Pregabalin and topiramate regulate behavioural and brain gene transcription changes induced by spontaneous cannabinoid withdrawal in mice

Authors

  • Auxiliadora Aracil-Fernández,

    1. Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain
    2. Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain
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  • Pilar Almela,

    1. Departamento de Farmacología, Facultad de Medicina, Universidad Murcia, Spain
    2. Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain
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  • Jorge Manzanares

    Corresponding author
    1. Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain
    2. Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain
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Jorge Manzanares, Instituto de Neurociencias-Universidad Miguel Hernández-CSIC, Apartado de correos 18, 03550 San Juan de Alicante, Spain. E-mail: jmanzanares@umh.es

ABSTRACT

This study examined the actions of pregabalin and topiramate on behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice.

Tolerance was induced in mice by administration of CP-55,940 (0.5 mg/kg/12 hours; i.p.; 7 days). Behavioural assessment of spontaneous cannabinoid withdrawal was performed by measuring motor activity, somatic signs and anxiety-like behaviour on days 1 and 3 after cessation of treatment with CP-55,940. On days 1–3 of cannabinoid withdrawal, mice received pregabalin (40 mg/kg/12 hours; p.o.) or topiramate (50 mg/kg/12 hours; p.o.) and their actions on signs of withdrawal and anxiety-like behaviour were evaluated.

The administration of CP-55,940 decreased rectal temperature and motor activity on day 1. On day 1 after interruption of cannabinoid administration, motor activity and the number of rearings increased compared with control group. Anxiety-like behaviour induced by cessation of cannabinoid treatment increased significantly on days 1 and 3 of withdrawal. The administration of pregabalin or topiramate blocked the motor signs and reduced significantly anxiety-like behaviour. Cannabinoid withdrawal decreased tyrosine hydroxylase (TH) gene expression in the ventral tegmental area and µ-opioid receptor gene expression in the nucleus accumbens (NAcc) and increased CB1 receptor gene expression in the NAcc. Treatment with topiramate or pregabalin blocked the decrease of TH and the increase of CB1 gene expressions induced by cannabinoid withdrawal. Both drugs failed to alter µ-opioid receptor gene expression.

These results suggest that pregabalin and topiramate may result useful for the treatment of anxiety-like behaviour and motor symptoms associated with spontaneous cannabinoid withdrawal.

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