Heritable differences in the dopaminergic regulation of sensorimotor gating

Swerdlow, Neal R.; Shoemaker, Jody M.; Auerbach, Pamela P.; Pitcher, Leia; Goins, Jana; Platten, Amanda

doi:10.1007/s00213-003-1480-4

Cited by 52 publications

(9 citation statements)

References 33 publications

(45 reference statements)

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“…However, at short prepulse intervals (10-20 ms), the low dose of memantine increased PPI (Figure 1), comparable to effects reported with some DA agonists (e.g. Swerdlow et al 2001, 2002, 2004). ANOVA of %PPI revealed a significant main effect of memantine (F=4.27, df 2,10, p<0.05) and prepulse interval (F=5.08, df 4,40, p<0.03), but no significant dose × interval interaction (F=1.32, df 8,40, ns).…”

Section: Resultssupporting

confidence: 78%

“…Some findings suggest differential neurochemical substrates regulating drug effects on short- and long-interval PPI, e.g. a prominent role of D1-like systems in regulating short interval PPI, and D2-like systems in regulating long interval PPI (Swerdlow et al 2004). At a psychological level, short interval PPI is linked to substrates regulating more automatic, preconscious inhibition, while long interval PPI is linked to more volitional, consciously controlled inhibition (cf.…”

Section: Discussionmentioning

confidence: 99%

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The Effects of Memantine on Prepulse Inhibition

Swerdlow

Bergeijk

Bergsma

et al. 2009

Neuropsychopharmacol

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Background Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. Methods PPI was measured in male Sprague-Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, sc). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either: 1) placebo vs. 20 mg of the NMDA antagonist memantine (n=19), or 2) placebo vs. 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Results Memantine had dose- and interval-dependent effects on PPI in rats: compared to vehicle, 10 mg/kg increased short-interval (10-20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. Conclusion NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

The Effects of Memantine on Prepulse Inhibition

Swerdlow

Bergeijk

Bergsma

et al. 2009

Neuropsychopharmacol

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“…We previously reported greater sensitivity of SD than LE rats to the PPI-disruptive effects of systemically administered DAergic agonists such as APO, AMPH, or QUIN (Swerdlow et al, 2001b, 2003, 2004a, b, c; Weber and Swerdlow, 2008). The strain differences in PPI-APO and -QUIN sensitivity were confirmed in this study and extended by detailed analyses showing that these strain differences could not be attributed to strain differences with respect to 1) baseline (vehicle) PPI, 2) baseline (vehicle) startle magnitude; 3) drug effects on startle magnitude, or 4) drug effects on NOSTIM levels.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Sprague Dawley rats from Harlan Laboratories (SD) are significantly more sensitive to the PPI-disruptive effects of APO, QUIN, and the indirect DA agonist amphetamine (AMPH), compared to Long Evans rats from Harlan Laboratories (LE; Swerdlow et al, 2001b, 2003b, 2004a, b, c; Weber and Swerdlow, 2008). These differences are innate (Swerdlow et al, 2004a, c), neurochemically specific (Swerdlow et al, 2003, 2004b), independent of stimulus modality (Weber and Swerdlow, 2008) and cannot be explained by differences in maternal behavior (Swerdlow et al, 2004a). Finally, these strain differences appear to be linked to inherited properties of DA-linked G-protein function (Swerdlow et al, 2006), and to differential nucleus accumbens gene expression, particularly among genes associated with DA signaling pathways (Shilling et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation

Weber

Chang

Breier

et al. 2008

Behavioural Pharmacology

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Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating that is deficient in several brain disorders and is disrupted in rats by dopamine agonists. There are robust heritable strain differences between Sprague Dawley (SD) and Long Evans (LE) strains in the sensitivity to the PPI-disruptive effects of dopamine agonists associated with differential gene expression in the nucleus accumbens. Here we compared the contribution of D2 vs. D3 receptors to this heritable difference, using the D3-preferential agonist, pramipexole, the mixed D3/D2 agonist, quinpirole, the mixed D1/D2-like agonist, apomorphine, and the preferential D2 antagonist L741,626. All DA agonists disrupted PPI in SD and LE rats. Greater SD than LE sensitivity for this effect was evident with apomorphine and quinpirole, but not pramipexole. The selective D2 antagonist L741,626 preferentially reversed apomorphine-induced PPI deficits at a dose that did not alter pramipexole-induced PPI deficits. We conclude that the heritable pattern of greater PPI “disruptability” by DA agonists in SD vs. LE rats reflects differences in D2 but not D3 receptor-associated mechanisms.

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“…PPI is under strong genetic control in rodents (Francis et al 2003) and humans (Greenwood et al 2007), and the neurochemical regulation of PPI also appears to be a heritable phenotype (Swerdlow et al 2004a, b). For example, albino Sprague–Dawley (SD) rats are more sensitive to the PPI-disruptive effects of APO compared to hooded Long Evans (LE) rats (Swerdlow et al 2001b); these differences are inherited with simple generational patterns (Swerdlow et al 2004a, b), are present at the earliest measurable age (Swerdlow et al 2004b), are neurochemically specific (Swerdlow et al 2003a, 2004c), and are not due to differences in maternal behavior (Swerdlow et al 2004b). Strain differences in PPI APO sensitivity are accompanied by differences in nucleus accumbens (NAC) gene expression (Shilling et al 2008) and D2-mediated G-protein coupling (Swerdlow et al 2006), which culminates downstream with differences in sensitivity to NAC APO-suppressed c-Fos expression (Saint Marie et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats

2011

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Background Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague–Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats. Methods The effects of APO (vehicle vs. 0.5 mg/kg) on PPI were tested in SD and LE rats in a within-subject design. Seven days later, under conditions mimicking PPI testing, half of the rats from each strain received either vehicle or APO (0.5 mg/kg) 20 min before euthanasia. NAC CREB and phospho-CREB levels were quantified from tissue sections reacted immunohistochemically. Results APO reduced PPI in both strains, with a significantly greater effect in SD vs. LE rats. APO also significantly reduced NAC core phospho-CREB levels in both strains, with a significantly greater effect in SD vs. LE rats. Among SD rats receiving APO, the reduction in NAC core CREB phosphorylation correlated significantly with the APO-induced reduction in PPI (R=0.49). Conclusions A dose of APO that disrupts PPI of acoustic startle causes a profound suppression of CREB phosphorylation in the NAC; both dopamine-sensitive behavioral and molecular phenotypes are more robust in SD vs. LE rats, and within SD rats, they are significantly correlated.

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Heritable differences in the dopaminergic regulation of sensorimotor gating

Cited by 52 publications

References 33 publications

The Effects of Memantine on Prepulse Inhibition

The Effects of Memantine on Prepulse Inhibition

Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation

Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats

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