Atypical antipsychotic drugs (APDs) such as clozapine, olanzapine, quetiapine, risperidone, and ziprasidone are serotonin (5-HT)2A antagonists and relatively weaker dopamine (DA) D2 antagonists, with variable 5-HT2C antagonist properties. The ability of atypical APDs to preferentially increase DA release in the cortex compared to the limbic system is believed to be due in part to their antagonism of 5-HT2A and D2 receptors and believed to contribute to their beneficial effects on cognition, negative, and psychotic symptoms. Previous studies from this laboratory using microdialysis have shown that pretreatment of the 5-HT2A antagonist M100907 with the typical APD and D2 antagonist haloperidol produced an increase in the medial prefrontal cortex (mPFC), but not in the nucleus accumbens (NAC), DA release. However, pretreatment with the 5-HT2A/2C receptor antagonist SR46349-B with haloperidol increased both mPFC and NAC DA release, suggesting that both 5-HT2A and 5-HT2C properties may be important for atypical APD effects.
The purpose of this study was to examine the effects of a novel putative atypical APD ACP-103 on mPFC and NAC DA release using in vivo microdialysis in freely moving rats that are awake. ACP-103 is an inverse agonist at both 5-HT2A and 5-HT2C receptors and has intermediate affinities for 5-HT2C receptors relative to their affinities for 5-HT2A receptors compared to M100907 and SR46349-B. In addition, the effects of ACP-103 were compared to M100907 and SR46349-B, and ACP-103 was also coadministered with haloperidol.
ACP-103 10.0 mg/kg, but not 3.0 mg/kg, increased DA release in the mPFC, while neither dose increased DA release in the NAC. Like M100907, ACP-103 (3.0 mg/kg) potentiated 0.1 mg/kg haloperidol-induced DA release in the mPFC while inhibiting that in the NAC. However, ACP-103 (3.0 mg/kg), similar to SR46349-B, potentiated a high dose of haloperidol (1.0 mg/kg)-induced DA release in both regions. The potent 5-HT2C antagonist SB242084 1.0 mg/kg significantly potentiated 0.1 mg/kg haloperidol-induced DA release in both the mPFC and NAC. However, SB242084, at 0.2 mg/kg, significantly potentiated DA release only in the NAC. Moreover, SB242084 0.2 mg/kg potentiated DA release in the NAC produced by the combination treatment of 3 mg/kg ACP-103 and 0.1 mg/kg haloperidol.
These data suggest that the relative extent of 5-HT2A and 5-HT2C antagonism, as well as the extent of D2 receptor blockade, has a critical influence on DA release in the mPFC and NAC and may be a determining factor in the action of this class of atypical APDs on these two potentially clinically relevant parameters.
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Supported in part by a grant from Acadia Pharmaceuticals Inc.
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Li, Z., Ichikawa, J., Huang, M. et al. ACP-103, a 5-HT2A/2C inverse agonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Psychopharmacology 183, 144–153 (2005). https://doi.org/10.1007/s00213-005-0170-9
- 5-HT2A and 5-HT2C receptors
- D2 receptor
- Medial prefrontal cortex
- Nucleus accumbens