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Genetic deletion of dopamine D1 receptors increases the sensitivity to cannabinoid CB1 receptor antagonist-precipitated withdrawal when compared with wild-type littermates: studies in female mice repeatedly exposed to the Spice cannabinoid HU-210

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Abstract

Rationale

The emergence of the consumption of highly potent synthetic cannabinoid receptor agonists (spice drugs) that produce important neurological symptoms has prompted the research on the consequences of acute and chronic use of these new psychoactive substances. Most studies on cannabinoid dependence have been performed in male animals, and there is a need of studies using female subjects.

Objectives

In the present study, we evaluated only in female animals the role of dopamine D1 receptors in the behavioral responses induced by acute and repeated stimulation of cannabinoid CB1 receptors, including the development of physical dependence, since cannabinoid CB1 receptors are co-localized with dopamine D1 receptors on GABAergic neurons projecting to the substantia nigra.

Methods

To this end, female dopamine D1 receptor-deficient mice and wild-type littermates were treated with HU-210, a potent synthetic cannabinoid agonist.

Results

Mutant mice displayed an enhanced response to acute motor and hypothermic effects to HU-210 when compared with wild-type females. The administration of SR141716A precipitated behavioral signs of withdrawal in mice treated subchronically with HU-210. Severity of cannabinoid withdrawal syndrome was potentiated in dopamine D1-deficient female mice. Indeed, 4 of 6 abstinence signs were increased in mutant mice.

Conclusions

These results support for a role of dopamine D1 receptors in the acute, chronic, and withdrawal actions of spice drugs.

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Funding

This work was supported by Red de Trastornos Adictivos, Instituto de Salud Carlos III and European Regional Development Funds-European Union (RD16/0017/001 to F.R.F); Ministerio de Economía y Competitividad, Instituto de Salud Carlos III and European Regional Development Funds-European Union (PI19/01755 to F.R.F and PI17/02026 to A.S); and Plan Nacional sobre Drogas and Ministerio de Sanidad, Servicios Sociales e Igualdad (PND2019/040, PND2018/044, PND2018/033, PND2017/043). AS, FJP and JS hold Miguel Servet research contracts funded by Instituto de Salud Carlos III and European Regional Development Funds-European Union (CP14/00173 to A.S, CP14/00212 to F.J.P and CPII17/00024 to J.S.).

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Authors and Affiliations

  1. Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Malaga, Spain

    Antonia Serrano, Evelyn Vadas, Belen Ferrer, Juan Suárez, Francisco Javier Pavon & Fernando Rodríguez de Fonseca

  2. Laboratorio de Medicina Regenerativa, Instituto IBIMA, Hospital Regional Universitario de Málaga, Av. Carlos Haya 82, sótano., 29010, Malaga, Spain

    Antonia Serrano, Evelyn Vadas, Belen Ferrer, Juan Suárez & Fernando Rodríguez de Fonseca

  3. Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany

    Ainhoa Bilbao

  4. Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), 28002, Madrid, Spain

    Noelia Granado & Rosario Moratalla

Authors
  1. Antonia Serrano
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  2. Evelyn Vadas
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  3. Belen Ferrer
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  4. Ainhoa Bilbao
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  5. Noelia Granado
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  6. Juan Suárez
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  7. Francisco Javier Pavon
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  8. Rosario Moratalla
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  9. Fernando Rodríguez de Fonseca
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Correspondence to Antonia Serrano or Fernando Rodríguez de Fonseca.

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Serrano, A., Vadas, E., Ferrer, B. et al. Genetic deletion of dopamine D1 receptors increases the sensitivity to cannabinoid CB1 receptor antagonist-precipitated withdrawal when compared with wild-type littermates: studies in female mice repeatedly exposed to the Spice cannabinoid HU-210. Psychopharmacology 238, 551–557 (2021). https://doi.org/10.1007/s00213-020-05704-8

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  • DOI: https://doi.org/10.1007/s00213-020-05704-8

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