Amanda Platten

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.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague-Dawley (SDH) versus Long Evans (LEH) rats. In the present study, we assessed the generational pattern of this phenotypic difference across parental SDH and LEH strains under in- and cross-fostering conditions, offspring (F1) of an SDH×LEH cross, and subsequent offspring (N2) of an SDH×F1 cross. Apomorphine sensitivity followed a gradient across generations that suggested relatively simple additive effects of multiple genes. Cross fostering studies confirmed that SDH>LEH apomorphine sensitivity did not reflect post-natal maternal influences. Generational patterns of PPI apomorphine sensitivity were not associated with albino versus hooded phenotypes per se, but apomorphine sensitivity in hooded N2 rats was strongly related to body surface area of fur pigmentation. The association between pigmentation and PPI apomorphine sensitivity may provide an important clue to specific biochemical and genetic substrates responsible for population differences in the regulation of sensorimotor gating.

Heritable differences in the effects of amphetamine but not DOI on startle gating in albino and hooded outbred rat strains

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We reported heritable differences in sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine (APO) in Harlan Sprague-Dawley (SDH) and Long-Evans (LEH) rats, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. In this study, we assessed the neurochemical specificity of this heritable phenotype across parental SDH and LEH strains, and their F1 and N2 offspring, based on their sensitivity to the PPI-disruptive effects of the indirect DA agonist D-amphetamine (AMPH) and the 5HT2A agonist DOI. AMPH sensitivity followed a gradient of SDH>N2>F1>LEH, consistent with past findings with APO. DOI sensitivity did not differ across strains or generations. These findings demonstrate that the heritable phenotype in this model is not specific to a particular compound (APO), and reflects physiological differences in the DAergic, but not serotonergic, regulation of PPI.

Genetic differences in startle gating-disruptive effects of apomorphine: evidence for central mediation.

Strain differences in sensitivity to dopamine agonist-induced disruption of prepulse inhibition (PPI) may be a useful model for the genetics of PPI deficits in neuropsychiatric disorders. Compared with Long-Evans (LE) rats, Sprague-Dawley (SD) rats are more sensitive to the PPI-disruptive effects of the DA agonist apomorphine. The authors tested the hypothesis that this strain difference reflects brain function rather than peripheral physiology. Significant SD > LE PPI-disruptive effects of apomorphine were observed despite equal apomorphine levels in SD and LE rats in forebrain regions that regulate PPI. SD > LE PPI-disruptive effects of apomorphine were also independent of peripheral versus central route of administration. This model for PPI genetics is sensitive to differences in central rather than peripheral substrates.

Sensitivity to sensorimotor gating-disruptive effects of apomorphine in two outbred parental rat strains and their F1 and N2 progeny.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague–Dawley (SDH) vs Wistar (WH) rats. In the present study, we assessed the inheritance pattern of this phenotypic difference. Sensitivity to the PPI-disruptive effects of apomorphine was compared across parental SDH and WH strains, offspring (F1) of an SDH×WH cross, and subsequent offspring (N2) of an SDH×F1 cross. Apomorphine sensitivity followed a gradient of SDH>N2>F1>WH. Parental SDH and WH strains exhibited comparable sensitivity to the PPI-disruptive effects of phencyclidine. The nature of this gradient of APO sensitivity suggests relatively simple additive effects of multiple genes on the phenotype of PPI sensitivity.

121. Towards the genetics of a complex phenotype: strain analyses of drug effects on startle gating

Sensorimotor gating of the startle reflex, measured by PPI, is impaired in humans with specific neuropsychiatric disorders, and is disrupted in humans and rats by dopamine (DA) agonists. Animal models are clarifying the genetics of PPI and its sensitivity to neurochemical regulation. Differences in sensitivity to the PPI-disruptive effects of APO across rat strains (eg. Sprague Dawley (SD) vs. Wistar (W)), and within strains, across suppliers (eg. Harlan [“H”] vs. Bantin-Kingman [“BK”]) must reflect relatively subtle genetic drift, which might be manipulated by pharmacogenetic strategies and serve as targets for QTL or other approaches for understanding the genetics of complex phenotypes. We assessed the scope and development of PPI APO sensitivity differences in SD vs. W rats (H and BK). Findings confirmed significant SDH . WH sensitivity to the PPI-disruptive effects of APO in adults and d18 pups; an SDH 3 WH F1 exhibited the WH parental phenotype. Both BK rat strains were less sensitive than SDH rats to the PPI-disruptive effects of APO; in SDBKs, APO effects on PPI interacted with changes in startle magnitude. SDH . SDBK sensitivity was also noted in the PPI-disruptive effects of the D1 agonist SKF82958, but not the D2 agonist quinpirole. Substrain differences in PPI drug sensitivity are DA receptor subtypespecific. SDH . WH APO sensitivity in d18 pups suggests that genetic differences in DAergic sensitivity are expressed early in development; for this substrate, efficient phenotype screening can be completed in pups.