Abstract
The psychotomimetic drug -amphetamine (AMPH), disrupts prepulse inhibition (PPI) of the startle response, an operational measure of sensorimotor gating that is deficient in schizophrenia patients. Historically, this effect has been attributed to dopaminergic substrates; however, AMPH also increases norepinephrine (NE) levels, and enhancement of central NE transmission has been shown recently to disrupt PPI. This study examined the extent to which NE might participate in AMPH-induced disruptions of PPI and increases in locomotor activity, another classic behavioral effect of AMPH, by determining whether antagonism of postsynaptic NE receptors blocked these effects. Separate groups of male Sprague–Dawley rats received either the α1 receptor antagonist, prazosin (0, 0.3, 1 mg/kg), or the β receptor antagonist timolol (0, 3, 10 mg/kg) before administration of AMPH (0 or 1 mg/kg) before testing for PPI or locomotor activity. As an initial exploration of the anatomical substrates underlying possible α1 receptor-mediated effects on AMPH-induced PPI deficits, the α1 receptor antagonist terazosin (0 or 40 μg/0.5 μl) was microinfused into the nucleus accumbens shell (NAccSh) in conjunction with systemic AMPH administration before startle testing in a separate experiment. Prazosin, but not timolol, blocked AMPH-induced hyperactivity; both drugs reversed AMPH-induced PPI deficits without altering baseline startle responses. Interestingly, AMPH-induced PPI deficits also were partially blocked by terazosin in NAccSh. Thus, behavioral sequelae of AMPH (PPI disruption and hyperactivity) may be mediated in part by NE receptors, with α1 receptors in NAccSh possibly having an important role in the sensorimotor gating deficits induced by this psychotomimetic drug.
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This work was funded by RO1 MH075980 (VPB) and F31 MH077465 (KMA).
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Dr Bakshi has no conflicts to report. Dr Alsene was a graduate student in Dr Bakshi's laboratory during the time when the studies in this paper were completed, and while the paper was written, thus has no conflicts to report. At the present time, Dr Alsene is a full-time employee (Medical Writer) with Covance, which has no relationship to the present work. At no time during the course of the studies described in this paper was any author receiving any materials or compensation from any outside company.
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Alsene, K., Fallace, K. & Bakshi, V. Ventral Striatal Noradrenergic Mechanisms Contribute to Sensorimotor Gating Deficits Induced by Amphetamine. Neuropsychopharmacol 35, 2346–2356 (2010). https://doi.org/10.1038/npp.2010.106
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