Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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 (ES50) and a response measure, the maximal achievable response (R MAX) were derived from the stimulus–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 (ES50) 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Allebeck P, Adamsson C, Engstrom A, Rydberg U (1993) Cannabis and schizophrenia: a longitudinal study of cases treated in Stockholm County. Acta Psychiatr Scand 88:21–24

    Article  PubMed  CAS  Google Scholar 

  • Andreasson S, Allebeck P, Engstrom A, Rydberg U (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 2:1483–1486

    Article  PubMed  CAS  Google Scholar 

  • Anguiano B, Valverde C (2001) Cold-induced increment in rat adrenal gland type II deiodinase is corticosterone dependent. Endocrine 15:87–91

    Article  PubMed  CAS  Google Scholar 

  • Barnes TR, Mutsatsa SH, Hutton SB, Watt HC, Joyce EM (2006) Comorbid substance use and age at onset of schizophrenia. Br J Psychiatry 188:237–242

    Article  PubMed  Google Scholar 

  • Black MD, Stevens RJ, Rogacki N, Featherstone RE, Senyah Y, Giardino O, Borowsky B, Stemmelin J, Cohen C, Pichat P, Arad M, Barak S, De Levie A, Weiner I, Griebel G, Varty GB (2011) AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents. Psychopharmacology (Berl) 215:149–163

    Article  CAS  Google Scholar 

  • Bortolato M, Aru GN, Frau R, Orru M, Luckey GC, Boi G, Gessa GL (2005) The CB receptor agonist WIN 55,212-2 fails to elicit disruption of prepulse inhibition of the startle in Sprague-Dawley rats. Psychopharmacology (Berl) 177:264–271

    Article  CAS  Google Scholar 

  • Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V, La Rana G, Russo R, Calignano A, Gessa GL, Cuomo V, Piomelli D (2006a) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659

    Article  PubMed  CAS  Google Scholar 

  • Bortolato M, Frau R, Orru M, Casti A, Aru GN, Fa M, Manunta M, Usai A, Mereu G, Gessa GL (2006b) Prenatal exposure to a cannabinoid receptor agonist does not affect sensorimotor gating in rats. Eur J Pharmacol 531:166–170

    Article  PubMed  CAS  Google Scholar 

  • Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343

    Article  PubMed  CAS  Google Scholar 

  • Brown TT, Dobs AS (2002) Endocrine effects of marijuana. J Clin Pharmacol 42:90S–96S

    PubMed  CAS  Google Scholar 

  • Buwalda B, de Boer SF, Van Kalkeren AA, Koolhaas JM (1997) Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat. Psychoneuroendocrinology 22:297–309

    Article  PubMed  CAS  Google Scholar 

  • Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24:4393–4400

    Article  PubMed  CAS  Google Scholar 

  • Compton DR, Aceto MD, Lowe J, Martin BR (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Ther 277:586–594

    PubMed  CAS  Google Scholar 

  • Corchero J, Fuentes JA, Manzanares J (1999) Chronic treatment with CP-55,940 regulates corticotropin releasing factor and proopiomelanocortin gene expression in the hypothalamus and pituitary gland of the rat. Life Sci 64:905–911

    Article  PubMed  CAS  Google Scholar 

  • Curzon P, Decker MW (1998) Effects of phencyclidine (PCP) and (+)MK-801 on sensorimotor gating in CD-1 mice. Prog Neuropsychopharmacol Biol Psychiatry 22:129–146

    Article  PubMed  CAS  Google Scholar 

  • Czyrak A, Mackowiak M, Chocyk A, Fijal K, Gadek-Michalska A, Wedzony K (2003) 8-OHDPAT-induced disruption of prepulse inhibition in rats is attenuated by prolonged corticosterone treatment. Neuropsychopharmacology 28:1300–1310

    Article  PubMed  CAS  Google Scholar 

  • Dean B, Bradbury R, Copolov DL (2003) Cannabis-sensitive dopaminergic markers in postmortem central nervous system: changes in schizophrenia. Biol Psychiatry 53:585–592

    Article  PubMed  CAS  Google Scholar 

  • Fregly MJ (1960) Interaction of adrenals and thyroid in maintenance of body temperature of rats exposed to cold. Am J Physiol 199:437–444

    PubMed  CAS  Google Scholar 

  • Frisher M, Crome I, Macleod J, Millson D, Croft P (2005) Substance misuse and psychiatric illness: prospective observational study using the general practice research database. J Epidemiol Community Health 59:847–850

    Article  PubMed  Google Scholar 

  • Fritzsche M (2001) Are cannabinoid receptor knockout mice animal models for schizophrenia? Med Hypotheses 56:638–643

    Article  PubMed  CAS  Google Scholar 

  • Gallistel CR, Freyd G (1987) Quantitative determination of the effects of catecholaminergic agonists and antagonists on the rewarding efficacy of brain stimulation. Pharmacol Biochem Behav 26:731–741

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez S, Bisogno T, Wenger T, Manzanares J, Milone A, Berrendero F, Di Marzo V, Ramos JA, Fernandez-Ruiz JJ (2000) Sex steroid influence on cannabinoid CB(1) receptor mRNA and endocannabinoid levels in the anterior pituitary gland. Biochem Biophys Res Commun 270:260–266

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez S, Manzanares J, Berrendero F, Wenger T, Corchero J, Bisogno T, Romero J, Fuentes JA, Di Marzo V, Ramos JA, Fernandez-Ruiz J (1999) Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology 70:137–145

    Article  PubMed  CAS  Google Scholar 

  • Green MF, Satz P, Smith C, Nelson L (1989) Is there atypical handedness in schizophrenia? J Abnorm Psychol 98:57–61

    Article  PubMed  CAS  Google Scholar 

  • Grillon C (2002) Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 52:958–975

    Article  PubMed  Google Scholar 

  • Gupta S, Hendricks S, Kenkel AM, Bhatia SC, Haffke EA (1996) Relapse in schizophrenia: is there a relationship to substance abuse? Schizophr Res 20:153–156

    Article  PubMed  CAS  Google Scholar 

  • Hall W, Solowij N (1997) Long-term cannabis use and mental health. Br J Psychiatry 171:107–108

    Article  PubMed  CAS  Google Scholar 

  • Healy DG, Harkin A, Cryan JF, Kelly JP, Leonard BE (1999) Metyrapone displays antidepressant-like properties in preclinical paradigms. Psychopharmacology (Berl) 145:303–308

    Article  CAS  Google Scholar 

  • Hince DA, Martin-Iverson MT (2005) Differences in prepulse inhibition (PPI) between Wistar and Sprague-Dawley rats clarified by a new method of PPI standardization. Behav Neurosci 119:66–77

    Article  PubMed  Google Scholar 

  • Ingram N, Martin S, Wang JH, van der Laan S, Loiacono R, van den Buuse M (2005) Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice. Neuropharmacology 48:80–92

    Article  PubMed  CAS  Google Scholar 

  • Jablensky A, McGrath J, Herrman H, Castle C, Gureje O, Morgan V (1999) National Survey of Mental Health and Wellbeing Report 4. People living with psychotic illness: an Australian study 1997–98. IN. National Mental Health Strategy, Australia: 103

  • Johnson KM, Dewey WL, Ritter KS, Beckner JS (1978) Cannabinoid effects on plasma corticosterone and uptake of 3H-corticosterone by mouse brain. Eur J Pharmacol 47:303–310

    Article  PubMed  CAS  Google Scholar 

  • Jones P, Murray RM (1991) The genetics of schizophrenia is the genetics of neurodevelopment. Br J Psychiatry 158:615–623

    Article  PubMed  CAS  Google Scholar 

  • Kedzior KK, Martin-Iverson MT (2006) Chronic cannabis use is associated with attention-modulated reduction in prepulse inhibition of the startle reflex in healthy humans. J Psychopharmacol 20:471–484

    Article  PubMed  CAS  Google Scholar 

  • Kedzior KK, Martin-Iverson MT (2007) Attention-dependent reduction in prepulse inhibition of the startle reflex in cannabis users and schizophrenia patients—a pilot study. Eur J Pharmacol 560:176–182

    Article  PubMed  CAS  Google Scholar 

  • Long LE, Malone DT, Taylor DA (2006) Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology 31:795–803

    Article  PubMed  CAS  Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94:507–514

    Article  CAS  Google Scholar 

  • Mansbach RS, Rovetti CC, Winston EN, Lowe JA 3rd (1996) Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats. Psychopharmacology (Berl) 124:315–322

    Article  CAS  Google Scholar 

  • Manzanares J, Corchero J, Fuentes JA (1999) Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of delta(9)-tetrahydrocannabinol in rats. Brain Res 839:173–179

    Article  PubMed  CAS  Google Scholar 

  • Martin-Calderon JL, Munoz RM, Villanua MA, del Arco I, Moreno JL, de Fonseca FR, Navarro M (1998) Characterization of the acute endocrine actions of (−)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats. Eur J Pharmacol 344:77–86

    Article  PubMed  CAS  Google Scholar 

  • Martin-Iverson MT, Stevenson KN (2005) Apomorphine effects on emotional modulation of the startle reflex in rats. Psychopharmacology (Berl) 181:60–70

    Article  CAS  Google Scholar 

  • Martin RS, Secchi RL, Sung E, Lemaire M, Bonhaus DW, Hedley LR, Lowe DA (2003) Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat. Psychopharmacology (Berl) 165:128–135

    CAS  Google Scholar 

  • Meloni EG, Gerety LP, Knoll AT, Cohen BM, Carlezon WA Jr (2006) Behavioral and anatomical interactions between dopamine and corticotropin-releasing factor in the rat. J Neurosci 26:3855–3863

    Article  PubMed  CAS  Google Scholar 

  • Miller AS, Sanudo-Pena MC, Walker JM (1998) Ipsilateral turning behavior induced by unilateral microinjections of a cannabinoid into the rat subthalamic nucleus. Brain Res 793:7–11

    Article  PubMed  CAS  Google Scholar 

  • Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328

    Article  PubMed  Google Scholar 

  • Murphy LL, Munoz RM, Adrian BA, Villanua MA (1998) Function of cannabinoid receptors in the neuroendocrine regulation of hormone secretion. Neurobiol Dis 5:432–446

    Article  PubMed  CAS  Google Scholar 

  • Murray RM, Jones P, O'Callaghan E (1991) Fetal brain development and later schizophrenia. CIBA Found Symp 156:155–163, discussion 163–70

    PubMed  CAS  Google Scholar 

  • Nagai H, Egashira N, Sano K, Ogata A, Mizuki A, Mishima K, Iwasaki K, Shoyama Y, Nishimura R, Fujiwara M (2006) Antipsychotics improve Delta9-tetrahydrocannabinol-induced impairment of the prepulse inhibition of the startle reflex in mice. Pharmacol Biochem Behav 84:330–336

    Article  PubMed  CAS  Google Scholar 

  • Piazza PV, Rouge-Pont F, Deroche V, Maccari S, Simon H, Le Moal M (1996) Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission. Proc Natl Acad Sci U S A 93:8716–8720

    Article  PubMed  CAS  Google Scholar 

  • Pryce CR, Bettschen D, Bahr NI, Feldon J (2001) Comparison of the effects of infant handling, isolation, and nonhandling on acoustic startle, prepulse inhibition, locomotion, and HPA activity in the adult rat. Behav Neurosci 115:71–83

    Article  PubMed  CAS  Google Scholar 

  • Quednow BB, Kuhn KU, Hoenig K, Maier W, Wagner M (2004) Prepulse inhibition and habituation of acoustic startle response in male MDMA ('ecstasy') users, cannabis users, and healthy controls. Neuropsychopharmacology 29:982–990

    Article  PubMed  CAS  Google Scholar 

  • Rawls SM, Cabassa J, Geller EB, Adler MW (2002) CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212–2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)- 6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia. J Pharmacol Exp Ther 301:963–968

    Article  PubMed  CAS  Google Scholar 

  • Rawls SM, Tallarida RJ, Kon DA, Geller EB, Adler MW (2004) GABAA receptors modulate cannabinoid-evoked hypothermia. Pharmacol Biochem Behav 78:83–91

    Article  PubMed  CAS  Google Scholar 

  • Risbrough VB, Hauger RL, Roberts AL, Vale WW, Geyer MA (2004) Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. J Neurosci 24:6545–6552

    Article  PubMed  CAS  Google Scholar 

  • Schneider M, Koch M (2002) The cannabinoid agonist WIN 55,212-2 reducessensorimotor gating and recognition memory in rats. Behav Pharmacol 13:29–37

    Article  PubMed  CAS  Google Scholar 

  • Schneider M, Koch M (2003) Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology 28:1760–1769

    Article  PubMed  CAS  Google Scholar 

  • Scholes KE, Martin-Iverson MT (2009) Alterations to pre-pulse inhibition (PPI) in chronic cannabis users are secondary to sustained attention deficits. Psychopharmacology (Berl) 207:469–484

    Article  CAS  Google Scholar 

  • Scholes KE, Martin-Iverson MT (2010) Disturbed prepulse inhibition in patients with schizophrenia is consequential to dysfunction of selective attention. Psychophysiology 47:223–235

    Article  PubMed  Google Scholar 

  • Solowij N, Michie PT (2007) Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci 32:30–52

    PubMed  Google Scholar 

  • Stanley-Cary CC, Harris C, Martin-Iverson MT (2002) Differing effects of the cannabinoid agonist, CP 55,940, in an alcohol or Tween 80 solvent, on prepulse inhibition of the acoustic startle reflex in the rat. Behav Pharmacol 13:15–28

    Article  PubMed  CAS  Google Scholar 

  • Stevens KE, Bullock AE, Collins AC (2001) Chronic corticosterone treatment alters sensory gating in C3H mice. Pharmacol Biochem Behav 69:359–366

    Article  PubMed  CAS  Google Scholar 

  • Stoddart CW, Noonan J, Martin-Iverson MT (2008) Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice. Behav Neurosci 122:516–526

    Article  PubMed  CAS  Google Scholar 

  • Strube MJ, Bobko P (1989) Testing hypotheses about ordinal interactions: simulations and further comments. J Appl Psychol 74:247–252

    Article  Google Scholar 

  • Swerdlow NR, Eastvold A, Karban B, Ploum Y, Stephany N, Geyer MA, Cadenhead K, Auerbach PP (2002) Dopamine agonist effects on startle and sensorimotor gating in normal male subjects: time course studies. Psychopharmacology (Berl) 161:189–201

    Article  CAS  Google Scholar 

  • Swerdlow NR, Stephany N, Wasserman LC, Talledo J, Shoemaker J, Auerbach PP (2003) Amphetamine effects on prepulse inhibition across-species: replication and parametric extension. Neuropsychopharmacology 28:640–650

    Article  PubMed  CAS  Google Scholar 

  • van den Buuse M, Morris M, Chavez C, Martin S, Wang J (2004) Effect of adrenalectomy and corticosterone replacement on prepulse inhibition and locomotor activity in mice. Br J Pharmacol 142:543–550

    Article  PubMed  Google Scholar 

  • van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H (2002) Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 156:319–327

    Article  PubMed  Google Scholar 

  • Verdoux H, Sorbara F, Gindre C, Swendsen JD, van Os J (2003) Cannabis use and dimensions of psychosis in a nonclinical population of female subjects. Schizophr Res 59:77–84

    Article  PubMed  Google Scholar 

  • Waddington JL, Torrey EF, Crow TJ, Hirsch SR (1991) Schizophrenia, neurodevelopment, and disease. The Fifth Biannual Winter Workshop on Schizophrenia, Badgastein, Austria, January 28 to February 3, 1990. Arch Gen Psychiatry 48:271–273

    Article  PubMed  CAS  Google Scholar 

  • Weidenfeld J, Feldman S, Mechoulam R (1994) Effect of the brain constituent anandamide, a cannabinoid receptor agonist, on the hypothalamo-pituitary-adrenal axis in the rat. Neuroendocrinology 59:110–112

    Article  PubMed  CAS  Google Scholar 

  • Weiser M, Noy S (2005) Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci 7:81–85

    PubMed  Google Scholar 

  • Wenger T, Jamali KA, Juaneda C, Leonardelli J, Tramu G (1997) Arachidonyl ethanolamide (anandamide) activates the parvocellular part of hypothalamic paraventricular nucleus. Biochem Biophys Res Commun 237:724–728

    Article  PubMed  CAS  Google Scholar 

  • Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G (2002) Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 325:1199

    Article  PubMed  Google Scholar 

  • Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank NHMRC and Western Australian Institute for Medical Research (WAIMR) for their generous support of this research.

Author information

Authors and Affiliations

  1. School of Pharmacology and Medicine, The University of Western Australia, Perth, Western Australia, Australia

    Vincent Cornelisse & Mathew Thomas Martin-Iverson

  2. Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, The University of Western Australia, Perth, Western Australia, Australia

    Avdesh Avdesh & Mathew Thomas Martin-Iverson

Authors
  1. Avdesh Avdesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincent Cornelisse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mathew Thomas Martin-Iverson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mathew Thomas Martin-Iverson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Avdesh, A., Cornelisse, V. & Martin-Iverson, M.T. 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. Psychopharmacology 220, 405–415 (2012). https://doi.org/10.1007/s00213-011-2493-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2493-z

Keywords

Search

Navigation