schedule-induced drinking

“…Both groups treated with THC reached lower peak licks kept licking longer, through the FT interval until second 21. A similar result was obtained when animals were chronically treated for 14 days with THC and tested on SID in a later phase (Fuentes-Verdugo et al 2022 ). The peak percentage of licks was affected in the same way, and the animals kept licking longer instead of only drinking in the first few seconds immediately after the food delivery.…”

“…The peak percentage of licks was affected in the same way, and the animals kept licking longer instead of only drinking in the first few seconds immediately after the food delivery. The peak time was also delayed in Fuentes-Verdugo et al ( 2022 ), so it seems that time estimation might be more affected after long, repeated treatments. The SID procedure has demonstrated its usefulness as a tool for assessing temporal estimation (Ruiz et al 2016 ), hence the interest in testing the effects of different drugs on these temporal features.…”

“…Similar results were obtained on grooming behaviour induced by 2,5-dimethoxy‐4‐iodoamphetamine —an animal model of Tourette syndrome—, in which 5 mg/kg of THC inhibited grooming in juvenile and young adult mice (Gorberg et al 2020 ). We have recently shown that THC delayed SID acquisition when it had been previously chronically administered, and reduced SID after being re-administered acutely (Fuentes-Verdugo et al 2022 ). Thus, chronic THC administration delays SID acquisition but increased it when SID is steadily established before its administration.…”

“…Given the slow-elimination profile of cannabinoids, THC effects may differ depending on the moment the behaviour is evaluated. It is possible that after one hour of a single acute administration, the 5 mg/kg dose of THC may reduce licking behaviour (Fuentes-Verdugo et al 2022 ), but the residual effects (23 h after) of repeated administration of the same dose may produce opposing effects by increasing SID.…”

Neuronal and Astrocytic Morphological Alterations Driven by Prolonged Exposure with Δ9-Tetrahydrocannabinol but Not Cannabidiol

“…Chronic THC affects schedule-induced drinking development, confirming that it can disrupt learning, possibly causing alterations in time estimation. In addition, chronic THC leads to sensitisation of animals when they are re-exposed to the drug after long periods without drug exposure [16]. These behavioural effects following prolonged exposure to THC and CBD, however, are not corroborated by functional electrophysiological synaptic plasticity experiments performed following prolonged incubation to cannabinoids.…”