title: Ventral striatal noradrenergic mechanisms contribute to sensorimotor gating deficits induced by amphetamine.
abstract: The psychotomimetic drug D-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.
authors.affiliation: Department of Psychiatry, University of Wisconsin-Madison, Madison, WI 53719, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Alsene
authors.forename: Katie
authors.initials: K
authors.lastname: Fallace
authors.forename: Vaishali P
authors.initials: VP
authors.lastname: Bakshi
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000661:Amphetamine / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects*; D004347:Drug Interactions; D007266:Inhibition, Psychological; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects; D011224:Prazosin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects* / Q000502:physiology*; D013999:Timolol / Q000494:pharmacology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D013999:Timolol; C041226:Terazosin; D000661:Amphetamine; D011224:Prazosin