Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

Neuropharmacology. 2021 Oct 1:197:108747. doi: 10.1016/j.neuropharm.2021.108747. Epub 2021 Aug 5.


Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.

Keywords: D1 receptor; D2 receptor; Dopamine transporter; Mesocorticolimbic system; Rat; Schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / adverse effects*
  • Behavior, Animal / drug effects
  • Cerebral Cortex / drug effects
  • Dextroamphetamine / pharmacology
  • Dopamine / pharmacology
  • Dopamine / physiology*
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dopamine Uptake Inhibitors / pharmacology
  • Haloperidol / pharmacology
  • Limbic System / drug effects
  • Male
  • Motor Activity / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D2 / drug effects


  • Antipsychotic Agents
  • Dopamine Agonists
  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Haloperidol
  • Dextroamphetamine
  • Dopamine