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mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor
G L Dalton1, M D Lee, G A Kennett
1Department of Psychology, Sussex University, Brighton BN1 9QG, UK.
Abstract:
The serotonin receptor agonist mCPP induces hyperlocomotion in 5-HT2C receptor knockout (KO) mice or in the presence of a 5-HT2C receptor antagonist. In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice. We also assess the ability of agonists at these receptors to induce hyperactivity in wildtype (WT) mice pre-treated with a selective 5-HT2C receptor antagonist. As previously reported, mCPP (3 mg/kg) induced hyperactivity in 5-HT2C KO mice. A combination of the 5-HT1B receptor agonist CP-94,253 (20 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg) induced marked hyperactivity in WT but not in 5-HT2C KO mice, nor in mice treated with the selective 5-HT2C receptor antagonist, SB 242084 (1.5 mg/kg). Neither CP-94,253 nor 8-OH-DPAT had any intrinsic effect on locomotion in WTs. mCPP-induced hyperactivity was attenuated in 5-HT2C KO mice by the 5-HT1B receptor antagonist SB 224289 (2.5 mg/kg), and the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg) and M100907 (0.01 mg/kg) but not by the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg). The 5-HT(2A/2B/2C) receptor agonist, Ro 60-0175 (3 mg/kg), induced a modest increase in locomotor activity in WT mice pre-treated with SB 242084. However, the combination of Ro 60-0175 with CP-94,253 induced a substantial increase in activity in 5-HT2C KO mice, an effect comparable to mCPP-induced hyperactivity. Thus, joint activation of 5-HT1A and 5-HT1B receptors stimulates locomotion in WT mice but this response is dependent on a functional 5-HT2C receptor population and hence is absent in 5-HT2C KO mice. By contrast, mCPP-induced hyperactivity depends on the inactivation of a separate 5-HT2C receptor population and is mediated by 5-HT2A and 5-HT1B receptor activation.
Insights
The serotonin receptor agonist mCPP causes hyperactivity in mice lacking the 5-HT2C receptor, mediated by 5-HT2A and 5-HT1B receptors. Joint activation of 5-HT1A and 5-HT1B receptors stimulates locomotion, but this requires a functional 5-HT2C receptor.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- The serotonin 5-HT2C receptor plays a role in regulating locomotion.
- The agonist mCPP induces hyperactivity in 5-HT2C receptor knockout (KO) mice.
Purpose of the Study:
- To investigate the roles of 5-HT1A, 5-HT1B, and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice.
- To assess the hyperactivity induced by agonists of these receptors in wildtype (WT) mice pre-treated with a 5-HT2C receptor antagonist.
Main Methods:
- Utilized 5-HT2C receptor knockout mice and wildtype mice.
- Administered various serotonin receptor agonists and antagonists, including mCPP, CP-94,253, 8-OH-DPAT, Ro 60-0175, SB 242084, SB 224289, ketanserin, M100907, and WAY 100635.
- Measured locomotor activity to assess hyperactivity.
Main Results:
- mCPP induced hyperactivity in 5-HT2C KO mice.
- Combined 5-HT1A and 5-HT1B receptor agonists caused hyperactivity in WT mice, but not in 5-HT2C KO mice or mice treated with a 5-HT2C antagonist.
- mCPP-induced hyperactivity was reduced by 5-HT1B and 5-HT2A receptor antagonists, but not by a 5-HT1A antagonist.
- The combination of a 5-HT(2A/2B/2C) agonist and a 5-HT1B agonist induced hyperactivity in 5-HT2C KO mice.
Conclusions:
- Locomotion stimulated by joint 5-HT1A and 5-HT1B receptor activation is dependent on functional 5-HT2C receptors.
- mCPP-induced hyperactivity is mediated by 5-HT2A and 5-HT1B receptor activation, contingent on the inactivation of a separate 5-HT2C receptor population.
