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Paroxetine combined with a 5-HT1A receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats

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Abstract

Rationale

“Diminished interest or pleasure” in rewarding stimuli is an affective symptom of amphetamine withdrawal and a core symptom of depression. An operational measure of this symptom is elevation of brain stimulation reward thresholds during drug withdrawal. Data indicated that increasing serotonin neurotransmission by co-administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the serotonin-1A receptor antagonist p-MPPI reversed reward deficits observed during drug withdrawal (Harrison et al. 2001).

Objectives

We tested the hypothesis that increased serotonergic and noradrenergic neurotransmission, using the SSRI paroxetine which also inhibits noradrenaline reuptake, would alleviate affective aspects of amphetamine withdrawal.

Methods

A discrete-trial, current-threshold, self-stimulation procedure was used to assess brain reward function. The effects of paroxetine and p-MPPI alone and in combination were assessed in non-drug-withdrawing animals. We assessed also the effects of paroxetine and p-MPPI alone and in combination on reward deficits associated with amphetamine withdrawal.

Results

Paroxetine or p-MPPI alone had no effect on thresholds, while the co-administration of p-MPPI (3 mg/kg) and paroxetine (1.25 mg/kg) elevated thresholds in non-withdrawing rats. Amphetamine withdrawal resulted in threshold elevations. The co-administration of p-MPPI and paroxetine reduced the duration of amphetamine-withdrawal-induced reward deficits.

Conclusions

Increased serotonergic and noradrenergic neurotransmission decreased reward function in non-withdrawing rats, while the same treatment reversed reward deficits associated with amphetamine withdrawal. Considering that paroxetine acts on both the serotonin and noradrenaline transporter, these results indicate that the affective symptoms of amphetamine withdrawal, similar to non-drug-induced depressions, may be, in part, mediated through reduced serotonergic and noradrenergic neurotransmission.

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Acknowledgements

This work was supported by a National Institute of Mental Health grant (MH 62527) and a Novartis Research grant and to A.M. We thank Ms. Christina Glennon for technical assistance and Mr. Mike Arends for editorial assistance. This is publication 14411-NP from The Scripps Research Institute.

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Author notes

  1. Amanda A. Harrison

    Present address: School of Psychology, University of Leeds, Leeds, LS2 9JT, UK

Authors and Affiliations

  1. Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Athina Markou, Amanda A. Harrison & Jessica Chevrette

  2. Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

    Daniel Hoyer

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  1. Athina Markou
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  2. Amanda A. Harrison
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Correspondence to Athina Markou.

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Markou, A., Harrison, A.A., Chevrette, J. et al. Paroxetine combined with a 5-HT1A receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats. Psychopharmacology 178, 133–142 (2005). https://doi.org/10.1007/s00213-004-2008-2

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  • DOI: https://doi.org/10.1007/s00213-004-2008-2

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