Rat strain differences in startle gating-disruptive effects of apomorphine occur with both acoustic and visual prepulses

Abstract

Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia and is disrupted in rats by dopamine (DA) agonists like apomorphine (APO). Using acoustic prepulses and acoustic startle pulses, previous studies have demonstrated heritable strain differences between Sprague Dawley (SD) and Long Evans (LE) rats in the sensitivity to the PPIdisruptive effects of APO. As PPI deficits in schizophrenia are evident with both uni-and crossmodal stimuli, we tested whether strain differences in the gating-disruptive effects of APO occur with a cross-modal visual and acoustic stimulus combination. APO caused a dose-dependent disruption of both acoustic and visual PPI in SD rats. Compared to LE rats, SD rats were more sensitive to the PPI-disruptive effects of APO with both acoustic and visual PPI. These findings suggest that SD vs. LE strain differences in PPI APO sensitivity are mediated outside of the auditory system, within higher circuitry that regulates or processes multi-modal information. The present findings provide further validation for this heritable model of impaired sensorimotor gating in schizophrenia, which can be detected across multiple sensory modalities.

Activation of Nociceptin/Orphanin FQ Peptide Receptors Disrupts Visual but Not Auditory Sensorimotor Gating in BALB/cByJ Mice: Comparison to Dopamine Receptor Agonists

“…Like SKF-81297, apomorphine reduced visual PPI at prepulse intervals above 100 ms. On the other hand, it caused a slight delay in the onset of visual PPI, thus mimicking the effect of D2-like agonists. These findings extend previous studies showing that apomorphine disrupts visual PPI in rats (Campeau and Davis, 1995;Taylor et al, 1995;Weber and Swerdlow, 2008). However, they contrast with those reported by Taylor et al (1995) suggesting a lack of effect of apomorphine on visual sensitivity.…”

Realistic expectations of prepulse inhibition in translational models for schizophrenia research

“…In fact, this signal is comparable to that detected on "NOSTIM" trials, i.e., when no motor activity is recorded in the absence of stimulus delivery, suggesting that this small signal reflects ongoing motor activity rather than a prepulse-elicited motor response (e.g. Swerdlow et al 2004c;Weber and Swerdlow 2008). Importantly, only a small fraction of studies utilize prepulses with suprathreshold intensities, and among these, most also utilize much weaker prepulses as internal comparisons.…”

“…An instructive example from preclinical studies of PPI is found in the report that inbred Brown Norway (BN) rats exhibit "deficient" PPI compared to outbred Sprague Dawley (SD) rats, based on measurements with 100 ms prepulse intervals (Palmer et al 2000). Subsequent studies reproduced this finding, but also demonstrated that at shorter prepulse intervals, the opposite relationship existed: BN rats exhibited significantly more PPI compared to SD rats (Swerdlow et al 2006a(Swerdlow et al , 2008. Thus, depending on the stimulus parameters, populations can exhibit either relatively reduced or excessive PPI.…”

“…Inbred Brown Norway rats exhibit significantly more PPI at short prepulse intervals and significantly less PPI at long prepulse intervals, compared to outbred Sprague Dawley (SD) rats (Swerdlow et al 2006a). These differences are heritable (Swerdlow et al 2008), and must reflect genetically mediated differences in brain organization. Albino SD and hooded Long Evans (LE) rats differ significantly in their sensitivity to the PPI-disruptive effects of dopamine (DA) agonists (e.g., Swerdlow et al 2004aSwerdlow et al , 2006d and in the expression of DA-regulatory enzymes [e.g., catechol-o-methyl transferase (COMT)] and signal transduction enzymes (e.g., protein kinase) within the nucleus accumbens (Shilling et al 2008).…”

“…We might predict that a common drug receptor (e.g., D1 or D2) might mediate two processes (reduced PPI and increased prepulse-induced motor activity), via effects within different brain substrates. Similar to changes in startle magnitude, a given drug might elicit either increases, decreases, or no change in prepulseinduced motor responses, yet have a consistent effect on PPI (e.g., Weber and Swerdlow 2008); even in cases where drug-induced changes in prepulse-induced activity are detected, they amount to shifts of less than 1% of the total "signal" of the startle response and, as noted above, are comparable to changes observed in "NOSTIM" activity. Thus, while it is a reasonable precaution to consider measuring prepulse-elicited motor activity to ascertain whether it is significantly greater than ongoing background motor activity, and whether it might potentially interact with the startling effects of the startle pulse, in our experience, such an exercise amounts to "much ado about [almost] nothing" (Swerdlow 2005).…”