ORIGINAL INVESTIGATION Corticosteroid dependent and independent effects of a cannabinoid agonist on core temperature, motor activity, and prepulse inhibition of the acoustic startle reflex in Wistar rats Avdesh Avdesh & Vincent Cornelisse & Mathew Thomas Martin-Iverson Received: 29 May 2011 /Accepted: 3 September 2011 /Published online: 27 September 2011 # Springer-Verlag 2011 Abstract Rationale There are inconsistent reports on the effects of cannabinoid agonists on prepulse inhibition of the startle reflex (PPI) with increases, decreases, and no effects. It has been hypothesized that the conflicting observations may be as a result of modulation of the effects of cannabinoid agonists by the regulation of corticosteroid release. Objective The purpose of the present study was to determine the effects of CP55940, a cannabinoid agonist, and metyrapone, a corticosteroid synthesis inhibitor on core temperature, motor activity, the startle reflex, and PPI. Methods Startle responses were measured in 64 male Wistar rats while varying startling stimulus intensities, analogous to dose–response curves. A stimulus potency measure (ES 50 ) and a response measure, the maximal achievable response (R MAX ) were derived from the stimu- lus–response curves. Results CP55940 reduced core temperature and motor activity; these effects were potentiated by metyrapone. CP55940 increased R MAX of startle in the absence of a prepulse by a corticosteroid-dependent mechanism but decreased it when metyrapone was administered before CP55940, a corticosteroid-independent mechanism. The inverse of stimulus potency (ES 50 ) was not affected by either drug alone but was increased by the combined drugs. CP55940 increased the prepulse motor gating effects and decreased the prepulse sensory gating effects of the same prepulses but only when given after metyrapone. Conclusions The most parsimonious interpretation of these effects is that CP55940 has some effects through corticosteroid-dependent actions and opposite effects by corticosteroid-independent actions. These two putative sites of actions affect stimulus gating opposite to their effects on response gating. Keywords Prepulse inhibition . Startle reflex . Cannabinoid agonist . CB1 receptor . Corticosteroid . Metyrapone . CP55940 Introduction There is evidence for a possible relationship between cannabis use and schizophrenia (Andreasson et al. 1987; Hall and Solowij 1997; Jablensky et al. 1999; van Os et al. 2002; Verdoux et al. 2003; Zammit et al. 2002). The nature of such a relationship is unclear with every possible type of relationship being posited (Allebeck et al. 1993; Barnes et al. 2006; Dean et al. 2003; Frisher et al. 2005; Fritzsche 2001; Gupta et al. 1996; Weiser and Noy 2005). Some experiments have assessed the effects of cannabinoid agonists in rodents on a measure of the schizophrenic “endophenotype”, prepulse inhibition of the startle reflex (PPI), which is decreased in schizophrenia (Braff et al. 1978). PPI is decreased in rats by drugs that induce psychosis in people, such as amphetamine (Curzon and V. Cornelisse : M. T. Martin-Iverson School of Pharmacology and Medicine, The University of Western Australia, Perth, Western Australia, Australia A. Avdesh : M. T. Martin-Iverson (*) Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, The University of Western Australia, Perth, Western Australia, Australia e-mail: mathew@cyllene.uwa.edu.au Psychopharmacology (2012) 220:405–415 DOI 10.1007/s00213-011-2493-z