Latent Inhibition

Ina Weiner1

1 Tel‐Aviv University, Tel‐Aviv, Israel
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 8.13
DOI:  10.1002/0471142301.ns0813s16
Online Posting Date:  November, 2001
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Abstract

Latent inhibition (LI) refers to the deleterious effects of nonreinforced stimulus preexposure on its subsequent conditioning. LI is considered to index an organism's ability to ignore inconsequential stimuli and as such provides a useful tool to measure attentional processes as well as their disruption and enhancement by various pharmacological, physiological and behavioral manipulations. During the last decade, LI has received increasing interest as an animal model of schizophrenia and of antipsychotic drug action. This unit describes the measurement of LI in the conditioned emotional response and two‐way active avoidance procedures, including parametric variations which allow the demonstration of the disruption and the potentiation of this phenomenon.

     
 
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Table of Contents

  • Basic Protocol 1: Latent Inhibition (LI) in the Conditioned Emotional Response (CER) Procedure
  • Alternate Protocol 1: Adding Drugs, Lesions, or Other Manipulations: Disruption and Potentiation of LI
  • Basic Protocol 2: LI in a Two‐Way Active Avoidance Procedure
  • Alternate Protocol 2: LI in Two‐Way Avoidance with Context Shift
  • Alternate Protocol 3: Adding Treatments in the Two‐Way Avoidance Procedure:Disruption and Potentiation of LI
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Latent Inhibition (LI) in the Conditioned Emotional Response (CER) Procedure

  Materials
  • 3‐ to 4‐month‐old male Wistar rats
  • Operant chambers (e.g., Campden Instruments or any commercially available rodent operant chambers, or any Plexiglas or aluminum boxes constructed according to the following specifications; see Figure ), located in an experimental room (separate from the vivarium) that is dimly lit for experiments. The operant chambers are 25‐cm wide, 23‐cm deep, and 21‐cm high (inner box measures), with a floor made of stainless steel rods (4 mm in diameter, 1 cm apart), 4.5 cm above a sawdust pan. Each chamber is enclosed in a ventilated sound‐attenuating chamber. In the middle of the left wall of the chamber, there is a 2.3‐cm diameter hole, 3.8 cm above the floor (hole center). Behind the hole at a distance of 4 mm, there is a square piece of metal with a 1‐cm diameter hole in it, fixed to be concentric to the chamber hole. A retractable 140‐ml bottle fitted with stainless steel twin ball point sleeve (Classic Pet Products) is positioned on the outer side of the chamber, 3 mm behind the piece of metal, at a 30° angle. The bottle sleeve and the square piece of metal are connected to a drinkometer (Campden Instruments), so that each lick the rat makes is recorded. When the bottle is not present, the chamber hole is covered by a metal lid. The floor of the chamber is connected to a shock scrambler which is connected to a shock source/generator set at a 0.5‐mA intensity and 1‐sec duration. The chamber has three light bulbs on the left wall (two on the sides and one in the center), a light bulb on the roof of the chamber, which generates the house light, and two Sonalert modules (Campden Instruments) located on the roof of the chamber, one for generating tones and the other for generating white noise. The preexposed, to‐be‐conditioned stimulus is a 10‐sec, 80‐dB, 2.8‐kHz tone generated from the Sonalert module.
  • An interface (fabricated in‐house) connects the chambers, Sonalert modules, shock sources and drinkometers to a personal computer equipped with software programs that control stimuli administration and data collection.
  • Software programs can be written in‐house (e.g., in Pascal) or commercially available software packages can be used, such as ABET (Animal Behavioural Environment Test system run on Windows 98/2000; the computer is interfaced to the operant chambers using the ABET interface system and the ABET computer interface card; Campden Instruments and Lafayette Instruments); WMPC (MED‐PC for Windows; the computer is interfaced to the operant chambers using SmartCard, Med Associates); or WINLINC (the computer is interfaced to the operant chambers using LABLINC HABITEST LINC, Coulbourn Instruments). Three software programs are used, one for baseline, one for preexposure and conditioning, and one for test. All the results per rat are displayed continuously on the computer screen.
  • Baseline program controls the house light, side lights, session length, and number of blocks for data recording. The output is an ASCII file that includes rat number, time to first lick, total number of licks, and number of licks per block.
  • Preexposure and conditioning program controls the house light, the side lights, the type of intertrial interval (fixed or variable) and its average duration (which also defines the time between beginning of session and the beginning of the first trial as well as the time between the end of the last trial and end of session), presence of stimuli (on or off), the type of stimuli delivered on each trial (e.g., tone in preexposure, tone and shock in conditioning), delay of onset of each stimulus from the beginning of the trial, their duration and frequency (in the case of flashing lights or white noise).
  • Test program controls the type of stimulus, number of licks to stimulus onset, stimulus duration, and number of blocks for data recording, and creates an ASCII file for each rat including: rat number, time to first lick (pre‐A period first lick), time to complete the first 50 licks (pre‐A period, licks 1 to 50), time to complete 25 licks prior to tone onset (A period, licks 51 to 75), time from tone onset to the third lick (B period, third lick; the third, not the first, lick is measured since sometimes a drop of water between the metal square and the bottle sleeve may be wrongly counted as a lick), time to complete 25 licks after tone onset (B period, licks 76 to 100), total number of licks during the tone, and number of licks per block from tone onset.
  • Standard statistical package (e.g., STATVIEW, SUPERANOVA, SPSS, or STATISTICA)

Alternate Protocol 1: Adding Drugs, Lesions, or Other Manipulations: Disruption and Potentiation of LI

  Materials
  • 3‐ to 4‐month‐old male Wistar rats, housed four to a cage under reversed cycle lighting (lights on: 7:00 p.m. ‐ 7:00 a.m.).
  • Four commercially available shuttle boxes (e.g., Campden Instruments or Coulbourn Instruments) containing house lights, side lights (on the side walls) and tone/white noise generators, with no barrier between the two compartments of the box, each set in a soundproof shelter equipped with fans. The preexposed to‐be‐conditioned stimulus is a 10 sec, 2.8 kHz, 80 dB tone produced by a Sonalert module located on the roof of the chamber. Shock is supplied to the grid floor by a scrambled shock generator set at 0.5 mA intensity. In‐house interface connects the shuttle boxes, Sonalert modules/light sources, and shock sources to a PC computer that is equipped with a software program (programs written in‐house, as well as commercially available software packages, e.g., from Campden Instruments, Med Associates, or Coulbourn Instruments, can be used).
  • The software program controls the house lights, the side lights, stage (preexposure, test), number of trials, the type of intertrial interval (fixed or variable) and its average duration (which also defines the time between beginning of session and the beginning of the first trial as well as the time between the end of the last trial and end of session), presence of stimuli (on or off), the type of stimuli delivered on each trial, delay of onset of each stimulus from the beginning of the trial, their duration and frequency (in the case of flashing lights or white noise), number of blocks (blocks of equal duration in preexposure and blocks of equal number of trials in test), and creates two ASCII files, one for preexposure and one for test: the former includes rat number, total number of crossings, and number of crossings per block; the latter includes in addition, total number of escape responses (crossings during shock), total number of avoidance responses (crossings during the stimulus), and number of escape and avoidance responses per block. Escape and avoidance responses terminate the stimuli currently on (namely, escape response terminates the tone and the shock, and avoidance response terminates the tone) and initiate the intertrial interval.

Basic Protocol 2: LI in a Two‐Way Active Avoidance Procedure

  • Ylang‐Ylang oil and cinnamon oil, or any two oils with distinct scents, e.g., rose oil or eucalyptus oil
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Figures

Videos

Literature Cited

   Arnt, J. and Skarsfeldt, T. 1998. Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18:63‐101.
   Baruch, I., Hemsley, D., and Gray, J.A. 1988a. Differential performance of acute and chronic schizophrenics in a latent inhibition task. J. Nerv. Ment. Dis. 176:598‐606.
   Baruch, I., Hemsley, D.R., and Gray, J.A. 1988b. Latent inhibition and “psychotic pronness” in normal subjects. Pers. Indiv. Differ. 9:777‐783.
   Coutureau, E., Galani, R., Gosselin, O., Majchrzak, M., and Di Scala, G. 1999. Entorhinal but not hippocampal or subicular lesions disrupt latent inhibition in rats. Neurobiol. Learn. Mem. 72:143‐157.
   Dunn, L.A., Atwater, G.E., and Kilts, C.D. 1993. Effects of antipsychotic drugs on latent inhibition: Sensitivity and specificity of an animal behavioral model of clinical drug action. Psychopharmacology 112:315‐323.
   Gosselin, G., Oberling, P., and Di Scala, G. 1996. Antagonism of amphetamine‐induced disruption of latent inhibition by the atypical antipsychotic olanzapine in rats. Behav. Pharmacol. 7:820‐826.
   Gray, J.A., Moran, P.M., Grigoryan, G., Peters, S.L., Young, A.M., and Joseph, M.H. 1997. Latent inhibition: The nucleus accumbens connection revisited. Behav. Brain Res. 88:27‐34.
   Gray, N.S., Pickering, A.D., Hemsley, D.R., Dawling, S., and Gray, J.A. 1992. Abolition of latent inhibition by a single 5 mg dose of d‐amphetamine in man. Psychopharmacology 107:425‐430.
   Gray, N.S., Pilowsky, L.S., Gray, J.A., and Kerwin, R.W. 1995. Latent inhibition in drug naive schizophrenics: Relationship to duration of illness and dopamine D2 binding using SPET. Schiz. Res. 17:95‐107.
   Grecksch, G., Bernstein, H.G., Becker, A., Hollt, V., and Bogerts, B. 1999. Disruption of latent inhibition in rats with postnatal hippocampal lesions. Neuropsychopharmacology 20:525‐532.
   Honey, R.C. and Good, M. 1993. Selective hippocampal lesions abolish the contextual specificity of latent inhibition and conditioning. Behav. Neurosci. 107:23‐33.
   Lubow, R.E. 1989. Latent Inhibition and Conditioned Attention Theory. Cambridge University Press, Cambridge.
   Lubow, R.E. and Gewirtz, J.C. 1995. Latent inhibition in humans: Data, theory, and implications for schizophrenia. Psychol. Bull. 117:87‐103.
   Lubow, R.E. and Josman, Z.E. 1993. Latent inhibition deficits in hyperactive children. J. Child Psychol. Psychiatry 84:859‐875.
   Lubow, R.E., Dressler, R., and Kaplan, O. 1999. Visual search and latent inhibition in de novo Parkinson patients. Neuropsychology 13:415‐423.
   Rochford, J., Sen, A.P., Rousse, I., and Welner, S.A. 1996. The effect of quisqualic acid‐induced lesions of the nucleus basalis magnocellularis on latent inhibition. Brain Res. Bull. 41:313‐317.
   Shadach, E., Feldon, J., and Weiner, I. 1999. Clozapine‐induced potentiation of latent inhibition is due to its action in the conditioning stage: Implications for the mechanism of action of antipsychotic drugs. Int. J. Neuropsychopharmacology 2:283‐291.
   Shadach, E., Gaisler, I., Schiller, D., and Weiner, I. 2000. The latent inhibition model dissociates between clozapine, haloperidol and ritanserin. Neuropsychopharmacology 23:151‐161.
   Shalev, U., Feldon, J., and Weiner, I. 1998. Gender‐ and age‐dependent differences in latent inhibition following pre‐weaning non‐handling: Implications for a neurodevelopmental animal model of schizophrenia. Int. J. Dev. Neurosci. 16:279‐288.
   Solomon, P., Nichols, G.L., Kiernan, J.M.I., Kamer, R.S., and Kaplan, L.J. 1980. Differential effects of lesions in medial and dorsal raphe of the rat: Latent inhibition and septo‐hippocampal serotonin levels. J. Comp. Physiol. Psychol. 94:145‐154.
   Solomon, P.R. and Staton, D.M. 1982. Differential effects of microinjections of d‐amphetamine into the nucleus accumbens or the caudate putamen on the rat's ability to ignore an irrelevant stimulus. Biol. Psychiatry 17:743‐756.
   Solomon, P.R., Crider, A., Winkelman, J.W., Turi, A., Kamer, R.M., and Kaplan, L.J. 1981. Disrupted latent inhibition in the rat with chronic amphetamine or haloperidol‐induced supersensitivity: Relationship to schizophrenic attention disorder. Biol. Psychiatry 16:519‐537.
   Sotty, F., Sandner, G., and Gosselin, O. 1996. Latent inhibition in conditioned emotional response: c‐fos immunolabelling evidence for brain areas involved in the rat. Brain Res. 737:243‐254.
   Swerdlow, N.R., Braff, D.L., Hartston, H., Perry, W., and Geyer, M.A. 1996. Latent inhibition in schizophrenia. Schiz. Res. 20:91‐103.
   Swerdlow, N.R., Hartston, H.J., and Hartman, P.L. 1999. Enhanced latent inhibition in obsessive compulsive disorder. Biol. Psychiatry 45:482‐488.
   Trimble, K.M., Bell, R., and King, D.J. 1997. Enhancement of latent inhibition in the rat by the atypical antipsychotic agent remoxipride. Pharmacol. Biochem. Behav. 56:809‐816.
   Weiner, I. 1990. Neural substrates of latent inhibition: The switching model. Psychol. Bull. 108:442‐461.
   Weiner, I. 2000. The latent inhibition model of schizophrenia. In Contemporary Issues in Modeling Psychopathology (M. Myslobodsky and I. Weiner, eds.) Kluwer Academic Publishers, Boston.
   Weiner, I. and Feldon, J. 1987. Facilitation of latent inhibition by haloperidol in rats. Psychopharmacology 91:248‐253.
   Weiner, I. and Feldon, J. 1997. The switching model of latent inhibition: An update of neural substrates. Behav. Brain Res. 88:11‐25.
   Weiner, I., Lubow, R.E., and Feldon, J. 1981. Chronic amphetamine and latent inhibition. Behav. Brain Res. 2:285‐286.
   Weiner, I., Lubow, R.E., and Feldon, J. 1984. Abolition of the expression but not the acquisition of latent inhibition by chronic amphetamine in rats. Psychopharmacology 83:194‐199.
   Weiner, I., Feldon, J., and Katz, Y. 1987a. Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats. Pharmacol. Biochem. Behav. 26:241‐246.
   Weiner, I., Feldon, J., and Ziv‐Harris, D. 1987b. Early handling and latent inhibition in the conditioned suppression paradigm. Dev. Psychobiol. 20:233‐240.
   Weiner, I., Lubow, R.E., and Feldon, J. 1988. Disruption of latent inhibition by acute administration of low doses of amphetamine. Pharmacol. Biochem. Behav. 30:871‐878.
   Weiner, I., Gal, G., Rawlins, J.N., and Feldon, J. 1996a. Differential involvement of the shell and core subterritories of the nucleus accumbens in latent inhibition and amphetamine‐induced activity. Behav. Brain Res. 81:123‐133.
   Weiner, I., Shadach, E., Tarrasch, R., Kidron, R., and Feldon, J. 1996b. The latent inhibition model of schizophrenia: Further validation using the atypical neuroleptic, clozapine. Biol. Psychiatry 40:834‐843.
   Weiner, I., Shadach, E., Barkai, R., and Feldon, J. 1997. Haloperidol‐ and clozapine‐induced enhancement of latent inhibition with extended conditioning: Implications for the mechanism of action of neuroleptic drugs. Neuropsychopharmacology 16:42‐50.
   Weiner, I., Hairston, I., Shayit, M., Feldman, G., and Joel, D. 1998. Strain differences in latent inhibition. Psychobiology 26:57‐64.
   Weiner, I., Gal, G., and Feldon, J. 1999. Disrupted and undisruptable latent inhibition following shell and core lesions. Ann. N.Y. Acad. Sci. 877:723‐727.
   Williams, J.H., Wellman, N.A., Geaney, D.P., Cowen, P.J., Feldon, J., and Rawlins, J.N. 1996. Antipsychotic drug effects in a model of schizophrenic attentional disorder: A randomised trial of the effects of haloperidol on latent inhibition in healthy people. Biol. Psychiatry 40:1135‐1143.
   Young, A.M.J., Joseph, M.H., and Gray, J.A. 1993. Latent inhibition of conditioned dopamine release in rat nucleus accumbens. Neuroscience 54:5‐9.
Key References
   Lubow, 1989. See above.
  This is the most comprehensive summary of LI literature from an empirical and theoretical perspective.
   Lubow and Gewirtz, 1995. See above.
  Provides a comparative review of human LI data and its similarity to animal data.
   Weiner, 1990. See above.
  Reviews the neural substrates of LI and advances a model to accommodate them within a unifying framework.
   Gewirtz and Feldon, 1997. See above.
  Extension and refinement of the above.
   Weiner, 2000. See above.
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