Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice, Andreza B. Sonego et al., 2016

Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice

Andreza B. Sonego; Felipe V. Gomes; Elaine A. Del Bel; Francisco S. Guimaraes

Behavioural Brain Research, 2016, 21.

Doi : 10.1016/j.bbr.2016.04.042



 Cannabidiol (CBD) attenuated haloperidol-induced catalepsy.
 CBD reduced c-Fos protein expression in the dorsal striatum induced by haloperidol.
 CBD effects were blocked by 5-HT1A receptor antagonist.



Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant. Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic. In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol. To further investigate this latter effect, we tested whether CBD (15-60mg/kg) would attenuate the catalepsy and c-Fos protein expression in the dorsal striatum induced by haloperidol (0.6mg/kg). We also evaluated if these effects occur through the facilitation of 5-HT1A receptor mediated neurotransmission. For this, male Swiss mice were treated with CBD and haloperidol systemically and then subjected to the catalepsy test. Independent groups of animals were also treated with the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). As expected, haloperidol induced catalepsy throughout the experiments, an effect that was prevented by systemic CBD treatment 30 minutes before haloperidol administration. Also, CBD, administered 2.5 hours after haloperidol, reversed haloperidol-induced catalepsy. Haloperidol also increased c-Fos protein expression in the dorsolateral striatum, an effect attenuated by previous CBD administration. CBD effects on catalepsy and c-Fos protein expression induced by haloperidol were blocked by the 5-HT1A receptor antagonist. We also evaluated the effects of CBD (60nmol) injection into the dorsal striatum on haloperidol-induced catalepsy. Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors.

Keywords : cannabinoids, catalepsy, typical antipsychotics, Fos expression, 5-HT1A receptors.

1. Introduction

Antipsychotic drugs are used for the treatment of schizophrenia and act mainly as antagonists of dopamine D2 receptors. They can be classified into two major groups, typical and atypical. Typical antipsychotics comprise older agents that are effective in attenuation of positive symptoms (e.g., delusions, hallucinations) but can induce several adverse effects (e.g. Parkinson-like symptoms) due to their high affinity for D2 receptors. Atypical compounds include those with different pharmacological profile that are associated with a lower incidence of motor side effects [1].

The main adverse consequence of typical antipsychotics use is the extrapyramidal effects that follow the blockade of D2 receptors in the nigrostriatal pathway. They include parkinsonian-like symptoms such as postural rigidity, slowness of movement and tremors [1]. In rodents these side effects are expressed as catalepsy, which is characterized by the maintenance of abnormal postures [2]. In fact, haloperidol, a typical antipsychotic, induces catalepsy in rodents, while clozapine, an atypical antipsychotic, does not [2,3]. This haloperidol effect is associated with neuronal activation of the dorsal striatum, indicated by an increased expression of the c- Fos protein, an effect that does not occur after treatment with atypical antipsychotics [3,4].

The striatum is a subcortical structure that belongs to a set of interconnected nuclei named the basal ganglia. Its dorsal portion is closely associated with sensorimotor function [5]. The striatum influence on motor control depends on two functionally opposite pathways. Whereas the direct pathway promotes a disinhibition of target structures and facilitates movement, the indirect pathway leads to inhibition of the thalamus and cortex to suppress the movement. Motor disorders are often associated with an imbalance between these two pathways, and in Parkinson’s disease this balance is shifted to the indirect pathway [6].

Cannabidiol (CBD) is a major component of Cannabis sativa that is devoid of the psychoactive effects of its main psychotropic compound, Δ9-tetrahydrocannabinol (THC). On the contrary, CBD is able to antagonize the psychotomimetic effects induced by high doses of THC, which lead to the proposal that CBD could have antipsychotic properties [7].

Preclinical studies suggest that CBD has a pharmacological profile similar to atypical antipsychotics, reducing psychotic-like symptoms at doses unable to induce catalepsy [8,9,10,11]. Similar to clozapine, CBD increased c-Fos protein expression in the nucleus accumbens but not in the dorsal striatum [9]. Furthermore, CBD ameliorated psychotic-like symptoms induced by L-dopa treatment of Parkinson’s disease [12]. At the same time, results from this study indicated that CBD could also improve motor function. Finally, a recent clinical-trial revealed that CBD was effective in reducing psychotic symptoms in schizophrenia patients without causing motor sideeffects [13].

Based on these pieces of evidence, we investigated if CBD could attenuate catalepsy, as well as c-Fos expression in the dorsolateral striatum, induced by haloperidol. Also, considering that among the several mechanisms involved in its pharmacological effects, CBD can facilitated 5-HT1A receptor-mediated neurotransmission [14,15,16] and agonists of this serotonergic receptor subtype attenuate haloperidol-induced catalepsy in rodents [17,18,19,20], we also tested if CBD effects would be mediated by 5-HT1A receptors.