Startle and Sensorimotor Gating in Rats Lacking CCK-A Receptors

Abstract

Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the dizocilpine (0.1 mg/ kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 Cholecystokinin (CCK), a gut-brain peptide, has been implicated in the modulation of mesolimbic dopamine transmission. CCK coexists with dopamine in a large proportion of mesolimbic neurons that terminate in the medial-posterior nucleus accumbens (mpNAC) (Hokfelt et al. 1980). CCK co-localized in mesolimbic dopamine cells appears to potentiate dopamine transmission via CCK-A receptors in the mpNAC (Crawley 1991). CCK in the periphery has also been shown to regulate mesolimbic function by what appears to be a presynaptic mechanism of action mediated by peripheral CCK-A receptors (Kariya et al. 1994;Kihara et al. 1993). Because of its ability to regulate mesolimbic function, the CCK-A system could contribute to mechanism underlying psychiatric disorders such as schizophrenia.Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a spontaneous mutation (Funakoshi et al. 1995). These rats have been studied extensively as a model to understand the metabolic role of peripheral CCK as they have a tendency to demonstrate diabetes-like changes after 18 weeks of age (Otsuki et al. 1995). OLETF rats represent a potentially useful model to investigate the role of the endogenous CCK-A system in the regulation of mesolimbic dopamine function. A previous study found that OLETF rats exhibited decreased spontaneous locomotor activity relative to Long Evans Tokushimo Otsuka (LETO) rats, 24 , NO . 6 their control counterparts, and the authors suggested that this difference may be the result of perturbations in basal dopamine regulation in OLETF rats (Kobayashi et al. 1996). We previously reported that amphetamineinduced early gene expression, as measured by zif 268 mRNA expression in the NAC, did not differ between LETO and OLETF rats (Shilling et al. 2000).To further examine the role of the CCK-A receptor in the regulation of mesolimbic dopamine function, this study investigated prepulse inhibition (PPI) in OLETF and LETO rats. PPI is the normal suppression of the startle response when the intense startling stimulus (pulse) is preceded immediately (50-200 msecs) by a much weaker, non-startling stimulus (prepulse) such as an auditory "click". PPI was studied because it is an operational measure of sensorimotor gating and the ba...

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

“…The authors attributed the lack of effects of clozapine to its (baseline) startle-inhibiting effects, although they also noted that when this drug has an effect, it is often in a narrow dose range (i.e., it is likely to miss an effective dose in a particular study) and that its effects (both on startle and on PPI) vary between different rat strains, with Wistar rats (which are the original strain from which the RHA/RLA lines were derived) being a particularly resistant strain (Hadamitzky et al 2007). These results are in contrast with previous studies usually showing that typical antipsychotics do not ameliorate PPI deficits while atypical antipsychotics revert PPI deficits (among other negative and cognitive symptoms) in naive rats (see Geyer et al 2001; but also see Cilia et al 2010; Feifel et al 2001; Hadamitzky et al 2007). …”

Altered dopamine D2 receptor function and binding in obese OLETF rat

“…The present findings together with further DA-related deficits described earlier in the OLETF rats (e.g., learning, memory, motor, and sensory-motor gating deficits [9,17,21,35]) and with the suggested role of CCK in behavioral sensitization to psychostimulants [8] supports the notion that altered sweet preference and overall augmented ingestive responses may represent a component of a more generalized increase in sensitivity of the reward system in this obese rat model.…”

Neuropeptidergic Mediators of Spontaneous Physical Activity and Non-Exercise Activity Thermogenesis

“…Finally, studies in transgenic mice further support the idea that CCK modulates psychostimulant-induced, dopaminergic dependant SPA. In contrast to Otsuka-Long-Evans rats, which naturally lack CCK-A receptors and display reduced AMPH-induced hyperactivity compared to the lean rats [229], mice lacking CCK-B receptors exhibit a greater increase in AMPH-induced SPA, a suppression of apomorphine-induced SPA [230, 231] and increased density of dopamine-2 receptors as compared to wild types [231]. Taken together, these data demonstrate that the CCK-dopamine interactions within VTA-NAcc circuits are important to the control of SPA, and in particular psychostimulant-induced SPA.…”