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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2015 Jul 30;173(13):2122–2134. doi: 10.1111/bph.13232

Selective activation of D 1 dopamine receptors impairs sensorimotor gating in Long–Evans rats

Laura J Mosher 1,2,3,†, Roberto Frau 4,†, Alessandra Pardu 4, Romina Pes 1, Paola Devoto 4, Marco Bortolato 1,2,3,✉
PMCID: PMC4908197  PMID: 26101934

Abstract

Background and Purpose

Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the prepulse inhibition (PPI) of the acoustic startle reflex. Notably, PPI deficits are associated with numerous neuropsychiatric conditions characterized by gating disturbances, including schizophrenia and Tourette syndrome. Ample evidence has shown that dopamine plays a key role in PPI regulation and, in particular, rodent studies indicate that this neurotransmitter modulates PPI through D 1 and D 2 dopamine receptors. In mice, the relative contributions of these two families of receptors are strain‐dependent. Conversely, the role of D 1 receptors in the regulation of PPI across different rat strains remains unclear.

Experimental Approach

We tested the effects of selective D 1 and D 2 receptor agonists and antagonists on the startle reflex and PPI of Sprague‐Dawley, Wistar and Long–Evans rats.

Key Results

In contrast with Sprague‐Dawley and Wistar rats, the full D 1 receptor agonist SKF82958 elicited significant PPI deficits in Long–Evans rats, an effect sensitive to the selective D1 antagonist SCH23390.

Conclusions and Implications

Our results suggest that, in Long–Evans rats, D 1 receptor activation may be sufficient to significantly impair PPI. These data emphasize the role of D 1 receptors in the pathophysiology of neuropsychiatric disorders featuring alterations in sensorimotor gating, and uphold the importance of the genetic background in shaping the role of dopamine receptors in the regulation of this key information‐processing function.

Linked Articles

This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc

Abbreviations

LE

Long–Evans

PPI

prepulse inhibition of the acoustic startle reflex

SD

Sprague‐Dawley

WIS

Wistar

Tables of Links

TARGETS
GPCRs
Dopamine D1 receptors
Dopamine D2 receptors
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LIGANDS
Apomorphine Quinpirole
Ecopipam SCH23390
L741,626 SKF 38393
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013).

Introduction

The enactment of adaptive behavioural responses to salient environmental cues is contingent on the ability to filter out irrelevant or redundant sensory information (Geyer and Braff, 1987). Deficits in this function, termed sensorimotor gating, have been documented in numerous neuropsychiatric disorders characterized by information‐processing deficits, including schizophrenia and Tourette syndrome (Braff et al., 2001).

One of the best‐validated operational indices to measure gating integrity is the prepulse inhibition (PPI) of the acoustic startle reflex. This endophenotype consists of the reduction of startle response triggered by a dim pre‐stimulus immediately preceding the response‐eliciting burst (Hoffman and Ison, 1980). Over the past two decades, PPI has attracted substantial interest in neuroscience and psychiatric research, in view of its well‐consolidated relevance to psychopathology as well as a number of operational advantages, including its validity as a cross‐species testing paradigm for humans and experimental animals, which makes it particularly appealing in the context of translational studies (Swerdlow et al., 1999; 2008).

In line with the pivotal function of dopamine in information‐processing functions, several studies have shown that this neurotransmitter plays a major role in the orchestration of PPI in humans (Bitsios et al., 2005), as well as rodents (Dulawa and Geyer, 1996; Zhang et al., 2000; Geyer et al., 2001; Swerdlow et al., 2001) and other vertebrates (Burgess and Granato, 2007). In rats and mice, agonists of dopamine receptors have been shown to produce robust PPI deficits (Mansbach et al., 1988; Dulawa and Geyer, 1996; Geyer et al., 2001). These impairments have been likened to the sensorimotor gating deficits observed in neuropsychiatric patients, by virtue of their sensitivity to antipsychotic agents (Mansbach et al., 1988; Geyer et al., 1990; 2001; Swerdlow et al., 1991).

Numerous studies have shown that the role of dopamine in PPI is mediated by both D1‐ and D2‐like receptors; nevertheless, the specific contributions of these receptors to sensorimotor gating vary across different rodent models. While PPI deficits are elicited by D2 dopamine receptor agonists in Sprague‐Dawley (SD) and Wistar (WIS) albino outbred rats (Peng et al., 1990; Varty and Higgins, 1998), these drugs fail to disrupt PPI in most mouse strains commonly used in behavioural research (Ralph‐Williams et al., 2003; Ralph and Caine, 2005). Conversely, D1‐like receptor agonists produce robust PPI deficits in most mouse strains, but are inherently unable to reduce PPI in SD rats. However, these drugs potentiate the effects of D2 receptor agonists and other key PPI disruptors, such as NMDA glutamate receptor antagonists (Wan et al., 1996; Bortolato et al., 2005). It should be noted that high doses of the full D1 receptor agonist SKF82958 were shown to induce PPI deficits in SD rats but these changes were found to be mediated by D2, rather than D1 receptors (Wan et al., 1996).

The dichotomy between mice and rats with respect to their different sensitivity to dopamine receptor agonists was originally posited to reflect interspecies differences. More recently this interpretation has been challenged by Ralph and Caine (2007), who identified PPI deficits also in response to D2 receptor agonists in less commonly used mouse strains. Although few studies have documented the occurrence of PPI deficits in rats following administration of D1 receptor agonists (Ralph and Caine, 2005), the lack of concomitant experiments on D1 receptor antagonists in those studies leaves the question open as to whether some rat strains may exhibit independent D1‐mediated PPI deficits in a fashion similar to that observed in most mouse strains.

To address this issue, we have studied the effects of different D1 receptor agonists and antagonists in SD, WIS and Long–Evans (LE) hooded rats. Our data indicate that, under specific protocol settings, LE rats (but not albino strains) showed a specific reduction of PPI in response to a moderate, D1‐selective dose of SKF82958 and that this effect was sensitive to D1 receptor antagonism.

Methods

Animals

All animal care and experimental procedures were in compliance with the National Institute of Health guidelines and approved by the Institutional Animal Use Committees of the University of Kansas and Cagliari. All studies involving animals are reported in accordance with the ARRIVE guidelines for reporting experiments involving animals (Kilkenny et al., 2010; McGrath et al., 2010). The present study was conducted on 207 male SD, 106 WIS (Harlan, Italy) and 174 LE rats (Charles River Laboratories, Raleigh, NC, USA). Rats (3–4 months old; 300–350 g of body weight) were housed 3–4 per cage in rooms maintained at a temperature of 22 ± 2°C and a humidity of 60%. Animals were given ad libitum access to food and water and held under an artificial 12/12 h light/dark cycle, with lights off from 10:00 a.m. to 10:00 p.m. In order to reduce stress during the experiment, each rat was handled gently for 5 min each day of the week preceding the behavioural testing. Care was taken in ascertaining the uniformity of all husbandry conditions across the two facilities where the experiments were performed (University of Kansas and University of Cagliari, Italy).

Apparatus and experimental procedure

Startle and PPI were tested as previously described (Frau et al., 2007). The apparatus used for detection of startle reflexes (Med Associates, St Albans, VT, USA) consisted of six standard cages placed in sound‐attenuated chambers with fan ventilation. Each cage consisted of a Plexiglas cylinder of 9 cm diameter, mounted on a piezoelectric accelerometric platform connected to an analogue‐digital converter. Two separate speakers conveyed background noise and acoustic bursts, each one properly placed so as to produce a variation of sound within 1 dB across the startle cage. Both speakers and startle cages were connected to a main PC, which detected and analysed all chamber variables with specific software. Before each testing session, acoustic stimuli and mechanical responses were calibrated via specific devices supplied by Med Associates.

Rats were first subjected to a pre‐test session, during which they were exposed to a sequence of seventeen trials, consisting of 40 ms, 115 dB burst, with a 70 dB background white noise. Experimental groups were defined based on the average startle amplitude of the rats, so as to maintain comparable values of average startle response across all groups.

Three days after the pre‐test session, rats were treated and were exposed to a test session (Figure 1). This session featured a 5 min acclimatization period, with a 70 dB background white noise, which continued for the remainder of the session. The acclimatization period was followed by three blocks, each consisting of a sequence of trials: the first and the third block consisted of five pulse‐alone trials of 115 dB (identical to those used in the pre‐test session). The second block consisted of a pseudorandom sequence of 50 trials, including 12 pulse‐alone trials, 30 trials of pulse preceded by 74, 78 or 82 dB pre‐pulses (10 for each level of pre‐pulse loudness), and eight no‐pulse trials, where only the background noise was delivered. Inter‐trial intervals (i.e. the time between two consecutive trials) were selected randomly between 10 and 15 s.

Figure 1.

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Scheme of the PPI paradigm. The green horizontal bar represents the 70 dB background noise; the blue vertical bars represent the 120 dB pulse trials; the red vertical bars represent the three prepulse levels of 74 dB, 78 dB and 82 dB. The complete session is outlined at the top with a portion enlarged to detail a subset of the trials. The acclimatization represents 5 min of exposure to the background noise; block 1 represents five pulse‐alone trials; block 2 represents 50 trials containing a pseudorandom sequence of no stimulus trials, pulse alone trials and prepulse‐pulse trials; block 3 represents five pulse‐alone trials.

The % PPI was calculated only on the values relative to the second period, as well, using the following formula:

100−(mean startle amplitude for prepulse pulse trialsmean startle amplitude for pulse alone trials)×100

For both the pre‐test and the test session, the interstimulus interval (i.e. the duration between the prepulse and the pulse in each trial) was kept at 100 ms. The selection of this interstimulus interval was based on pilot data and previously published experiments from our group (Bortolato et al., 2005), which showed this parameter to be optimally suited to reveal PPI deficits in response to indirect and direct DA receptor agonists in rats under our experimental settings.

Experimental procedure

This study encompassed six experiments, each involving 8–13 rats per group. The first experiment was aimed at assessing what doses of the full D1 receptor agonist SKF82958 (1–5 mg·kg−1, s.c., in comparison with saline, 10 min before behavioural testing) may produce alterations in PPI in SD, WIS and LE rats under our experimental conditions.

Although SKF82958 is one of the most potent D1 receptor agonists, its D1:D2 selectivity ratio (10:1) has been shown to be relatively modest in comparison with other benzazepine D1 receptor agonists (Murray and Waddington, 1990). Indeed, previous reports showed that, in SD rats, its PPI‐disrupting effects were primarily mediated by D2, rather than D1 receptors (Wan et al., 1996). To assess whether the effects of this agent on other rat strains may be ascribed to similar phenomena, in the second experiment, we tested whether the PPI‐disrupting effects of SKF82958 across different strains may be prevented by the selective D1 receptor antagonist SCH23390 (0.1 mg·kg−1, s.c.). Rats from each strain were therefore pretreated with either saline or the potent D1 receptor antagonist, SCH23390; 10 min later, rats were injected with either saline or a dose of SKF82958 that induced PPI deficits (based on the results of the first experiment). Testing occurred 10 min after SKF82958 injection. The third experiment mirrored the design of the second, and assessed the highly selective D2 receptor antagonist L741626 (1 mg·kg−1, s.c.) in SD and LE rats. Rats were pretreated with either the D2 receptor antagonist L741626 or VEHL; 20 min later, animals were injected with either saline or SKF82958. Testing occurred 10 min after SKF82958 administration.

The fourth experiment was conducted to determine the effects of the partial D1 receptor agonist SKF38393 (5–10 mg·kg−1, s.c.) on PPI in SD, WIS and LE rats. Animals were treated with SKF38393 or saline, 10 min prior to being placed in the startle apparatuses for testing.

In the fifth experiment, we evaluated the effects of the prototypical D2 receptor agonist quinpirole (0.6 mg·kg−1, s.c., 5 min prior to testing) in SD and LE rats. Furthermore, to assess the specificity of this effect, we assessed whether the PPI deficits induced by quinpirole may be prevented by L741626 (1 mg·kg−1, s.c., 25 min prior to quinpirole injection).

In the sixth and final experiment, we tested the effects of the D1/D2 receptor agonist apomorphine (0.25–0.5 mg·kg−1, s.c.) on sensorimotor gating in SD, WIS and LE rats. Apomorphine was injected immediately before placing the animals in the startle apparatuses for testing.

Materials

The following drugs were used: SKF 82958 hydrobromide, SKF 38393, SCH23390, L741626, apomorphine hydrochloride and quinpirole (Sigma Aldrich, St. Louis, MO, USA). SKF 82958, SKF 38393, SCH 23390 and quinpirole were dissolved in 0.9% saline solution. L741626 was dissolved in a vehicle (VEHL) of 1 mg·mL−1 lactic acid and 0.9% saline. Apomorphine was dissolved in a vehicle (VEHA) of 0.9% saline and 1 mg·mL−1 ascorbic acid to prevent oxidation. All drugs were administered via either s.c. or i.p injection, in 1 mL·kg−1 injection volume.

Data analysis

Normality and homoscedasticity of data were verified by Kolmogorov–Smirnov and Bartlett's tests. Data were compared across groups by one‐way or two‐way anovas, as appropriate. As no interaction between prepulse levels and treatment were found in the statistical analysis, %PPI values were collapsed across prepulse intensity to represent average %PPI. Post hoc analyses were performed using Tukey's test with Spjøtvoll Stoline correction. Significance threshold was set at 0.05.

Results

Assessment of effects of D 1 receptor agonists in SD, WIS and LE rats

In the first series of experiments (Figure 2), we tested the effects of the full D1 receptor agonist SKF82958 (1–5 mg·kg−1, SC) on the startle responses and PPI of SD, WIS and LE rats. In SD rats (Figure 2A–B; n = 9 per group), this drug did not significantly modify startle amplitude; however, in conformity with previously published data (Wan et al., 1996), its highest dose (5 mg·kg−1, s.c.) produced a marked reduction of PPI in comparison with saline [F(2,24) = 8.71, P < 0.05]. Conversely, the dose of 1 mg·kg−1 of SKF82958 was sufficient to reduce PPI in both WIS (Figure 2C–D) and LE rats (Figure 2E–F; n = 9 per group for each strain) {WIS: [F(1,16) = 4.69]; LE: [F(1,16) = 29.38], Ps < 0.05}, without altering startle amplitude.

Figure 2.

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Effects of the D 1 receptor full agonist SKF82958 or its vehicle, saline (SAL), on startle reflex and PPI of the startle in SD, WIS and LE rats. Values represent mean ± SEM for each experimental group. Doses of SKF82958 (1 or 5 mg·kg−1, s.c.) are indicated below the horizontal axis. *P < 0.05 in comparison with saline‐treated controls. For more details, see text.

In SD rats (n = 10 per group), SCH23390 produced a significant reduction in startle amplitude [main effect: F(1,36) = 5.28, P < 0.05]; conversely, this parameter was not affected by either SKF82958 (5 mg·kg−1, s.c.) treatment or its interaction with SCH23390 (Figure 3A). In the same strain, SKF82958 significantly reduced PPI [main effect: F(1,36) = 35.30, P < 0.05]; however, in confirmation of previous data (Wan et al., 1996), this effect was not countered by the D1 receptor (Figure 3B), confirming that, in SD rats, the PPI‐disrupting effects of SKF82958 are not mediated by D1 receptors. These results were mirrored by our findings in WIS rats (n = 9 per group). Indeed, in this strain, SCH23390 produced a significant reduction of startle amplitude [main effect: F(1,32) = 19.09, P < 0.05] (Figure 3C); furthermore, while SKF82958 (1 mg·kg−1, s.c.) reduced PPI levels in this strain [F(1,32) = 15.82, P < 0.05], this effect was not prevented by SCH23390 (Figure 3D).

Figure 3.

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Involvement of D 1 receptors in the effects of SKF82958 (SKF; 5 mg·kg−1, s.c.) in SD rats and 1 mg·kg−1, s.c.) in WIS and LE rats) on the regulation of startle reflex and PPI in different rat strains, as tested through the combined treatment with the selective D 1 receptor antagonist SCH23390 (SCH; 0.1 mg·kg−1, IP). Values represent mean ± SEM for each experimental group. Doses of SKF are indicated in mg·kg−1. *P < 0.05, significantly different as indicated. For more details, see text.

In contrast with albino strains, in LE rats (n = 8–10 rats per group), SCH23390 pretreatment produced a significant enhancement in startle amplitude [main effect: F(1,34) = 10.75, P < 0.05]; conversely, anova failed to detect a significant main effects for SKF82958 or interactions between the two treatments (Figure 3E). The analysis of PPI confirmed that SKF82958 significantly reduced this index [F(1,34) = 26.84, P < 0.05]; however, in contrast with the other rat strains, this effect was prevented by SCH23390 [pretreatment × treatment interaction: F(1,34) = 6.76, P < 0.05], suggesting that the PPI‐disrupting effects of SKF82958 were mediated by D1 receptors in this strain (Figure 3F).

We then examined whether the PPI deficits induced by SKF82958 may be countered by the selective D2 receptor antagonist L741626. The combination of L741,626 (1 mg·kg−1, s.c.) and SKF82958 (5 mg·kg−1, s.c.) failed to induce significant alterations in startle magnitude in both SD (n = 10 per group; Figure 4A) and LE rats (n = 8 per group; Figure 4C). Conversely, the PPI deficits induced by SKF82958 were significantly prevented by L741,626 in SD [F(1,36) = 17.29, P < 0.05] (Figure 4B), but not LE rats (Figure 4D).

Figure 4.

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Involvement of D 2 receptors in the effects of SKF82958 (SKF) on the regulation of startle reflex and PPI in different rat strains, as tested through the combined treatment with the selective D 2 receptor antagonist L741,626 (L; 1 mg·kg−1, s.c.). Values represent mean ± SEM for each experimental group. PPI values are represented as the means of all prepulse‐loudness values. Doses of SKF are indicated in mg·kg−1. VEHL, vehicle for L741,626; *P < 0.05, significantly different as indicated. For more details, see text.

Finally, we studied the effects of the partial D1 receptor agonist SKF38393 (5–10 mg·kg−1, s.c.) on the startle reflex and PPI of SD, WIS and LE rats. Notably, this drug failed to affect either parameter in any strain (Figure 5).

Figure 5.

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Effects of the D 1 receptor partial agonist SKF38393 or its vehicle,saline (SAL), on startle reflex and PPI of the startle in SD, WIS and LE rats. Values represent mean ± SEM for each experimental group. Doses of SKF38393 (in mg·kg−1, s.c.) are indicated below the horizontal axis. For more details, see text.

Assessment of effects of D 2 receptor activation in SD and LE rats

In SD rats, quinpirole treatment decreased the mean startle amplitude [F(1,36) = 48.51, P < 0.05], but this effect was not modified by the D2 antagonist L741626 (Figure 6A). Both L741626 [main effect; F(1,36) = 10.12, P < 0.05] and quinpirole [main effect; F(1,36) = 14.88, P < 0.05] significantly modified PPI, but no significant interaction of their effects was found (Figure 6B). In LE rats, startle analyses showed a significant interaction between quinpirole and L741626 [F(1,28) = 6.8, P < 0.05]; post hoc analyses revealed that L741626 increased startle response, while quinpirole significantly decreased it both in VEHL‐ and L741626‐pretreated animals (Figure 6C). The analysis of PPI in LE rats detected a significant interaction between quinpirole and L741626 [F(1,28) = 8.07, P < 0.05]. Post hoc analyses revealed that quinpirole led to a significant PPI deficit, which was fully countered by L741626 (Figure 6D).

Figure 6.

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Involvement of D 2 receptors in the effects of quinpirole (QUI) on the regulation of startle reflex and PPI in different rat strains, as tested through the combined treatment with the selective D 2 receptor antagonist L741,626 (L; 1 mg·kg−1, s.c.). Values represent mean ± SEM for each experimental group. PPI values are represented as the means of all prepulse‐loudness values. VEHL, vehicle for L741,626; *P < 0.05, significantly different as indicated. For more details, see text.

Assessment of effects of apomorphine in SD, WIS and LE rats

In SD rats (n = 10 per group), apomorphine failed to affect startle magnitude (Figure 7A), but reduced PPI [F(2,27) = 5.09, P < 0.05]. Post hoc analyses showed that the reduction in PPI was produced by the dose of 0.25 mg·kg−1 (Figure 7B). In WIS rats (n = 10 per group), apomorphine did not reduce startle amplitude (Figure 7C); the higher dose of apomorphine significantly decreased PPI [F(2,27) = 4.25, P < 0.05]. In LE rats (n = 10–12 per group), apomorphine did not significantly affect startle amplitude, but produced a robust PPI disruption [F(2,32) = 13.27, P < 0.05]. Significant differences were found for both the doses of 0.25 and 0.5 in comparison with VEHA.

Figure 7.

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Effects of the non‐selective dopaminergic agonist apomorphine or its vehicle (VEHA) on startle reflex and PPI of the startle in SD, WIS and LE rats. Values represent mean ± SEM for each experimental group. Doses of apomorphine (in mg·kg−1, s.c.) are indicated below the horizontal axis. *P < 0.05, in comparison to vehicle‐treated controls. For more details, see text.

Discussion

The main result of this study show that, in contrast with SD and WIS albino rats, hooded LE animals display a significant impairment in sensorimotor gating in response to selective, full stimulation of D1 dopamine receptors. Specifically, under our experimental settings, the full D1 agonist SKF82958, but not the partial D1 agonist SKF38393 produced a significant PPI reduction, which was not paralleled by variations in startle amplitude, and was countered by D1, but not D2 receptor antagonism.

To the best of our knowledge, this is one of the first reports demonstrating PPI deficits following the selective and independent activation of D1 receptors in rats. Numerous rat studies have shown the implication of both D1 and D2 receptors in the PPI‐disrupting properties of non‐selective dopaminergic agonists in SD, WIS and LE rats (Mansbach et al., 1988; Wan et al., 1996; Rasmussen et al., 1997; Feifel, 1999). The general consensus, however, has pointed to an ancillary role of D1 dopamine receptors in the regulation of sensorimotor gating in rats. This assumption has been largely based on numerous experimental results on albino rat strains, which showed that D1 receptor agonists, albeit able to potentiate the PPI‐disrupting properties of D2 receptor agonists or NMDA glutamate receptor blockers, failed to intrinsically reduce PPI in a selective fashion (Wan et al., 1996; Bortolato et al., 2005). For example, while SD rats display PPI deficits in response to SKF82958 or related agents (such as R‐6‐Br‐APB [R(+)‐6‐bromo‐7,8‐dihydroxy‐3‐allyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine]; Wan et al., 1996; Swerdlow et al., 2001; Ralph and Caine, 2005), these impairments were found to reflect the activation of D2, rather than D1 receptors (Wan et al., 1996). Accordingly, the present results showed that, in albino rats, the PPI disruption caused by SKF82958 was prevented by administration of L741626, but not SCH23390. In this perspective, our findings highlight an unequivocal link between D1 receptor activation and sensorimotor gating deficits, and provide an experimental model to elucidate the role of these receptors in the regulation of rat PPI.

The mechanisms underpinning the role of D1 or D2 receptors in PPI regulation are incompletely understood. While several studies have identified that the PPI‐disrupting properties of non‐selective dopaminergic agonists are primarily contributed by the nucleus accumbens (Swerdlow et al., 1990), the specific localization of each receptor subtype is not well understood. In particular, recent data have shown that D1 receptors in the prefrontal cortex may play an opposing role (Shoemaker et al., 2005). Thus, it is possible that the specific effects of D1 receptor agonists may result from the sum of opposing contributions of this receptor across different brain areas. Further studies will be needed to ascertain this possibility. Interestingly, previous studies have shown that the differences between LE and SD rats on the role of dopamine receptors in PPI regulation depends on mechanisms of dopamine receptor signalling in the nucleus accumbens (Saint Marie et al., 2006; Swerdlow et al., 2006; 2007; Shilling et al., 2008). From this perspective, it is worth noting that these results provide a first experimental platform to study the mechanism supporting the independent contributions of D1 and D2 receptor activation to dopaminergic PPI deficits in different rat strains.

In contrast with the effects of SKF82958, SKF38393 failed to impair PPI in any strain. The inability of the latter drug to produce PPI deficits confirms previous data from our group and others (Bortolato et al., 2005), and is likely to result from its partial efficacy in activating the adenyl cyclase coupled to D1 receptors, which corresponds approximately to 50–70% of that of dopamine (Arnt et al., 1988; Andersen and Jansen, 1990; Gnanalingham et al., 1995) and is markedly lower than that of SKF82958, a full D1 receptor agonist (O'Boyle et al., 1989; Andersen and Jansen, 1990). Indeed, comparative analyses of these two benzazepine derivatives have shown that SKF82958 elicits a number of phenotypes not typically observed following administration of SKF38393, including activation of early‐response genes (Gerfen et al., 1990; Jiang et al., 1990; Robertson et al., 1991; Wirtshafter and Asin, 1994; Wang and McGinty, 1996), tyrosine phosphorylation of NMDA receptor subunits (Dunah and Standaert, 2001) and activation of vertical locomotor activity (Meyer and Shults, 1993). Thus, these data may signify that, in LE rats, PPI deficits may be triggered only by the full stimulation of D1 receptors and its downstream signalling machinery.

Pharmacological and genetic studies have shown that D1 receptors play a predominant role in the dopaminergic modulation of dopamine in mice (Ralph‐Williams et al., 2002; 2003). While these findings initially suggested a potential dichotomy between mice and rats with respect to the regulation of sensorimotor gating, this conclusion was later challenged by further studies, which showed that D2 receptor activation could disrupt PPI in other mouse strains used less commonly in research (Ralph and Caine, 2007). The present results further expand on these observations, and indicate that, at least within specific setting conditions, PPI may be independently regulated by both D1 and D2 receptors in mice and rats, and that inter‐strain variations may play a critical role in the relative importance of each target in sensorimotor gating. In line with this conclusion, previous studies have shown that the dopaminergic regulation of startle reactivity and PPI is strongly influenced by differences in strains and genetic background in rats (Swerdlow et al., 2004; 2006).

We have shown here that, while SKF82958 failed to affect startle response across all rat strains, SCH23390 had apparently opposing intrinsic roles in affecting startle amplitude. Indeed, while this parameter was mildly, yet significantly reduced by D1 receptor blockade in SD and WIS rats, it was modestly increased in LE animals. While this discrepancy cannot account for the observed differences in PPI responses across these strains, our data may suggest that the role of D1 receptors in LE rats may also diverge with respect to the regulation of startle reactivity. Our data are apparently in partial contrast with previous reports, which documented that D1 receptor activation enhances startle response in SD rats (Meloni and Davis, 1999). A likely explanation for this apparent divergence lies in the characteristics of our testing protocol, which was optimized for the assessment of dopaminergic effects on PPI, rather than startle reactivity. Irrespective of these considerations, future comparative studies are warranted to evaluate the specific impact of D1 receptors in the modulation of acoustic startle amplitude across different rat strains.

Although the present studies do not provide any direct mechanism to account for the differential responsiveness of LE rats to D1 receptor activation with respect to PPI, several data indicate that the dopaminergic system in this strain is distinctly different from that of albino rats. In rats, albinism is primarily due to a genetic defect in tyrosinase (Searle, 1990), leading to low melanin production. In the presence of tyrosinase, dopamine and its precursor l‐DOPA inactivate the rate‐limiting enzyme for dopamine synthesis, tyrosine hydroxylase (Xu et al., 1998). Accordingly, intracerebral infusion of tyrosinase leads to enhanced dopamine release (Amicarelli et al., 1999). Previous studies have documented that the tyrosinase levels in LE rats were associated with higher dopamine turnover in comparison with SD rats (Swerdlow et al., 2005) and, indeed, LE rats display higher corticolimbic levels of the dopamine metabolic enzyme catechol‐O‐methyl transferase (Shilling et al., 2008). Furthermore, fur pigmentation in LE rats is negatively correlated with the effects of apomorphine on PPI (Swerdlow et al., 2006), suggesting that the activity of dopamine receptors is also influenced by different levels of tyrosinase. Taken together, these data suggest that the differences in PPI regulation between albino and LE rats may be underpinned by changes in D1 receptor responsiveness. The possibility that albino rats may present alterations in D1 response is also supported by evidence showing that the domestication process of rats has led to significant differences in dopaminergic responses (Nikulina et al., 1992), likely to be due to the active selection of tameness and exclusion of aggressive traits (Himmler et al., 2013).

Given that LE rats were originally obtained by crossing a WIS dam with a wild sire (Freudenberger, 1932; Altman and Katz, 1979), our data raise the possibility that wild rats or other fully pigmented strains may exhibit an even greater responsiveness to D1 receptor agonists than that of LE animals. Although logistical and safety considerations pose important problems in behavioural testing of wild rats, further studies are warranted to analyse the differential impact of albino and pigmented strains with respect to the dopaminergic regulation of sensorimotor gating.

As previously indicated, it should be emphasized that the PPI‐disrupting effects of D1 receptor activation in LE rats were revealed under specific protocol settings. Different testing conditions and protocol indices can greatly influence PPI, such as the loudness of the startle‐eliciting pulse and the prepulses (with respect to the background noise), the duration of the inter‐stimulus and inter‐trial intervals, as well as the resilience of the accelerometric platform (Geyer and Swerdlow, 1998). In this respect, it is important to notice that our results were paralleled by Swerdlow and colleagues at the University of California San Diego (N. Swerdlow, pers. comm.), who found that, when tested with inter‐stimulus intervals of 120 ms, LE rats exhibited a %PPI baseline of approximately 80%, and responded to the full D1 receptor agonist SKF81927 with a significant reduction of PPI to about 60%. However, in the presence of shorter inter‐stimulus intervals, the same D1 receptor agonist elicited either no significant effect or even enhancements of PPI (depending on the specific duration of the interval). It is also possible that the high baseline levels in our experiment may have facilitated the detection of D1‐mediated PPI deficits. Accordingly, previous studies have shown that baseline PPI values play a fundamental role in influencing the susceptibility to the effects of pharmacological treatments on PPI modulation. Indeed, similar conclusions were recently drawn in human studies (Bitsios et al., 2005). In light of these considerations, it is possible that, while the conditions of our testing protocol may be optimal to capture the contribution of D1 receptors to PPI regulation, extreme caution should be advocated in the interpretation and generalization of these results, as they are likely to refer to a relatively narrow range of experimental conditions, whose biological significance remains to be determined.

We also confirmed that, under the same settings, LE rats exhibited PPI deficits also in response to the D2 receptor agonist quinpirole (which were selectively reversed by the highly selective D2 receptor antagonist L741626) and the D1/D2 non‐selective agonist apomorphine. Conversely, although the same startle protocol evoked PPI impairments in SD and WIS rats in response to quinpirole and apomorphine, no significant D1‐dependent PPI deficits were identified in either strain. Indeed, while SKF82958 elicited PPI deficits in both strains, as previously published (Wan et al., 1996; Swerdlow et al., 2000), these impairments were prevented by the selective D2 receptor blocker L741626, rather than by the D1 receptor antagonist SCH23390. The sensitivity of all tested strains to quinpirole confirms that, in rats, D2 receptors serve a prominent role in the regulation of PPI.

As mentioned in the Introduction, PPI has gained wide acceptance as the main operational paradigm for sensorimotor gating testing, because of its cross‐species validity. Deficits in this index have been documented across several neuropsychiatric disorders, including schizophrenia and Tourette syndrome (Braff et al., 2001). Building from this observation, it is interesting to observe that D1 receptors have been implicated in the pathophysiology of both conditions. In schizophrenia, these targets have been widely implicated in the modulation of cognitive deficits and negative symptoms (Abi‐Dargham, 2003). In particular, both overstimulation and suppression of D1 receptors may result in impairments of working memory (Williams and Goldman‐Rakic, 1995), a core cognitive deficit of schizophrenia. Furthermore, while stimulation of D1 receptors has been largely advocated as a potential therapeutic strategy to reduce the severity of negative and cognitive symptoms, preliminary studies provided anecdotal support for an efficacy of D1 receptor blockers in the reduction of negative symptoms (de Beaurepaire et al., 1995; Den Boer et al., 1995; but see also Karlsson et al., 1995 for contrasting data). While the role of D1 receptors in the pathophysiology of Tourette syndrome is not as well established, emerging evidence has pointed to this receptor as a promising therapeutic target; indeed, the selective D1 receptor antagonist ecopipam has been recently shown to be effective in reducing tic severity (Gilbert et al., 2014).

The identification of a strain‐specific role of D1 receptors in PPI and startle regulation suggests that the specific interactions between this receptor and genetic factors may be essential in influencing PPI and, potentially, the pathophysiology of schizophrenia and Tourette syndrome. This concept is in keeping with ample evidence emphasizing the genetic roots of both disorders (Kendler and Diehl, 1993; Sullivan, 2005; O'Rourke et al., 2009; Deng et al., 2012).

Several limitations of our study should be acknowledged. First, our analyses did not include molecular studies to evaluate the mechanisms underpinning the observed interstrain differences with respect to the role of D1 receptor in startle and PPI regulation. Secondly, unlike the studies on D1 receptors, our experiments on the effects of quinpirole were only performed in animals subjected to a pretreatment; thus, we cannot rule out that some of the observed findings may be affected by the stress related to the pretreatment injection. Finally, although our experiments were performed on equivalent experimental protocols and apparatuses, it is worth noting that the experiments were performed in two different laboratories (SD and WIS at the University of Cagliari, and LE at the University of Kansas). Thus, we cannot completely exclude that these logistic differences, or divergences in the colonies from the suppliers. Accordingly, previous reports have shown that differences in PPI can reflect differences in substrains based on the specific location of the supplier (Swerdlow et al., 2000). Nevertheless, these potential concerns are tempered by preliminary studies in both laboratories, which essentially confirmed our findings on the three rat strains irrespective of the locations and source of the animals.

In summary, our study has identified a heuristic experimental platform to test the selective role of D1 receptors in producing gating deficits in rats. As stated above, PPI deficits are an endophenotypic feature of several neuropsychiatric disorders, including schizophrenia and Tourette syndrome. Thus, our results may prove valuable in the testing of specific hypotheses on the direct involvement of D1 receptors in rat models of these disorders.

Author contributions

L. J. M. executed part of the experiments, analysed the data and wrote the first draft of the manuscript. R. F., A. P. and R. P. executed part of the experiments. P. D. designed the studies and provided the funds for part of the experiments. M. B. designed the studies, provided the funds for the study, analysed the data and wrote the final version of the manuscript.

Conflict of interest

The authors certify that they have no conflict of interest in relation to the content of this article.

Acknowledgements

The authors are highly grateful to Dr. Neal Swerdlow for his valuable scientific and editorial suggestions, as well as data communications. The authors would also like to thank Hunter Strathman, Kelsey Joliff, Alexandria Ruby and Lyle Harte for their valuable support in the execution of the experiments. This work was partially supported by grants from the National Institute of Mental Health (NIH R01 MH104603, to M. B.), Tourette Syndrome Association (to M. B.), Kansas Strategic Initiative Grant (to M. B.) and a sub‐award from the NIH grant P20 GM103638 (to M. B.). The authors are indebted to the EU COST Action CM1103 ‘Structure‐based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain’ for supporting their international collaboration. None of the institutions had any further role in the decision to submit the paper for publication.

Mosher, L. J. , Frau, R. , Pardu, A. , Pes, R. , Devoto, P. , and Bortolato, M. (2016) Selective activation of D 1 dopamine receptors impairs sensorimotor gating in Long–Evans rats. Br J Pharmacol, 173: 2122–2134. doi: 10.1111/bph.13232.

References

  1. Abi‐Dargham A (2003). Probing cortical dopamine function in schizophrenia: what can D1 receptors tell us? World Psychiatry 2: 166–171. [PMC free article] [PubMed] [Google Scholar]
  2. Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL Spedding M et al (2013) The Concise Guide to PHARMACOLOGY 2013/14: G Protein‐Coupled Receptors. Br J Pharmacol 170: 1459–1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Altman PL, Katz DD (1979). Inbred and Genetically Defined Strains of Laboratory Animals, Part 1: Mouse And Rat, 1st edn Federation of American Societies for Experimental Biology: Bethesda, MD. [Google Scholar]
  4. Amicarelli F, Gasbarri A, Masciocco L, Pompili A, Pacitti C, Carlucci G et al (1999). The effect of intrastriatal injection of liposome‐entrapped tyrosinase on the dopamine levels in the rat brain. Cell Mol Biol 45: 1093–1097. [PubMed] [Google Scholar]
  5. Andersen PH, Jansen JA (1990). Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy. Eur J Pharmacol: Mol Pharmacol 188: 335–347. [DOI] [PubMed] [Google Scholar]
  6. Arnt J, Bogeso KP, Hyttel J, Meier E (1988). Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats. Pharmacol Toxicol 62: 121–130. [DOI] [PubMed] [Google Scholar]
  7. de Beaurepaire R, Labelle A, Naber D, Jones BD, Barnes TR (1995). An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states. Psychopharmacology (Berl) 121: 323–327. [DOI] [PubMed] [Google Scholar]
  8. Bitsios P, Giakoumaki SG, Frangou S (2005). The effects of dopamine agonists on prepulse inhibition in healthy men depend on baseline PPI values. Psychopharmacology (Berl) 182: 144–152. [DOI] [PubMed] [Google Scholar]
  9. Bortolato M, Aru GN, Fa M, Frau R, Orru M, Salis P et al (2005). Activation of D1, but not D2 receptors potentiates dizocilpine‐mediated disruption of prepulse inhibition of the startle. Neuropsychopharmacology 30: 561–574. [DOI] [PubMed] [Google Scholar]
  10. Braff DL, Geyer MA, Swerdlow NR (2001). Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156: 234–258. [DOI] [PubMed] [Google Scholar]
  11. Burgess HA, Granato M (2007). Sensorimotor gating in larval zebrafish. J Neurosci 27: 4984–4994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Den Boer JA, van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG et al (1995). Differential effects of the D1‐DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia. Psychopharmacology (Berl) 121: 317–322. [DOI] [PubMed] [Google Scholar]
  13. Deng H, Gao K, Jankovic J (2012). The genetics of Tourette syndrome. Nat Rev Neurol 8: 203–213. [DOI] [PubMed] [Google Scholar]
  14. Dulawa SC, Geyer MA (1996). Psychopharmacology of prepulse inhibition in mice. Chin J Physiol 39: 139–146. [PubMed] [Google Scholar]
  15. Dunah AW, Standaert DG (2001). Dopamine D1 receptor‐dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J Neurosci 21: 5546–5558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Feifel D (1999). Individual differences in prepulse inhibition of startle as a measure of individual dopamine function. Behav Neurosci 113: 1020–1029. [DOI] [PubMed] [Google Scholar]
  17. Frau R, Orru M, Fa M, Casti A, Manunta M, Fais N et al (2007). Effects of topiramate on the prepulse inhibition of the acoustic startle in rats. Neuropsychopharmacology 32: 320–331. [DOI] [PubMed] [Google Scholar]
  18. Freudenberger CB (1932). A comparison of the Wistar albino and the Long‐Evans hybrid strain of the Norway rat. Am J Anat 50: 293–349. [Google Scholar]
  19. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr et al (1990). D1 and D2 dopamine receptor‐regulated gene expression of striatonigral and striatopallidal neurons. Science 250: 1429–1432. [DOI] [PubMed] [Google Scholar]
  20. Geyer MA, Braff DL (1987). Startle habituation and sensorimotor gating in schizophrenia and related animal models. Schizophr Bull 13: 643–668. [DOI] [PubMed] [Google Scholar]
  21. Geyer MA, Swerdlow NR (1998). Measurement of startle response, prepulse inhibition, and habituation. Curr Protoc Neurosci 8, unit 8.7. [DOI] [PubMed]
  22. Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990). Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull 25: 485–498. [DOI] [PubMed] [Google Scholar]
  23. Geyer MA, Krebs‐Thomson K, Braff DL, Swerdlow NR (2001). Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156: 117–154. [DOI] [PubMed] [Google Scholar]
  24. Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE (2014). A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome. Clin Neuropharmacol 37: 26–30. [DOI] [PubMed] [Google Scholar]
  25. Gnanalingham KK, Hunter AJ, Jenner P, Marsden CD (1995). Stimulation of adenylate cyclase activity by benzazepine D‐1 dopamine agonists with varying efficacies in the 6‐hydroxydopamine lesioned rat – relationship to circling behaviour. Biochem Pharmacol 49: 1185–1193. [DOI] [PubMed] [Google Scholar]
  26. Himmler BT, Stryjek R, Modlinska K, Derksen SM, Pisula W, Pellis SM (2013). How domestication modulates play behavior: a comparative analysis between wild rats and a laboratory strain of Rattus norvegicus. J Comp Psychol 127: 453–464. [DOI] [PubMed] [Google Scholar]
  27. Hoffman HS, Ison JR (1980). Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev 87: 175–189. [PubMed] [Google Scholar]
  28. Jiang HK, McGinty JF, Hong JS (1990). Differential modulation of striatonigral dynorphin and enkephalin by dopamine receptor subtypes. Brain Res 507: 57–64. [DOI] [PubMed] [Google Scholar]
  29. Karlsson P, Smith L, Farde L, Härnryd C, Sedvall G, Wiesel FA (1995). Lack of apparent antipsychotic effect of the D1‐dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients. Psychopharmacology (Berl) 121: 309–316. [DOI] [PubMed] [Google Scholar]
  30. Kendler KS, Diehl SR (1993). The genetics of schizophrenia: a current, genetic‐epidemiologic perspective. Schizophr Bull 19: 261–285. [DOI] [PubMed] [Google Scholar]
  31. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG (2010). Animal research: Reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 160: 1577–1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mansbach RS, Geyer MA, Braff DL (1988). Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94: 507–514. [DOI] [PubMed] [Google Scholar]
  33. McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C (2010). Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 160: 1573–1576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meloni EG, Davis M (1999). Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958. Psychopharmacology (Berl) 144: 373–380. [DOI] [PubMed] [Google Scholar]
  35. Meyer ME, Shults JM (1993). Dopamine D1 receptor family agonists, SK&F38393, SK&F77434, and SK&F82958, differentially affect locomotor activities in rats. Pharmacol Biochem Behav 46: 269–274. [DOI] [PubMed] [Google Scholar]
  36. Murray AM, Waddington JL (1990). New putative selective agonists at the D‐1 dopamine receptor: behavioural and neurochemical comparison of CY 208–243 with SK&F 101384 and SK&F 103243. Pharmacol Biochem Behav 35: 105–110. [DOI] [PubMed] [Google Scholar]
  37. Nikulina EM, Avgustinovich DF, Popova NK (1992). Selection for reduced aggressiveness towards man and dopaminergic activity in Norway rats. Aggress Behav 18: 65–72. [Google Scholar]
  38. O'Boyle KM, Gaitanopoulos DE, Brenner M, Waddington JL (1989). Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor. Neuropharmacology 28: 401–405. [DOI] [PubMed] [Google Scholar]
  39. O'Rourke JA, Scharf JM, Yu D, Pauls DL (2009). The genetics of Tourette syndrome: a review. J Psychosom Res 67: 533–545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP et al; NC‐IUPHAR (2014). The IUPHAR/BPS Guide to PHARMACOLOGY: an expert‐driven knowledge base of drug targets and their ligands. Nucl. Acids Res 42 (Database Issue): D1098–D1106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Peng RY, Mansbach RS, Braff DL, Geyer MA (1990). A D2 dopamine receptor agonist disrupts sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia. Neuropsychopharmacology 3: 211–218. [PubMed] [Google Scholar]
  42. Ralph RJ, Caine SB (2005). Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: comparison of Sprague‐Dawley rats to Swiss‐Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice. J Pharmacol Exp Ther 312: 733–741. [DOI] [PubMed] [Google Scholar]
  43. Ralph RJ, Caine SB (2007). Effects of selective dopamine D1‐like and D2‐like agonists on prepulse inhibition of startle in inbred C3H/HeJ, SPRET/EiJ, and CAST/EiJ mice. Psychopharmacology (Berl) 191: 731–739. [DOI] [PubMed] [Google Scholar]
  44. Ralph‐Williams RJ, Lehmann‐Masten V, Otero‐Corchon V, Low MJ, Geyer MA (2002). Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock‐out mice. J Neurosci 22: 9604–9611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Ralph‐Williams RJ, Lehmann‐Masten V, Geyer MA (2003). Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice. Neuropsychopharmacology 28: 108–118. [DOI] [PubMed] [Google Scholar]
  46. Rasmussen K, Gates MR, Burger JE, Czachura JF (1997). The novel atypical antipsychotic olanzapine, but not the CCK‐B antagonist LY288513, blocks apomorphine‐induced disruption of pre‐pulse inhibition. Neurosci Lett 222: 61–64. [DOI] [PubMed] [Google Scholar]
  47. Robertson HA, Paul ML, Moratalla R, Graybiel AM (1991). Expression of the immediate early gene c‐fos in basal ganglia: induction by dopaminergic drugs. Can J Neurol Sci 18: 380–383. [DOI] [PubMed] [Google Scholar]
  48. Saint Marie RL, Neary AC, Shoemaker JM, Swerdlow NR (2006). The effects of apomorphine and D‐amphetamine on striatal c‐Fos expression in Sprague‐Dawley and Long Evans rats and their F1 progeny. Brain Res 1119: 203–214. [DOI] [PubMed] [Google Scholar]
  49. Searle AG (1990). Comparative genetics of albinism. Ophthalmic Paediatr Genet 11: 159–164. [DOI] [PubMed] [Google Scholar]
  50. Shilling PD, Saint Marie RL, Shoemaker JM, Swerdlow NR (2008). Strain differences in the gating‐disruptive effects of apomorphine: relationship to gene expression in nucleus accumbens signaling pathways. Biol Psychiatry 63: 748–758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Shoemaker JM, Saint Marie RL, Bongiovanni MJ, Neary AC, Tochen LS, Swerdlow NR (2005). Prefrontal D1 and ventral hippocampal N‐methyl‐D‐aspartate regulation of startle gating in rats. Neuroscience 135: 385–394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sullivan PF (2005). The genetics of schizophrenia. PLoS Med 2: e212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990). Schizophrenic‐like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology (Berl) 101: 414–420. [DOI] [PubMed] [Google Scholar]
  54. Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991). Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. J Pharmacol Exp Ther 256: 530–536. [PubMed] [Google Scholar]
  55. Swerdlow NR, Braff DL, Geyer MA (1999). Cross‐species studies of sensorimotor gating of the startle reflex. Ann N Y Acad Sci 877: 202–216. [DOI] [PubMed] [Google Scholar]
  56. Swerdlow NR, Martinez ZA, Hanlon FM, Platten A, Farid M, Auerbach P et al (2000). Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating‐disruptive effects of dopamine agonists. J Neurosci 20: 4325–4336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Swerdlow NR, Platten A, Kim YK, Gaudet I, Shoemaker J, Pitcher L et al (2001). Sensitivity to the dopaminergic regulation of prepulse inhibition in rats: evidence for genetic, but not environmental determinants. Pharmacol Biochem Behav 70: 219–226. [DOI] [PubMed] [Google Scholar]
  58. Swerdlow NR, Shoemaker JM, Platten A, Pitcher L, Goins J, Auerbach PP (2004). Heritable differences in the dopaminergic regulation of sensorimotor gating. I. Apomorphine effects on startle gating in albino and hooded outbred rat strains and their F1 and N2 progeny. Psychopharmacology (Berl) 174: 441–451. [DOI] [PubMed] [Google Scholar]
  59. Swerdlow NR, Kuczenski R, Goins JC, Crain SK, Ma LT, Bongiovanni MJ et al (2005). Neurochemical analysis of rat strain differences in the startle gating‐disruptive effects of dopamine agonists. Pharmacol Biochem Behav 80: 203–211. [DOI] [PubMed] [Google Scholar]
  60. Swerdlow NR, Krupin AS, Bongiovanni MJ, Shoemaker JM, Goins JC, Hammer RP Jr (2006). Heritable differences in the dopaminergic regulation of behavior in rats: relationship to D2‐like receptor G‐protein function. Neuropsychopharmacology 31: 721–729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Swerdlow NR, Shoemaker JM, Bongiovanni MJ, Neary AC, Tochen LS, Saint Marie RL (2007). Strain differences in the disruption of prepulse inhibition of startle after systemic and intra‐accumbens amphetamine administration. Pharmacol Biochem Behav 87: 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL (2008). Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 199: 331–388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Varty GB, Higgins GA (1998). Dopamine agonist‐induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors? Behav Pharmacol 9: 445–455. [DOI] [PubMed] [Google Scholar]
  64. Wan FJ, Taaid N, Swerdlow NR (1996). Do D1/D2 interactions regulate prepulse inhibition in rats? Neuropsychopharmacology 14: 265–274. [DOI] [PubMed] [Google Scholar]
  65. Wang JQ, McGinty JF (1996). Scopolamine augments c‐fos and zip/268 messenger RNA expression induced by the full D(1) dopamine receptor agonist SKF‐82958 in the intact rat striatum. Neuroscience 72: 601–616. [DOI] [PubMed] [Google Scholar]
  66. Williams GV, Goldman‐Rakic PS (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376: 572–575. [DOI] [PubMed] [Google Scholar]
  67. Wirtshafter D, Asin KE (1994). Interactive effects of stimulation of D1 and D2 dopamine receptors on fos‐like immunoreactivity in the normosensitive rat striatum. Brain Res Bull 35: 85–91. [DOI] [PubMed] [Google Scholar]
  68. Xu Y, Stokes AH, Roskoski R Jr, Vrana KE (1998). Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase. J Neurosci Res 54: 691–697. [DOI] [PubMed] [Google Scholar]
  69. Zhang J, Forkstam C, Engel JA, Svensson L (2000). Role of dopamine in prepulse inhibition of acoustic startle. Psychopharmacology (Berl) 149: 181–188. [DOI] [PubMed] [Google Scholar]

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