Heritable differences in the dopaminergic regulation of behavior in rats: relationship to D2-like receptor G-protein function.
We reported heritable differences between Sprague-Dawley (SD) and Long Evans (LE) rats in their sensitivity to the disruption of prepulse inhibition of startle (PPI) by dopamine (DA) agonists, and in their basal levels and turnover of forebrain DA. In an effort to better understand these differences, we assessed strain patterns in the efficacy of D2-like receptor-G-protein coupling using [35S]GTPgammaS binding in brain regions that contribute to the dopaminergic regulation of PPI. Sensitivity to the PPI-disruptive effects of apomorphine (APO) was examined in SD, LE, and F1 (SD x LE) rats. Basal and DA-stimulated [35S]GTPgammaS binding were then assessed in these rats using conditions that preferentially exclude Gs proteins to favor visualization of D2-like receptors. To explore the behavioral specificity of these strain differences, locomotor responses to APO and amphetamine (AMPH) were also assessed in SD, LE, and F1 rats. Strain differences were evident in the PPI-disruptive effects of APO (SD>F1>LE), and in the locomotor responses to AMPH (LE>F1>SD) and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DA-stimulated [35S]GTPgammaS binding in nucleus accumbens and caudatoputamen, while F1 progeny had intermediate levels. In conclusion, SD and LE rats exhibit heritable differences in D2-mediated behavioral and biochemical measures. Conceivably, genes that regulate heritable differences in forebrain D2 function may contribute to heritable differences in PPI in patients with specific neuropsychiatric disorders, including schizophrenia and Tourette Syndrome.
Swerdlow
Neal R
NR
Department of Psychiatry, University of California School of Medicine, San Diego, La Jolla, CA 92093, USA. nswerdlow@ucsd.edu
Krupin
Alison S
AS
Bongiovanni
Michele J
MJ
Shoemaker
Jody M
JM
Goins
Jana C
JC
Hammer
Ronald P
RP
D000161:Acoustic Stimulation / Q000009:adverse effects; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D016009:Chi-Square Distribution; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007266:Inhibition, Psychological; D008055:Lipids / Q000235:genetics; D008124:Locomotion / Q000187:drug effects; D008297:Male; D010641:Phenotype; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics*; D013045:Species Specificity; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
D018491:Dopamine Agonists; D008055:Lipids; D017448:Receptors, Dopamine D2; D013460:Sulfur Isotopes; C030631:pigment 462; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000661:Amphetamine; D019204:GTP-Binding Proteins; D001058:Apomorphine; D004298:Dopamine