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Mutual independence of 5-HT2 and α1 noradrenergic receptors in mediating deficits in sensorimotor gating

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Abstract

Rationale

Prepulse inhibition (PPI), a preattentional information-filtering mechanism, is disrupted by serotonin (5-HT) or norepinephrine (NE) agonists to model deficits seen in schizophrenia, but whether this effect occurs through interactions between these systems is not known.

Objectives

These studies investigated whether PPI/activity changes induced by agonists of one system were dependent on neurotransmission within the other.

Methods

Male Sprague–Dawley rats received the 5-HT2 receptor agonist DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane) (0, 0.3 mg/kg), with or without antagonists for α1 (prazosin:0, 0.3, or 1 mg/kg) or β (timolol:0, 3, or 10 mg/kg) receptors or their combination (0 or 0.3 mg/kg prazosin + 3 mg/kg timolol), or the 5-HT2 antagonist ritanserin (0, 2 mg/kg). Separately, the α1-adrenergic receptor agonist cirazoline (0, 0.68 mg/kg) was given with and without ritanserin (0, 0.5, or 2 mg/kg) or the NE antagonists (0 or 0.3 mg/kg prazosin + 3 mg/kg timolol). Finally, combinations of subthreshold doses of DOI (0, 0.01, 0.025 mg/kg) and cirazoline (0, 0.1, 0.25 mg/kg) were tested for their ability to disrupt PPI, and concomitant administration of all three antagonists (0 vs. 0.3 mg/kg prazosin + 3 mg/kg timolol + 2 mg/kg ritanserin) was assessed for its ability to modify PPI. Locomotion was assessed in an additional set of experiments.

Results

Doses/combinations of prazosin and timolol that reversed cirazoline-induced effects did not alter DOI-induced effects, and ritanserin did not affect cirazoline at doses that blocked DOI-mediated effects. Concomitant antagonism of α1 + β + 5-HT2 receptors did not modify PPI, nor did combinations of subthreshold doses of cirazoline and DOI.

Conclusions

5-HT2 receptors and α1 and β NE receptors may act through independent mechanisms to modulate sensorimotor gating and locomotor activity.

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Acknowledgments

This work was supported by R01-MH075980 (VPB) and T32-GM007507 (SKB and AKR). The authors would like to thank Akaila Cabell for her technical assistance and Brian Baldo for his comments on the manuscript. Facilities and procedures complied with animal use and care guidelines from the National Institutes of Health of the USA, and were approved by the Institutional Animal Care and Use Committee of the University of Wisconsin.

Conflict of interest

The authors have full control of all primary data and agree to allow the journal to review their data if requested. None of the authors has any conflict of interest or financial arrangements pertaining to this work.

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  1. Department of Psychiatry, UW-Madison, Madison, WI, USA

    Sarah K. Baisley, Katherine L. Fallace, Abha K. Rajbhandari & Vaishali P. Bakshi

  2. Neuroscience Training Program, UW-Madison, Madison, WI, USA

    Sarah K. Baisley, Abha K. Rajbhandari & Vaishali P. Bakshi

  3. Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, 6001 Research Park Blvd, Madison, WI, 53719, USA

    Vaishali P. Bakshi

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  1. Sarah K. Baisley
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Correspondence to Vaishali P. Bakshi.

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Baisley, S.K., Fallace, K.L., Rajbhandari, A.K. et al. Mutual independence of 5-HT2 and α1 noradrenergic receptors in mediating deficits in sensorimotor gating. Psychopharmacology 220, 465–479 (2012). https://doi.org/10.1007/s00213-011-2490-2

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