Skip to main content
SpringerLink
Log in

Neurochemical changes associated with the action of acute administration of diazepam in reversing the behavioral paradigm conditioned emotional response (CER)

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Neurotransmitter turnover of biogenic monoamines (dopamine, norepinephrine, and serotonin) and amino acids (glutamate, aspartate, and gamma-aminobutyric acid) was evaluated in rats exposed to the conditioned emotional response (CER) paradigm in the absence (total suppression) or presence of acute 5 mg/kg i.p. diazepam (which reversed suppression and restored normal responding). Based on previous studies of CER, with controls for shock and stimulus histories, the results with respect to the anxiolytic could be divided into several categories: changes in turnover which are associated only with the CER behavior; changes associated only with the drug, diazepam; changes which augmented the effects of the behavior; or changes which were the reverse of those associated with the behavior. Due to the multitude and complexity of the results, not all observations have clear explanations at this time. However, for the CER behavior per se, it is apparent that a combination of neurotransmitters, including some implications about acetylcholine, act in concert to bring about the behavioral suppression. The action of diazepam is more complex, involving the full spectrum of neurotransmitters to bring about its direct and indirect effects.

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

Similar content being viewed by others

References

  1. Estes, W. K., and Skinner, B. F. 1941. Some quantitative aspects of anxiety. J. Exptl. Psychol. 29:390–400.

    Google Scholar 

  2. Hunt, H., and Brady, J. 1951. Some effects of electro-convulsive shock on a conditioned emotional response (“anxiety”). J. Comp. Physiol. Psychol. 44:88–98.

    Google Scholar 

  3. Kamin, L., and Schwab, R. 1963. Effects of conditioned stimulus intensity on the conditioned response. J. Comp. Physiol. Psychol. 56:502–510.

    Google Scholar 

  4. Millenson, J. R., and Leslie, J. 1974. The conditioned emotional response (CER) as a baseline for the study of anti-anxiety drugs. Neuropharmacol. 13:1–9.

    Google Scholar 

  5. Hingten, J. W., Smith, J. E., Shea, P. A., Aprison, M. H., and Gaff, T. M. 1976. Cholinergic changes during conditioned suppression in rats. Science (Wash.) 193:332–334.

    Google Scholar 

  6. Zsilla, G., Cheney, D. L., and Costa, E. 1976. Regional changes in the rate of turnover of acetylcholine in rat brain following diazepam or muscimol. N.S. Arch. Pharmacol. 294:251–259.

    Google Scholar 

  7. Thiebot, M. H., Jobert, A., and Soubrie, P. 1980. Chlordiazepoxide and gaba injected into raphe dorsalis release the conditioned behavioral suppression induced in rats by a conflict procedure without nociceptive component. Neuropharmacol. 19:633–640.

    Google Scholar 

  8. Thiebot, M. H., Hamon, M., and Soubrie, P. 1982. Attenuation of induced anxiety in rats by chlordiazepoxide: role of raphe dorsalis benzodiazepine binding sites and serotoninergic neurons. Neuroscience, 7:2287–2294.

    Google Scholar 

  9. Lane, J. D., Sands, M. P., Freeman, M. E., Cherek, D. R., and Smith, J. E. 1982. Amino acid neurotransmitter utilization in discrete rat brain regions is correlated with conditioned emotional response. Pharmacol. Biochem. Behav. 16:329–340.

    Google Scholar 

  10. Lane, J. D., Sands, M. P., Co, C., Cherek, D. R., and Smith, J. E. 1982. Biogenic monoamine turnover in discrete rat brain regions is correlated with conditioned emotional response and its conditioning history. Brain Research 240:95–108.

    Google Scholar 

  11. Lane, J. D., Crenshaw, C. M., Guerin, G. F., Cherek, D. R., and Smith, J. E. 1982. Changes in biogenic amine and benzodiazepine receptors correlated with conditioned emotional response and its reversal by diazepam. Europ. J. Pharmacol. 83:183–189.

    Google Scholar 

  12. Lane, J. D. 1986. Muscarinic cholinergic binding sites respond to acquisition and extinction of conditioned emotional response (CER). Trends Pharmacol. Sci. Suppl.:95–96.

  13. Mao, C. C., Marco, E., Revuelta, A., Bertilsson, L., and Costa, E. 1977. The turnover rate of gamma-aminobutyric acid in the nuclei of telencephalon: Implications in the pharmacology of antipsychotics and of a minor tranquilizer. Biol. Psychiat. 12:359–371.

    Google Scholar 

  14. Costa, E., and Guidotti, A. 1979. Molecular mechanisms in the receptor action of benzodiazepines. Ann. Rev. Pharmacol. Toxicol. 19:531–545.

    Google Scholar 

  15. Haefely, W. E. 1978. Behavioral and neuropharmacological aspects of drugs used in anxiety and related states. Pages 1359–1374,in Lipton, M. A., DiMascio, A., and Killam, K. F. (eds), Psychopharmacology: A Generation of Progress, Raven Press, New York.

    Google Scholar 

  16. Tallman, J. F., Paul, S. M., Skolnick, P., and Gallager, D. W. 1980. Receptors for the age of anxiety: Pharmacology of the benzodiazepines. Science (Wash.) 207:274–281.

    Google Scholar 

  17. Klepner, C. A., Lippa, A. S., Benson, O. I., Sano, M. C., and Beer, B. 1979. Resolution of twobiochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol. Biochem. Behav. 11:457–462.

    Google Scholar 

  18. Young, W. S., Niehoff, D., Kubar, M. J., Beer, B., and Lippa, A. S. 1981. Multiple benzodiazepine receptor localization by light microscopic radiohistochemistry. J. Pharmacol. Exp. Ther. 216:425–430.

    Google Scholar 

  19. Bowling, A. C., and DeLorenzo, R. J. 1982. Micromolar affinity benzodiazepine receptors: Identification and characterization in central nervous system. Science (Wash.) 216:1247–1250.

    Google Scholar 

  20. Niehoff, D. L., Mashal, R. D., Horst, W. D., O'Brien, R. A., Palacios, J. M., and Kuhar, M. J. 1982. Binding of a radiolabelled triazolopyridazine to a subtype of benzodiazepine receptor in the rat cerebellum. J. Pharmacol. Exp. Ther. 221:670–678.

    Google Scholar 

  21. Braestrup, C., Nielsen, M., Honore, T., Jensen, L. H., and Petersen, E. N. 1983. Benzodiazepine receptor ligands with positive and negative efficacy. Neuropharmacology 22:1451–1458.

    Google Scholar 

  22. Sigel, E., Baur, R., Trube, G., Moehler, H., and Malherbe, P. 1990. The effect of subunit composition of rat brain GABAA receptors on channel function. Neuron. 5:703–711.

    Google Scholar 

  23. Olsen, R. W., and Tobin, A. J. 1990. Molecular biology of GABAA receptors. FASEB J. 4:1469–1480.

    Google Scholar 

  24. Lueddens, H., and Wisden, W. 1991. Function and pharmacology of multiple GABAA receptor subunits. Trends Pharmacol. Sci. 12:49–51.

    Google Scholar 

  25. Mochetti, I. 1990. Molecular biology of diazepam binding inhibitor peptide. Neurochem. Res. 15:125–130.

    Google Scholar 

  26. Feighner, J. P., and Boyer, W. F. 1989. Serotonin-1A anxiolytics: an overview. Psychopathology 22:21–26.

    Google Scholar 

  27. Hartig, P. R. 1989. Molecular biology of 5-HT receptors. Trends Pharmacol. Sci. 10:64–69.

    Google Scholar 

  28. Smith, J. E., Leckrone, W. R., and Co, C. 1977. Combination operant conditioning-liquid nitrogen immersion chamber for studying neurotransmitter system and behavior. Pharmacol. Biochem. Behav. 7:167–173.

    Google Scholar 

  29. Freeman, M. E., Co, C., Mote, T. R., Lane, J. D., and Smith, J. E. 1980. Determination of content and specific activity of amino acids in central nervous system tissue utilizing tritium and carbon-14 dual labelling. Analyt. Biochem. 106:191–194.

    Google Scholar 

  30. Co, C., Smith, J. E., and Lane, J. D. 1982. Use of a single compartment LCEC cell in the determinations of biogenic amine content and turnover. Pharmacol. Biochem. Behav. 16:641–646.

    Google Scholar 

  31. Kish, P. E., Fischer-Bovenkerk, C., and Uedi, T. 1989. Active transport of gamma-aminobutyric acid and glycine into synaptic vesicles. Proc. Natl. Acad. Sci. (USA) 86:3877–3881.

    Google Scholar 

  32. Zilversmit, D. B. 1960. The design and analysis of isotope experiments. Am. J. Med. 29, 832–848.

    Google Scholar 

  33. Smith, J. E., Co, C., Freeman, M. E., Sands, M. P., and Lane, J. D. 1980. Neurotransmitter turnover in rat striatum is correlated with morphine self-administration. Nature 287:152–155.

    Google Scholar 

  34. Smith, J. E., Co, C., Freeman, M. E., and Lane, J. D. 1982. Brain neurotransmitter turnover correlated with morphine-seeking behavior of rats. Pharmacol. Biochem. Behav. 16:509–519.

    Google Scholar 

  35. Lane, J. D., and Lasley, S. M. 1984. Invited review: Behavioral neurochemistry. Funct. Biol. Med. 3:152–164.

    Google Scholar 

  36. Neff, N. H., Spano, P. F., Groppetti, A., Wong, C., and Costa, E. 1971. A simple procedure for calculating the synthesis rate of norepinephrine, dopamine, and serotonin in rat brain. J Pharmacol. Exp. Ther. 176:701–710.

    Google Scholar 

  37. Umemoto, M., and Olds, M. E. 1975. Effects of chlordiazepoxide, diazepam, and chlorpromazine on conditioned emotional behavior and conditioned neuronal activity in limbic, hypothalamic and geniculate regions. Neuropharmacol 14:413–425.

    Google Scholar 

  38. Umemoto, M., Murai, Y., Kodama, M., and Kido, R. 1970. Neuronal discharge patterns in conditioned emotional response. Brain Research 24:347–351.

    Google Scholar 

  39. Applegate, C. D., Frysinger, R. C., Kapp, B. S., and Gallager, M. 1982. Multiple unit activity recorded from amygdala central nucleus during pavlovian heart rate conditioning in rabbit. Brain Research 238:457–462.

    Google Scholar 

  40. Ungerstedt, U. 1971. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol. Scand. Suppl. 367:1–48.

    Google Scholar 

  41. Storm-Mathisen, J. 1977. Localization of transmitter candidates in the brain: The hippocampal formation as a model. Frog. Neurobiol. 8:119–181.

    Google Scholar 

  42. Lisopranski, A., Herve, D., Blanc, G., Glowinski, J., and Tassin, J. P. 1980. Selective activation of the mesocortico-frontal dopaminergic neurons induced by lesions of the habenula in the rat. Brain Research 183:229–234.

    Google Scholar 

  43. Dray, A. 1979. The striatum and substantia nigra: A commentary on their relationship. Neuroscience 4:1407–1440.

    Google Scholar 

  44. Deniau, J. M., Thierry, A. M., and Feger, J. 1980. Electrophysiological identification of mesencephalic ventromedial tegmental (VMT) neurons projecting to the frontal cortex, septum and nucleus accumbens. Brain Research 189:315–326.

    Google Scholar 

  45. Lane, J. D., Smith, J. E., and Fagg, G. E. 1983. The origin and termination of neuronal pathways in mammalian brain and their putative neurohumors, Pages 3–56,in Smith, J. E. and Lane, J. D. (eds), The Neurobiology of Opiate Reward Processes, Elsevier, Amsterdam.

    Google Scholar 

  46. Fagg, G. E., and Foster, A. C. 1983. Commentary: Amino acid neurotransmitters and their pathways in the central nervous system. Neuroscience 9:701–719.

    Google Scholar 

  47. Fagg, G. E., Foster, A. C., and Ganong, A. H. 1986. Excitatory amino acid synaptic mechanisms and neurological function. Trends Pharmacol. Sci. 7:357–363.

    Google Scholar 

  48. Cotman, C. W., Monaghan, D. T., Ottersen, O. P., and Storm-Mathisen, J. 1987. Anatomical organization of excitatory amino acid receptors and their pathways. Trends Neurosci. 10:273–280.

    Google Scholar 

  49. Harvey, J. A., Lints, C. E., Jacobson, L. L., and Hunt, H. F. 1965. Effects of lesions in the septal area on conditioned tear and discriminated instrumental punishment in the albino rat. J. Comp. Physiol. Psychol. 59:37–48.

    Google Scholar 

  50. Schwartzbaum, J. S. 1975. Interrelationship among multiunit activity of the midbrain reticular formation and lateral geniculate nucleus, thalamocortical arousal and behavior in rats. J. Comp. Physiol. Psych. 89:131–157.

    Google Scholar 

  51. Spevak, A. A., Campbell, C. T., and Drake, L. 1975. Effect of amygdalectomy on habituation and CER in rats. Physiol. Behav. 15:199–207.

    Google Scholar 

  52. Hirasuna, N., Deadwyler, S. A., and Wyers, E. J. 1977. Disruption of the conditioned emotional response by caudate nucleus stimulation. Pharmacol. Biochem. Behav. 2:173–179.

    Google Scholar 

  53. Berger, T. W., and Thompson, R. F. 1978. Neuronal plasticity in the limbic system during classical conditioning of the rabbit nictitating membrane response. I. The Hippocampus. Brain Research 145:323–346.

    Google Scholar 

  54. Corwin, Z. V., and Slaughter, J. S. 1978. Effect of vagal stimulation on the learning of specific and diffuse conditioned suppression. Behav. Neurol. Biol. 25:364–370.

    Google Scholar 

  55. Schenberg, L. C., and Graeff, F. G.: 1978. Role of the periaqueductal gray substance in the antianxiety action of benzodiazepines. Pharmacol. Biochem. Behav. 9:287–295.

    Google Scholar 

  56. Berry, S. D., and Thompson, R. F. 1979. Medial septal lesions retard classical conditioning of the nictitating membrane response in rabbits. Science (Wash.) 205:209–210.

    Google Scholar 

  57. McIntyre, D. C. 1979. Effects of focal vs generalized kindled convulsions from anterior neocortex or amygdala on CER acquisition in rats. Physiol. Behav. 23:855–859.

    Google Scholar 

  58. Standish, L. J., and Feldman, R. S. 1979. Differential effects of chlordiazepoxide on conditioned and unconditioned behavior in mice with septal lesions. Psychopharmacol. (Berlin) 6:293–297.

    Google Scholar 

  59. Canarzi, A. R., Costa, E., and Guidotti, A. 1980. Potentiation by intraventricular muscimol of the anticonflict effect of benzodiazepines. Brain Research 196:447–453.

    Google Scholar 

  60. Shibata, K., Kataoka, Y., Gomita, Y., and Ueki, S. 1982. Localization of the site of the anticonflict action of benzodiazepines in the amygdaloid nucleus of rats. Brain Research 234:442–446.

    Google Scholar 

  61. Baum, M., Andrus, T., and Jacobs, W. J. 1990. Extinction of a conditioned emotional response: massed and distributed exposures. Behav. Res. Ther. 28:63–68.

    Google Scholar 

  62. Edeline, J. M., Dutrieux, G., and Neuenschwander-El Massioui, N. 1988. Multiunit changes in hippocampus and medial geniculate body in free-behaving rats during acquisition and retention of a conditioned response to a tone. Behav. Neural Biol. 50:61–79.

    Google Scholar 

  63. Izquierdo, I., Ramsey Barcik, N., and Brioni, J. D. 1989. Pretest β-endorphin and epinephrine, but not oxotremorine, reverse retrograde interference of a conditioned emotional response in mice. Pharmacol. Biochem. Behav. 33:545–548.

    Google Scholar 

  64. LeDoux, J. E., Sakaguchi, A., Iwata, J., and Reis, D. J. 1986. Interruption of projections from the medial geniculate body to an archi-neostriatal field disrupts the classical conditioning of emotional responses to acoustic stimuli. Neuroscience 17:615–627.

    Google Scholar 

  65. Mitchell, J. A., and Hall, G. 1988. Learning in rats with caudate-putamen lesions: unimpaired classical conditioning and beneficial effects of redundant stimulus cues on instrumental and spatial learning deficits. Behav. Neurosci 102:505–514.

    Google Scholar 

  66. Thomas, S. R., Lewis, M. E., and Iversen, S. D. 1985. Correlation of [3H] diazepam binding density with anxiolytic locus in the amygdaloid complex of the rat. Brain Research 342:85–90.

    Google Scholar 

  67. Pei, Q., Zetterstroem, T., and Fillenz, M. 1989. Both systemic and local administration of benzodiazepine agonists inhibit the in vivo release of 5-HT from ventral hippocampus. Neuropharmacol. 28:1–6.

    Google Scholar 

  68. LeDoux, J. E., Thompson, M. E., Iadecola, C., Tucker, L. W., and Reis, D. J. 1983. Local cerebral blood flow increases during auditory and emotional processing in the conscious rat. Science (Wash.) 221:576–578.

    Google Scholar 

  69. Robinson, S. E., Malthe-Sorenssen, D., Wood, P. L., and Commission, J. 1979. Dopaminergic control of the septal-hippocampal cholinergic pathway. J. Pharmacol. Exp. Ther. 280:476–479.

    Google Scholar 

  70. Braestrup, C., Schmiechen, R., Neef, G., Nielsen, M., and Petersen, E. N. 1982. Interaction of convulsive ligands with benzodiazepine receptors. Science (Wash.) 216:1241–1244.

    Google Scholar 

  71. Miczek, K. A. 1973. Effects of scopolamine, amphetamine and benzodiazepines on conditioned suppression. Pharmacol. Biochem. Behav. 1:401–411.

    Google Scholar 

  72. Fadda, F. 1978. Stress-induced increase in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the cerebral cortex and in the nucleus accumbens: Reversal by diazepam. Life Sci 23:2219–2224.

    Google Scholar 

  73. Lavielle, S., Tassin, J. P., Thierry, A. M., Blanc, G., Herve, D., Barthelemy, G., and Glowinski, J. 1978. Blockade by benzodiazepines of the selective high increase in dopamine turnover induced by stress in mesocortical dopaminergic neurons of the rat. Brain Research 168:585–594.

    Google Scholar 

  74. Graeff, F. G., and Silveira Fillio, N. G. 1978. Behavioral inhibition induced by electrical stimulation of the median raphe nucleus of the rat. Physiol. Behav. 21:477–484.

    Google Scholar 

  75. Graeff, F. G., and Rawlins, J. N. P. 1980. Dorsal periaqueductal gray punishment, septal lesions and the mode of action of minor tranquilizers. Pharmacol. Biochem. Behav. 12:41–45.

    Google Scholar 

  76. Taylor, D. P., Riblet, L. A., Stanton, H. C., Eison, A. S., Eison, M. S., and Temple, Jr., D. L. 1982. Dopamine and antianxiety activity. Pharmacol. Biochem. Behav. 17, Suppl. 1:25–31.

    Google Scholar 

  77. Yoneda, Y., Kanmori, K., Ida, S., and Kuriyama, K. 1983. Stress-induced alterations in metabolism of gamma-aminobutyric acid in rat brain. J. Neurochem. 40:350–358.

    Google Scholar 

  78. Pericic, D., Walters, J. R., and Chase, T. N. 1977. Effect of diazepam and pentobarbital on amino-oxyacetic acid-induced accumulation of GABA. J. Neurochem. 29:839–846.

    Google Scholar 

  79. Liljequist, S., and Engel, J. E. 1983. The effect of GABA or benzodiazepine receptor antagonists on the annconflict properties of diazepam or ethanol, Soc. Neurosci. Abst. 9:1235.

    Google Scholar 

  80. Wu, J.-Y., Lin, C.-T., Brandon, C., Chan, T.-S., Mohler, H., and Richards, J. G. 1982. Regulation and immunocytochemical characterization of glutamic acid decarboxylase, Pages 279–296,in Cytochemical Methods in Neuroanatomy, Alan R. Liss, Inc., New York.

    Google Scholar 

  81. Kelly, P. A. T., and McCulloch, J. 1982. Effects of the putative gabaergic agonists, muscimol and thip, upon local cerebral glucose utilization. J. Neurochem. 39:613–620.

    Google Scholar 

  82. Palacios, J. M., Kuhar, M. J., Rapoport, S. I., and London, E. D. 1982. Effects of gamma-aminobutyric acid agonist and antagonist drugs on local cerebral glucose utilization. J. Neurosci. 2:853–858.

    Google Scholar 

  83. Skerritt, J. H., Johnston, G. A. R., and Braestrup, C. 1983. Modulation of GABA binding to rat brain membranes by alkyl beta-carboline-3-carboxylate esters. Europ. J. Pharmacol. 86:299–303.

    Google Scholar 

  84. Burch, T. P., Thyagarajan, R., and Ticku, M. K. 1983. Group-selective reagent modification of the benzodiazepine-gamma-aminobutyric acid receptor-ionophore complex reveals that low-affinity gamma-aminobutyric acid receptors stimulate benzodiazepine binding. Molec. Pharmacol. 23:52–61.

    Google Scholar 

  85. Biggio, G., Concas, A., Sanna, E., and Corda, M. G. 1985. Stress-induced reduction of central GABA receptors: Involvement of an endogenous ligand for benzodiazepines. J. Neurochem. 44 Suppl.: S81.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Texas College of Osteopathic Medicine, 3500 Camp Bowie Blvd, 76107, Fort Worth, Texas

    John Douglas Lane

Authors
  1. John Douglas Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

In honor of Distinguished Professor Morris Herman Aprison

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lane, J.D. Neurochemical changes associated with the action of acute administration of diazepam in reversing the behavioral paradigm conditioned emotional response (CER). Neurochem Res 17, 497–507 (1992). https://doi.org/10.1007/BF00969898

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00969898

Key Words

Search

Navigation