Skip to main content
Log in

Behavioral and brain temperature responses to salient environmental stimuli and intravenous cocaine in rats: effects of diazepam

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

Abstract

Rationale

While diazepam is an effective anxiolytic and somnolent drug in humans, its physiological and behavioral effects in animals are often variable. Differences in basal activity state (basal arousal) may be important in determining both this response variability and the pattern of drug influence on behavioral and physiological responses to natural arousing stimuli and other drugs.

Objectives

To evaluate the changes in brain, muscle, and skin temperatures, and in locomotion induced in rats by several arousing stimuli and intravenous (i.v.) cocaine; and to assess how these responses are modulated by diazepam at a relatively low dose (1 mg/kg, i.p.).

Materials and methods

Male rats were implanted with thermal probes in the nucleus accumbens (NAcc), temporal muscle, and subcutaneously, and equipped with a chronic i.v. catheter. They were exposed to 1-min tail-pinch, 1-min social interaction with another male and cocaine (1 mg/kg, i.v.) after administration of diazepam or saline.

Results

While the injection of either diazepam or saline resulted in similar locomotor activation and temperature responses, diazepam decreased basal brain and muscle temperatures for about 3 h; the temperature-decreasing effect of diazepam was oppositely related to basal brain temperature (r = −0.51). After diazepam, rats also showed weaker temperature and locomotor responses to both arousing stimuli; the effect was stronger for tail-pinch and for absolute temperature increases than relative changes. Although diazepam significantly decreased cocaine-induced locomotor activation, it had virtually no effects on cocaine-induced temperature responses in all locations.

Conclusions

In accordance with the “law of initial values”, the temperature-increasing effects of all tested arousing stimuli and temperature-decreasing effect of diazepam depend upon basal brain temperature. The greatest temperature effects are seen with arousing stimuli at low basal arousal (increases) and with diazepam at high basal arousal (decreases). This is a likely explanation for the variability seen with the physiological and behavioral effects of diazepam in animals.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Altschule MD (1951) Emotion and circulation. Circulation 3:444–454

    PubMed  CAS  Google Scholar 

  • Bae DD, Brown PL, Kiyatkin EA (2007) Procedure of rectal temperature measurement affects brain, muscle, skin, and body temperature and modulates the effects of intravenous cocaine. Brain Res 1154:61–70

    Article  PubMed  CAS  Google Scholar 

  • Baker M, Cronin M, Mountjoy D (1976) Variability of skin temperature in the waking monkey. Am J Physiol 230:449–455

    PubMed  CAS  Google Scholar 

  • Beck CHM, Fibiger HC (1995) Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J Neurosci 15:709–720

    PubMed  CAS  Google Scholar 

  • Blech-Hermoni Y, Kiyatkin EA (2004) State-dependent action of cocaine on brain temperature and movement activity: implications for movement sensitization. Pharmacol Biochem Behav 77:823–837

    Article  PubMed  CAS  Google Scholar 

  • Braestrup C, Squires R (1978) Brain specific benzodiazepine receptors. Br J Psychiatry 133:249–260

    PubMed  CAS  Google Scholar 

  • Clark SM, Lipton JM (1981) Effects of diazepam on body temperature of the aged squirrel monkey. Brain Res Bull 7:5–9

    Article  PubMed  CAS  Google Scholar 

  • Conahan ST, Vogel WH (1986) The effect of diazepam administration on heart rate and mean arterial blood pressure in resting and stressful conscious rats. Res Commun Chem Pathol Pharmacol 53:301–317

    PubMed  CAS  Google Scholar 

  • Djeridane Y, Lemmer B, Touitou Y (2005) Diazepam affects both level and amplitude of rat locomotor activity rhythm but has no effect on core body temperature. Chronobiol Int 22:975–985

    Article  PubMed  CAS  Google Scholar 

  • Echizenva M, Mishima K, Satoh K, Kusanagi H, Sekine A, Ohkubo T, Shimizu T, Hishikawa Y (2004) Enhanced heat loss and age-related hypersensitivity to diazepam. J Clin Psychopharmacol 24:639–646

    Article  Google Scholar 

  • Elliot EE, White JM (2001) The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry. Neuropharmacology 40:717–721

    Article  PubMed  CAS  Google Scholar 

  • Finlay JM, Zigmond MJ, Abercrombie ED (1995) Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effect of diazepam. Neuroscience 64:619–628

    Article  PubMed  CAS  Google Scholar 

  • Friedman H, Abernethy DR, Greenblatt DJ, Shader RI (1986) The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma. Psychopharmacology (Berl) 88:267–270

    Article  CAS  Google Scholar 

  • Gillis RA, Hernandez YM, Erzouki HK, Raczkowski VF, Mandal AK, Kuhn FE, Dretchen KL (1995) Sympathetic nervous system mediated cardiovascular effects of cocaine are primarily due to a peripheral site of action of the drug. Drug Alcohol Depend 37:217–230

    Article  PubMed  CAS  Google Scholar 

  • Griauzde ML, Chen EH, Radulovacki M (1979) Effects of diazepam on sleep, temperature, 5-hydroxyindoleacetic and homovanillic acids in cisternal cerebrospinal fluid of cats. Pharmacology 19:149–155

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez LP (1993) Cocaine alters body temperature and behavioral thermoregulatory responses. Neuroreport 4:106–108

    Article  PubMed  CAS  Google Scholar 

  • Hollister LE, Muller-Oerlinghausen B, Rickels K, Shader RI (1993) Clinical use of benzodiazepines. J Clin Psychopharmacol 13(Suppl 1):1–169

    Google Scholar 

  • Igari Y, Sugiyama Y, Sawada Y, Iga T, Hanano M (1985) Kinetics of receptor occupation and anticonvulsive effects of diazepam in rats. Drug Metab Dispos 13:102–106

    PubMed  CAS  Google Scholar 

  • Irvine RE (1966) Hypothermia due to diazepam. Br Med J 22:1007

    Article  Google Scholar 

  • Kirvela O, Katila A, Aantaa B, Kanto J, Himberg JJ (1994) Metabolic and subjective responses to oral diazepam and midazolam. Eur J Anaesthesiol 11:365–369

    PubMed  CAS  Google Scholar 

  • Kiyatkin E (2005) Brain hyperthermia as physiological and pathological phenomena. Brain Res Brain Res Rev 50:27–56

    Article  PubMed  Google Scholar 

  • Kiyatkin EA, Brown PL (2005) Dopamine-dependent and dopamine-independent actions of cocaine as revealed by brain thermorecording in freely moving rats. Eur J Neurosci 22:930–938

    Article  PubMed  Google Scholar 

  • Kiyatkin EA, Mitchum R (2003) Fluctuations in brain temperatures during sexual behavior in male rats: an approach for evaluating neural activity underlying motivated behavior. Neuroscience 119:1169–1183

    Article  PubMed  CAS  Google Scholar 

  • Klotz U, Antonin KH, Bieck PR (1976) Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. J Pharmacol Exp Ther 199:67–73

    PubMed  CAS  Google Scholar 

  • Lippa AS, Klepper CA, Younger L, Sano M, Smith WV, Beer B (1978) Relationships between benzodiazepine receptors and experimental anxiety in rats. Pharmacol Biochem Behav 9:853–856

    Article  PubMed  CAS  Google Scholar 

  • Mailliet F, Galloux P, Poisson D (2001) Comparative effects of melatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats. Psychopharmacology 156:417–426

    Article  PubMed  CAS  Google Scholar 

  • Mitchum R, Kiyatkin EA (2004) Brain hyperthermia and temperature fluctuations during sexual interaction in female rats. Brain Res 1000:110–122

    Article  PubMed  CAS  Google Scholar 

  • Paxinos J, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Pettit HO, Justice JB (1991) Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens. Brain Res 539:94–102

    Article  PubMed  CAS  Google Scholar 

  • Schwartz MA, Koechlin BA, Postma E, Palmer S, Krol G (1965) Metabolism of diazepam in rat, dog, and man. J Pharmacol Exp Ther 149:423–435

    PubMed  CAS  Google Scholar 

  • Solomon GF, Moos RH, Stone GC, Fessel WJ (1964) Peripheral vasoconstriction induced by emotional stress in rats. Angiology 15:362–365

    Article  PubMed  CAS  Google Scholar 

  • Treit D (1985) The inhibitory effect of diazepam on defensive burying: anxiolytic vs. analgesic effects. Pharmacol Biochem Behav 22:47–52

    Article  PubMed  CAS  Google Scholar 

  • Valdman AV, Medvedev OS (1978) Modulation of autonomic correlates of emotional stress and adaptive responses. Fiziol Z SSSR im I.M. Secenova 64:618–625 (in Russian)

    CAS  Google Scholar 

  • van den Buuse M, Van Acker SA, Fluttert M, De Kloet ER (2001) Blood pressure, heart rate, and behavioral responses to psychological “novelty” stress in freely moving rats. Psychophysiology 38:490–499

    Article  PubMed  Google Scholar 

  • Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacology 21:1–7

    Article  CAS  Google Scholar 

  • Wilder J (1957) The law of initial value in neurology and psychiatry; facts and problems. J Nerv Ment Dis 125:73–86

    Article  PubMed  CAS  Google Scholar 

  • Wilder J (1958) Modern psychophysiology and the law of initial value. Am J Psychother 12:199–221

    PubMed  CAS  Google Scholar 

  • Williams J, Wasserberger J (2006) Crack cocaine causing fatal vasoconstriction of the aorta. J Emerg Med 31:181–184

    Article  PubMed  Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492

    Article  PubMed  CAS  Google Scholar 

  • Zarrindast MR, Dibayan M (1989) Involvement of GABA-A receptor sites in diazepam hypothermia. Gen Pharmacol 20:855–859

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, NIDA. We wish to thank Paul Leon Brown for his valuable comments on the matter of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eugene A. Kiyatkin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiyatkin, E.A., Bae, D. Behavioral and brain temperature responses to salient environmental stimuli and intravenous cocaine in rats: effects of diazepam. Psychopharmacology 196, 343–356 (2008). https://doi.org/10.1007/s00213-007-0965-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0965-y

Keywords

Navigation