Ventral Striatal Noradrenergic Mechanisms Contribute to Sensorimotor Gating Deficits Induced by Amphetamine

Neuropsychopharmacology (2010) 35, 2346–2356 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00 www.neuropsychopharmacology.org Ventral Striatal Noradrenergic Mechanisms Contribute to Sensorimotor Gating Deficits Induced by Amphetamine Karen M Alsene1, Katie Fallace1 and Vaishali P Bakshi*,1 1 Department of Psychiatry and Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA 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 a1 receptor antagonist, prazosin (0, 0.3, 1 mg/kg), or the b 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 a1 receptor-mediated effects on AMPH-induced PPI deficits, the a1 receptor antagonist terazosin (0 or 40 mg/0.5 ml) 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 a1 receptors in NAccSh possibly having an important role in the sensorimotor gating deficits induced by this psychotomimetic drug. Neuropsychopharmacology (2010) 35, 2346–2356; doi:10.1038/npp.2010.106; published online 4 August 2010 Keywords: startle; noradrenergic; noradrenaline; schizophrenia; locomotion; psychosis INTRODUCTION Prepulse inhibition (PPI) refers to the reduction in the magnitude of the startle response that normally is observed when a low intensity prestimulus is presented immediately before a startling stimulus (Graham, 1975; Hoffman and Ison, 1980; Ison and Hoffman, 1983), and is used as a measure of sensorimotor gating. Several decades of research have established deficient PPI as an exemplar of the information-processing deficits that are observed in multiple psychiatric illnesses, and PPI disturbances are a well-accepted endophenotype of schizophrenia (Braff et al, 2001b, 2008). To identify the neurochemical modulators and neuroanatomical circuits underlying these clinically observed deficits in sensorimotor gating, the neural substrates of PPI have been analyzed extensively in animal models (Geyer, 2008; Swerdlow et al, 2008). *Correspondence: Dr VP Bakshi, Department of Psychiatry, UWMadison SMPH, 6001 Research Park Boulevard., Madison, WI 53719, USA, Tel: + (608) 265 6062, Fax: + (608) 265 3050, E-mail: Received 21 February 2010; revised 23 June 2010; accepted 24 June 2010 One method for mimicking clinically manifested PPI deficits in rats is through the administration of psychotomimetic drugs such as amphetamine (AMPH). AMPH has long been known to produce psychotic symptoms in humans that closely resemble the symptoms of schizophrenia (Charalampous and Hug, 1963; Kokkinidis and Anisman, 1981; Snyder, 1973), and also can disrupt PPI in humans (Hutchison and Swift, 1999; Hutchison et al, 1999; Kumari et al, 1998), although see (Swerdlow et al, 2002). In rodents, AMPH disrupts PPI when given systemically (Kinney et al, 1999; Mansbach et al, 1988; Ott and Mandel, 1995; Ralph et al, 1999; Sills, 1999; Swerdlow et al, 2006) or directly into the brain (Wan et al, 1995; Wan and Swerdlow, 1996). To date, these effects have been attributed to the ability of AMPH to release dopamine (DA), because it is well documented that direct DA agonists disrupt PPI and DA receptor antagonists reverse these deficits (Mansbach et al, 1988; Swerdlow et al, 1986, 1994; Wan and Swerdlow, 1993). Clearly, DA receptors have a critical role in the PPI-disruptive effects of AMPH, given that AMPH-induced PPI deficits are reversed by DA receptor antagonists (Swerdlow et al, 2006). Nevertheless, AMPH also increases extracellular levels of norepinephrine (NE) (Carr and Moore, 1969; Kuczenski and NE basis of AMPH PPI KM Alsene et al 2347 Segal, 1992; Robertson et al, 2009) and some of the behavioral effects of AMPH that previously were attributed to its actions on DA systems have since been shown to also require stimulation of NE receptors (Auclair et al, 2004; Drouin et al, 2002a, b). For example, antagonism of a1 noradrenergic receptors blocks AMPH-induced hyperactivity (Blanc et al, 1994; Dickinson et al, 1988), and b NE receptors mediate the effects of AMPH on arousal (Berridge and Morris, 2000). Yet, whether NE receptors mediate AMPH-induced PPI deficits remains to be determined. Newly emerging evidence supports the regulation of PPI by NE. The NE receptor agonist, cirazoline, disrupts PPI (Carasso et al, 1998; Shilling et al, 2004; Varty et al, 1999) through activation of central a1 receptors (Alsene et al, 2006). Conversely, antagonism of a1 NE receptors blunts the PPI-disruptive effects of other psychotomimetic drugs that also indirectly increase NE levels, such as phencyclidine and cocaine (Bakshi and Geyer, 1997; van der Elst et al, 2006). Mice lacking a2A NE receptors show exaggerated deficits in PPI after administration of AMPH (Lahdesmaki et al, 2004); as a2 receptors function primarily as autoreceptors whose blockade or removal would result in an increase in NE levels (Hein et al, 1999; Starke et al, 1989), this finding is consistent with the notion that increasing central NE transmission reduces PPI. Thus, it is possible that the well-documented PPI-disrupting effects of AMPH could in part be mediated by indirect stimulation of postsynaptic NE receptors as a result of the potent NE-releasing properties of AMPH (Robertson et al, 2009). NE receptors are classified into three main subtypes: a1, a2, and b, with a1 and b receptors as the principal moieties that mediate postsynaptic effects of NE transmission (Pupo and Minneman, 2001). The present experiments tested the hypothesis that AMPH produces its behavioral effects through enhanced NE transmission by determining if blockade of postsynaptic NE receptors with either the a1 antagonist prazosin or the b antagonist timolol would prevent AMPH-induced deficits in PPI or AMPH-induc (...truncated)