Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251

Abstract

In this work we investigated the ability of AM251 to reverse schizophrenia-like symptoms produced by a neurodevelopmental animal model based on a social isolation procedure. First, we assessed the validity of our isolation-rearing protocol and, as expected, isolation-reared rats showed hyperlocomotion in a novel environment, cognitive impairment in the novel object recognition (NOR) test and a significant increase in the number of aggressive behaviours in the social interaction test compared to group-housed controls. This behavioural picture was associated with a reduction in CB₁ receptor/G protein coupling in specific brain areas as well as reduced c-Fos immunoreactivity in the prefrontal cortex and caudate putamen. In this model, chronic but not acute treatment with the CB₁ receptor antagonist AM251 counteracted isolation-induced cognitive impairment in the NOR test and aggressive behaviours in the social interaction test. This behavioural recovery was accompanied by the rescue of CB₁ receptor functionality and c-Fos levels in all brain regions altered in isolation-reared rats. Moreover, chronic AM251 also increased c-Fos immunoreactivity in the nucleus accumbens, as previously demonstrated for antipsychotic drugs. Interestingly, the behavioural recovery due to chronic AM251 administration persisted until 10 d after discontinuing the treatment, indicating a long-lasting effect of the cannabinoid antagonist on psychotic-like symptoms.

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

“…The deleterious effects of isolation rearing on SOR, for example, could be reduced by chronic, but not acute, treatment with a CB1 antagonist (1 h; Zamberletti et al 2010). While the mechanism behind this effect is unclear, Zamberletti and colleagues note that cannabinoid receptors have previously been shown to modulate dopaminergic transmission via effects on GABAergic and glutamatergic synapses (Chiu et al 2010;van der Stelt and Di Marzo 2003).…”

Disruption of peri-adolescent endocannabinoid signaling modulates adult neuroendocrine and behavioral responses to stress in male rats

“…For example, there is some evidence that chronic AM-251 treatment reverses isolation rearing-induced deficits in cognition and sensorimotor gating and normalizes eCB, dopaminergic and glutamatergic imbalances associated with this model of psychotic-like symptoms in male and female rats(Guidali et al, 2011;Zamberletti et al, 2012a;Zamberletti et al, 2012b).…”

Endocannabinoids and Mental Disorders

“…In this regard, CB1 stimulation by direct/indirect agonists improves social withdrawal in different animal models (Seillier et al 2010(Seillier et al , 2013Almeida et al 2014). However, the chronic administration of AM251, a CB1 receptor antagonist, also counteracted the increase in aggressive behaviors observed in rats reared in isolation (Zamberletti et al 2010). Accordingly, genetic deletion of the CB1 receptor prevented PCP-induced social deficits in mice (Haller et al 2005).…”

“…So far only a few studies have examined the effect of a pharmacological modulation of the ECS on cognitive deficits in animal models of schizophrenia. Treatment with direct or indirect agonists as well as antagonists exerted a beneficial effect in different cognitive tasks (Black et al 2011;Guidali et al 2011;Seillier et al 2010;Spano et al 2010;Zamberletti et al 2010).…”