Dynamic regulation of dopamine and serotonin responses to salient stimuli during chronic haloperidol treatment

Davide Amato, Sridhar Natesan, Leonid Yavich, Shitij Kapur, Christian P Müller

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

Antipsychotic drugs are the clinical standard for the treatment of schizophrenia. Although these drugs work initially, many compliant patients relapse due to treatment failure. The known biomarkers can not sufficiently explain antipsychotic treatment failure. We, therefore, enquired how the dynamic responses of the neurotransmitters, dopamine and serotonin, change in relation to treatment action and failure. Rats received either short-term (2-6 d) or long-term (12-14 d) treatment with haloperidol, which resembled human D2 receptor occupancy, using osmotic mini-pumps. Dopamine and serotonin basal levels and responses to novelty, appetitive food, and to an aversive tail pinch were measured in the prefrontal cortex, nucleus accumbens and caudate putamen using in-vivo microdialysis, and the behaviour was recorded. Subsequently, we used in-vivo voltammetry to measure dopamine overflow in the nucleus accumbens. Haloperidol decreased dopamine, but not serotonin baseline levels in a time-dependent way. Salient stimuli induced dopamine and serotonin responses. Short-term haloperidol treatment attenuated the mesolimbic dopamine responses to aversive stimulation, while the responses to appetitive stimulation were largely preserved. After long-term treatment, the initial response adaptations were reversed. Similar changes were also observed at the behavioural level. In-vivo voltammetry showed that nucleus accumbens dopamine adaptations and their reversal were mediated by changes in extracellular dopamine release. Chronic haloperidol treatment, which resembles human D2 receptor occupancy, modulates dopamine and behavioural responses to aversive and appetitive stimulation depending on the duration of treatment. Specific changes in dopamine response dynamics and their reversal may be a functional substrate of antipsychotic action and failure respectively.
Original languageEnglish
Pages (from-to)1327-1339
Number of pages13
JournalInternational Journal of Neuropsychopharmacology
Volume14
Issue number10
Early online date1 Feb 2011
DOIs
Publication statusPublished - Nov 2011

Keywords

  • Animals
  • Treatment Failure
  • Drug Administration Schedule
  • Pain Threshold
  • Infusion Pumps, Implantable
  • Brain
  • Caudate Nucleus
  • Exploratory Behavior
  • Appetitive Behavior
  • Prefrontal Cortex
  • Antipsychotic Agents
  • Serotonin
  • Putamen
  • Behavior, Animal
  • Rats
  • Haloperidol
  • Microdialysis
  • Rats, Sprague-Dawley
  • Dopamine
  • Nucleus Accumbens
  • Motor Activity
  • Time Factors
  • Male

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