Conditioned Emotional Response Paradigm Research Articles

Effects of intracerebral ventricular administration of gastrin-releasing peptide and its receptor antagonist RC-3095 on learned fear responses in the rat

Several lines of evidence have implicated bombesin and its mammalian analogue, gastrin-releasing peptide (GRP), in the mediation and/or modulation of the stress response. However, the physiological role of GRP in mediating conditioned fear responses remains to be elucidated. The objective of the present study was to characterize the role(s) of GRP and its receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) BB (6–14) (RC-3095) in fear-related responses using two animal models of conditioned fear. To this end, the effects of intracerebroventricular (i.c.v.) administration of GRP (0.062, 0.30, 3.0 nmol) and RC-3095 (0.3, 3.0 and 9.0 nmol) were assessed in the conditioned emotional response (CER) and the fear-potentiated startle (FPS) paradigms. In the CER paradigm, i.c.v. administration of GRP dose-dependently (all doses) attenuated the expression of both contextual and cued fear as reflected by a reduction in freezing behavior to both the context (cage where shock was received) and cue (tone paired with shock). Conversely, pretreatment with RC-3095 (high dose), blocked the reduction of contextual and cued fear normally observed over time. Further, in the FPS paradigm, i.c.v. administration of GRP significantly attenuated the fear-potentiated startle response at medium and high doses without affecting basal startle amplitude. In contrast, pretreatment with RC-3095 at the highest dose (9.0 nmol) significantly increased the basal startle amplitude without affecting fear-potentiation, suggesting elevated fear at the onset of testing. These data provide further evidence that GRP is involved in conditioned fear responses.

Differential effects of MPEP and diazepam in tests of conditioned emotional response and Pavlovian-to-instrumental transfer suggests ‘anxiolytic’ effects are mediated by different mechanisms

The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is reported to be anxiolytic in several animal models of anxiety, including the conditioned emotional response (CER) paradigm. Suppression of responding during conditioned stimulus (CS) presentation in CER may reflect behavioural competition between lever pressing and adopting a shock-avoidance posture, or it may alternatively reflect altered value of the food reward following its association with a footshock, thus reducing its ability to motivate responding. If this is the case, then drugs that reduce the CER may interfere with the mechanism by which CSs are able to motivate responding, rather than by reducing anxiety. The standard test of the ability of Pavlovian cues to motivate responding is the Pavlovian-to-instrumental transfer (PIT) paradigm and it has recently been suggested that CER may be 'negative PIT'. We compared the effect of MPEP (0, 3, 10 and 30 mg/kg) and diazepam (0, 1, 3 and 10 mg/kg) in CER and PIT. Both MPEP and diazepam significantly reduced conditioned suppression in the CER paradigm. MPEP, but not diazepam, significantly reduced PIT. The findings support the hypothesis that MPEP may reduce expression of anxiety in the CER paradigm by interfering with the way in which emotionally salient cues are able to affect behaviour, but do not support such an analysis of the effect of diazepam. Diazepam and MPEP may therefore achieve their effects in CER by influencing different psychological processes.

Assessment of anxiety-like behaviors in female rats bred for differences in kindling susceptibility and amygdala excitability

Two rat lines bred for kindling susceptibility were previously observed to engage in different behavioral strategies in tests of emotionality. In order to extend past research on defensive behaviors in these strains which largely used males, Fast- and Slow-kindling females were assessed for anxiety-like behaviors in a number of aversive paradigms. Fast rats entered and spent more time in the open arms and spent less time in the closed arms of the elevated plus-maze (EPM) compared to Slow animals. Fast rats had higher conditioned suppression ratios across testing days, defecated less often during conditioning, and successfully disinhibited suppression during extinction in the conditioned emotional response (CER) paradigm compared to Slow-kindlers. In order to pursue these differences in emotional reactivity between the strains and differentiate negative affect from motivational, learning, and impulsive explanations, a separate group of animals were assessed in the light-enhanced acoustic startle chamber, a test of anxiety. When initially exposed to a bright-light, Slow rats significantly increased their startle response while this was not observed in the Fast strain. In combination with previous research on these strains, the present data tentatively suggest that Fast and Slow animals utilize different neural systems in tests of fear and anxiety which may have been co-selected with the direct selection of amygdala-kindling susceptibility.

Overshadowing in conditioned taste aversion or in conditioned emotional response after neonatal ventral hippocampal lesions in rats

The neonatal hippocampus lesion thought to model schizophrenia should show the same modifications in behavioural tests as other models, especially pharmacological models, namely decreased latent inhibition, blocking and overshadowing. The present study is set out to evaluate overshadowing in order to complement our previous studies, which had tested latent inhibition. “Overshadowing” refers to the decreased conditioning that occurs when the to-be-conditioned stimulus is combined with another stimulus at the conditioning stage. We used the same two Pavlovian conditioning paradigms as in our previous works, namely conditioned taste aversion (CTA) and conditioned emotional response (CER). A sweet taste overshadowed a salty conditioned stimulus, and a tone overshadowed a flashing light. Totally different stimuli were used to counter possible sensory biases. The protocols were validated with two groups of Sprague Dawley rats. The same two protocols were then applied to a cohort of rats whose ventral hippocampus had been destroyed when they were 7 days old. Only rats with extended ventral hippocampus lesions were included. The overall effect of Pavlovian conditioning was attenuated, significantly so in the conditioned emotional response paradigm, but overshadowing appeared not to be modified in either the conditioned emotional response or the conditioned taste aversion paradigm.

7-OH-DPAT effects on latent inhibition: low dose facilitation but high dose blockade: Implications for dopamine receptor involvement in attentional processes

7-OH-DPAT is a dopamine D2/D3 agonist, which at low doses acts preferentially on D3 receptors but at high doses it acts on D2 and D3 receptors. The present study investigated the contribution of D3 and D2 receptors on latent inhibition (LI) by using two dose levels of 7-OH-DPAT: a low dose, 0.1 mg/kg (D3 receptor activation) and a high dose, 1.0 mg/kg, (D2/D3 receptor activation) in a conditioned emotional response (CER) paradigm. The LI Protocols included CS pre-exposure (10 or 40 CS alone trials), CER induction and a non-drug CER test phase. Additionally, the drug effects upon CER acquisition without LI were assessed using the same treatments and test environment pre-exposure protocols but without the tone CS. The effects of 7-OH-DPAT on crossing, rearing and grooming were also measured in an open field 1 day after the CER test phase. The results showed that the low dose 7-OH-DPAT treatment potentiated LI at 10 but not at 40 CS pre-exposures. The high dose 7-OH-DPAT treatment blocked LI at both the 10 and 40 stimulus pre-exposures; and it also induced hyperactivity. Thus, D3 stimulation induced by a low dose of 7-OH-DPAT can facilitate LI but these effects are contingent upon and are specific to the number of stimulus presentations. Altogether, these findings indicate that D3 stimulation can enhance attentional processes, but D2 stimulation can impair attentional processes.

Both α2 and α3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm

Mice with point-mutated alpha2 GABAA receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in unconditioned models of anxiety. We investigated the role of the alpha2 GABAA subtype in a model of conditioned anxiety. alpha2(H101R) and wildtype mice were trained in a conditioned emotional response (CER) task, in which lever-pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a conditioned stimulus (CS+) that predicted footshock. The ability of diazepam, ethanol and pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. Diazepam (0, 0.5, 1, 2, 4 and 8 mg/kg) induced a dose-dependent anxiolytic-like effect in wildtype mice. At high doses, diazepam (2, 4 and 8 mg/kg) was sedative in alpha2(H101R) mice. Analysis of the anxiolytic properties of nonsedative diazepam doses (0.5 and 1 mg/kg), showed that alpha2(H101R) mice were resistant to the anxiolytic effects of diazepam. Equivalent anxiolytic properties of pentobarbital (20 mg/kg) and ethanol (1 and 2 g/kg) were seen in both genotypes. These findings confirm the critical importance of the alpha2 GABAA subtype in mediating BZ anxiolysis. However, as a compound, L-838417, with agonist properties at alpha2, alpha3 and alpha5-containing receptors, gave rise to anxiolytic-like activity in alpha2(H101R) mice in the CER test, alpha3-containing GABA receptors are also likely to contribute to anxiolysis. Observations that alpha2(H101R) mice were more active, and displayed a greater suppression of lever pressing in response to fear-conditioned stimuli than wildtype mice, suggests that the alpha2(H101R) mutation may not be behaviourally silent.

Recovery from lesion-associated learning deficits by fetal amygdala transplants.

Bilateral lesions of the amygdaloid complex result in elimination or attenuation of the conditioned freezing that is normally seen in the conditioned emotional response (CER) paradigm and the active avoidance (AA) task. We observed the effect of amygdalar tissue transplantation on the ability of lesioned (central nucleus of amygdala, CeA) rats to learn CER and AA. In two groups of adult Wistar rats, sham operation or bilateral lesions of the CeA were produced electrolytically (2mA for 8 sec). In a third group, fetal amygdalar tissue was transplanted at the CeA-lesioned site 2 d postoperatively. All rats were trained on CER and AA from the 6th postoperative day. In comparison with the shamoperated group, bilaterally CeA-lesioned rats showed a significant (p<0.001) increase in all CER scores, indicating an acquisition deficit. After fetal amygdalar tissue transplantation, the CER scores significantly decreased (p<0.05) when compared with the lesioned group. A significant (p<0.01) decrease in the percentage of avoidance in the AA task occurring after CeA lesion returned to control values after amygdalar tissue transplantation. In conclusion, in CeA-lesioned rats a complete behavioral deficit in learning CER and AA was restored by transplanting fetal amygdalar tissue at the lesioned site.

Restoration of latent inhibition by olanzapine but not haloperidol in entorhinal cortex-lesioned rats

Latent inhibition (LI) refers to the decrease in conditioned response induced by the repeated non-reinforced pre-exposure to the conditioned stimulus before its pairing with the unconditioned stimulus during the conditioning stage. LI has been considered as a relevant animal model for the study of the biological bases of schizophrenia. LI has recently been demonstrated to depend on the integrity of the entorhinal cortex, as lesioning of this area disrupted LI. The present study aimed to verify whether the classical neuroleptic haloperidol and/or the atypical antipsychotic olanzapine would prevent the effect of entorhinal cortex lesioning. LI was studied in an off-baseline conditioned emotional response (CER) paradigm in which a tone is paired with a footshock. Entorhinal cortex lesions were produced by the electrolytic method. After a recovery period, both lesioned and control rats received either haloperidol (0.3 mg/kg), olanzapine (0.3 mg/kg) or vehicle before both the pre-exposure and conditioning stages of the experiment. In control rats, pre-exposure to the tone induced LI, which was affected by neither haloperidol nor olanzapine. Lesioning of the entorhinal cortex produced a deficit of LI, which was restored by olanzapine but not by haloperidol. This result suggests a dissociation of the anatomical and pharmacological targets of the two drugs. The possible involvement of dopamine D3 receptors in the effects of olanzapine is discussed.

14-111 - Pharmacological validation of latent inhibition situation in the conditioned emotional response paradigm in the rats

14-111 - Pharmacological validation of latent inhibition situation in the conditioned emotional response paradigm in the rats

A single administration of d-amphetamine prior to stimulus pre-exposure and conditioning attenuates latent inhibition.

The effect of a single administration of d-amphetamine (0.32 mg/kg, s.c.) upon latent inhibition (LI) in a one-session pre-exposure and conditioning procedure was investigated in rats in a conditioned emotional response paradigm. It was found that amphetamine attenuated LI. The effects could not be attributed to differences in unconditioned suppression nor to differences in response rates between the experimental groups. These results support the observations of Dunn and suggest that the disruption of LI may not depend upon a complex interaction between changes in neuronal processes consequent upon repetitive amphetamine administration and the schedule with which the drug is administered during the experimental procedure.

The effect of quisqualic acid-induced lesions of the nucleus basalis magnocellularis on latent inhibition.

Latent inhibition (LI) is a reduction in the rate of acquisition of a Pavlovian conditioned response that results from prior nonreinforced preexposure to a conditioned stimulus (CS). LI has been suggested to reflect the operation of mechanisms involved in stimulus selection for subsequent cognitive processing. The present experiment was conducted to assess the effect of bilateral lesions of the nucleus basalis magnocellularis (NBM) on LI employing a conditioned emotional response paradigm. Bilateral lesions of the NBM were produced by administration of 0.12 M quisqualic acid and resulted in decreased cortical acetylcholinesterase staining, as well as a 40% reduction in cortical choline acetyltransferase activity. Following lever press training, preexposed animals received 40 presentations of a 60-s tone CS. Nonpreexposed animals received no tone presentations. Acquisition of conditioned suppression was then assessed over the course of 4 tone-shock (0.6 mA, 0.5 s) pairings. Control, preexposed animals displayed a retarded rate of acquisition in comparison to nonpreexposed controls, thereby demonstrating that the parameters used in the present experiment produced LI. In contrast, lesioned animals preexposed to the CS acquired conditioned suppression as readily as nonpreexposed lesioned animals. However, the acquisition of conditioned suppression in both lesioned groups was found to be similar to that displayed in the preexposed control group. This pattern of results was interpreted as being attributable to a lesion-induced impairment in the ability to maintain stimulus processing, rather than a deficit in the ability to filter a stimulus.

Both Electrolytic and Excitotoxic Lesions of Nucleus Accumbens Disrupt Latent Inhibition of Learning in Rats

Evidence indicating a role for the nucleus accumbens in the development of latent inhibition of learning has accumulated. Two experiments were conducted using Wistar rats to investigate this role directly. Experiment 1 used a conditioned emotional response paradigm to assess the effects of discrete electrolytic lesions in the shell region of the nucleus accumbens. Latent inhibition was attenuated by this lesion. In order to determine the contribution made by damage to fibers en passage associated with electrolytic lesions, Experiment 2 assessed the effects of NMDA-induced lesions in the shell of the nucleus accumbens in the same task. Latent inhibition was again significantly attenuated. These findings support the proposition that an intact nucleus accumbens is necessary for the normal development of latent inhibition.

Morphine as a conditioned stimulus in a conditioned emotional response paradigm.

A Pavlovian conditioning experiment was conducted to determine whether morphine (6 mg/kg, IP) could act as a conditioned stimulus (CS) when paired with an electric shock unconditioned stimulus (US), and later produce a conditioned suppression of drinking (CR) in water deprived rats. Seven groups were tested for conditioning after exposure to one of the following conditioning procedures: (1) morphine paired with shock; (2) morphine alone with no shock; (3) shock but no morphine; (4) no shock and no morphine; (5) morphine paired with vocalizations of shocked rats; (6) saline paired with shock; (7) saline alone with no shock. Groups 1 and 2 tested whether morphine could act as a CS. Groups 3 and 4 tested for sensitization. Group 5 tested whether exposure to the vocalizations of other rats could act as a US when paired with a morphine CS. Groups 6 and 7 tested whether cues associated with the injection procedure could act as a CS. Only subjects in group 1 showed conditioned suppression of drinking, when compared to control groups. Overall, the results indicate that morphine could act as a conditioned stimulus and that several of the more obvious possible sources of artifact did not significantly contribute to the CR that is produced.

5-HT 1A agonists disrupt memory of fear conditioning in mice

A series of experiments was carried out to analyze the effects of the 5-HT 1A agonists tandospirone or buspirone on the retention of fear conditioning in mice. Fear was produced by pairing tone and shock in a conditioned emotional response (CER) paradigm and strength of conditioning was assessed by measuring suppression of drinking in presence of tone. Fear conditioning was disrupted if tandospirone and buspirone were administered before the conditioning session but not before the test trial. Diazepam disrupted conditioning at both times. Tandospirone did not disrupt performance if conditioning was tested 1 hr rather than 24 hr after training, suggesting that disrupted memory rather than impaired acquisition was responsible for the deficit. The effect of tandospirone on fear conditioning could be reversed by administration of d-amphetamine prior to the retention test, which suggests that information was stored but is inaccessible to normal retrieval cues. Tandospirone and buspirone also retarded extinction, a clear indication that the disruption caused by these drugs is unrelated to their anxiolytic action.

Nicotine blocks latent inhibition in rats: evidence for a critical role of increased functional activity of dopamine in the mesolimbic system at conditioning rather than pre-exposure

Latent inhibition (LI) is a cognitive process whereby repeated exposure of a stimulus without consequence impedes the formation of subsequent associations with that stimulus. A number of studies in the rat have reported that LI is impaired by moderate systemic doses of amphetamine, an effect believed to be mediated via dopamine (DA) release in the nucleus accumbens. We and others have reported that nicotine has a selective effect in releasing DA in the accumbens rather than the caudate nucleus. We have therefore examined the ability of nicotine to disrupt LI, using a conditioned emotional response paradigm. Pre-exposure of a tone stimulus impaired subsequent conditioning between that stimulus and mild footshock, as indexed by suppression of licking by the tone subsequently presented alone. This LI effect was prevented, by an effect confined to the pre-exposed group, by doses of 0.4 or 0.6 mg/kg nicotine SC, which are accumbens selective, given before pre-exposure and before conditioning. The effect of nicotine in disrupting LI was prevented by prior administration of haloperidol at a dose (0.5 mg/kg) reported to reverse the disruptive effect of amphetamine on LI. Although the amphetamine effect requires two administrations, the effect of two administrations of nicotine was reproduced by a single dose of nicotine given before conditioning, but not by a single dose before pre-exposure. The results are discussed in relation to studies in human control and schizophrenic subjects, which suggest that increased DA activity in humans is also associated with impaired LI.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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.

Conditioned neuroendocrine and cardiovascular stress responsiveness accompanying behavioral passivity and activity in aged and in young rats

Mean arterial pressure (MAP), heart rate (HR), plasma epinephrine (E), plasma norepinephrine (NE), and plasma corticosterone (CORT) were measured in 3-month- and 24-month-old male Wistar rats exposed to a conditioned emotional stress response (CER) paradigm and a conditioned defensive burying (CDB) paradigm. In the CER situation blood samples were taken during reexposure to the training environment one day after a single inescapable footshock (0.6 mA, AC for 3 s) had been administered. In the CER paradigm the young rats displayed passive behavior (immobility) accompanied by an increase in plasma levels of CORT and E, whereas both the control and conditioned animals showed increased NE responses. Previously shocked aged rats exhibited an attenuated plasma NE response, whereas levels of E remained elevated to a greater extent. Aged animals showed elevated basal levels of CORT one day after footshock administration. Stress-induced immobility was preserved in the aged rats. These animals had an increase in basal MAP values and a decrease in basal HR values compared to young ones. In the CDB paradigm, rats were exposed to a nonelectrified probe 1 day after the repeated shock (2 mA/contact) procedure. Young rats displayed defensive burying accompanied by increments in MAP, HR, CORT, and NE. The aged animals showed similar hormonal, autonomic, and behavioral stress responses. Thus, the age-related alterations in neuroendocrine and autonomic response patterns are apparent in stressed animals during behavioral passivity in absence of control (CER) rather than during active control (defensive burying).

Neurochemical, endocrine and immunological responses to stress in young and old Fischer 344 male rats

Two experiments were performed. In the first, a 20 min conditioned emotional response (CER) paradigm was used to compare the neurochemical, endocrine and immunological responses to stress of 7- and 22-month-old Fischer 344 (F344) male rats. In the second, corticosterone levels 20 min following ether stress, and regional brain type I and II corticosterone receptor densities were examined using 7- and 17.5-month-old F344 male rats. Dopamine (DA) metabolism in old nonstressed rats was significantly reduced in the medial frontal cortex, neostriatum, nucleus accumbens and hypothalamus, but not in the amygdala. The CER procedure, nevertheless, increased medial frontal cortical, nucleus accumbens and amygdaloid DA turnover in both the young and old rats. The young and old nonstressed rats did not evidence differences in norepinephrine (NE) and serotonin (5-HT) concentrations. However, stress resulted in a decrease in medial frontal cortex NE content in the young but not in the old rats. In contrast, the CER procedure resulted in increased medial frontal cortical 5-hydroxyindoleacetic acid (5-HIAA) and hypothalamic 5-HT levels in old but not in young animals. These observations suggest age-related differences in the response of central NE and 5-HT systems to stress. Ether and the CER procedure led to exaggerated corticosterone responses in the old rats (17.5 and 22 month, respectively). Hippocampal type I but not type II corticosterone receptors were decreased by 47% in the 17.5-month-old rats. Thus, age-related changes in hippocampal corticosterone receptor types do not occur in unison, and the exacerbated corticosterone response to stress precedes the reported down-regulation of hippocampal type II corticosterone receptors in aged rats. Age-related changes were not observed in the concentrations of corticosterone receptors in other brain regions, or in the prolactin response to stress. The old rats, however, evidenced a reduction in the availability of the renin substrate, angiotensinogen, and in stress-induced renin secretion. Immune function was impaired in the old nonstressed rats, and further compromised by exposure to the CER procedure. In comparison to the young control rats, the old nonstressed rats showed an increased percentage of splenic large granular lymphocytes, reduced splenic natural killer cytotoxicity, and impaired Con-A-stimulated splenic T lymphocyte proliferation. Reductions in T splenic cell proliferation and natural killer cytotoxicity were observed in the young rats subjected to the CER paradigm, but not to the same extent as in the old rats. These observations indicate that aging male F344 rats evidence major alterations in basal central monoamine, endocrine and immune functions, and an increased sensitivity of these systems to stress.

Stress-Induced Renin and Corticosterone Secretion Is Mediated by Catecholaminergic Nerve Terminals in the Hypothalamic Paraventricular Nucleus

Cell bodies in the hypothalamic paraventricular nucleus (PVN) mediate stress-induced increases in renin and corticosterone secretion. Since the PVN has an extensive catecholaminergic innervation, we wanted to determine the role of catecholamines in the neuroendocrine response to stress. The stressor was a conditioned emotional (fear) response paradigm (CER). The catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), was injected into the PVN 14 days before the rats were subjected to the CER procedure. Damage to noradrenergic nerve terminals was verified immunocytochemically, using an antibody against dopamine beta-hydroxylase. Injection of 6-OHDa into the PVN prevented the stress-induced increase in plasma renin activity (PRA), plasma renin concentration (PRC) and plasma corticosterone concentration, suggesting that intact catecholaminergic innervation of neurons in the PVN is necessary for the stress-induced increase in renin and corticosterone secretion. To determine if beta-adrenoceptors in the PVN mediate the effect of stress on renin and corticosterone secretion, the beta-adrenoceptor antagonist sotalol was injected into the PVN through chronically implanted bilateral cannulae. The injection was performed on the 4th day of the CER paradigm, just before the rats were placed into the CER chamber. Sotalol prevented the stress-induced increase in corticosterone concentration, but did not diminish the stress-induced increase in PRA and PRC. These results suggest that the stress-induced increase in corticosterone concentration is influenced by beta-adrenoceptors in the PVN. The stress-induced increase in PRA and PRC is mediated by different receptors whose ligands might be catecholamines acting at non-beta-receptors or other neuroactive substances colocalized in catecholaminergic nerve terminals.

Attenuation of latent inhibition after compound pre-exposure: associative and perceptual explanations.

Three experiments used rats as subjects and the conditioned emotional response (CER) paradigm to examine the effect of pre-exposure to a compound stimulus on the extent of latent inhibition to an element of that compound. In Experiment 1a a group of rats exposed to a compound that comprised a tone and a click exhibited less latent inhibition to the tone than did a group that had received pre-exposure to the tone in isolation. Experiment 1b showed that pre-exposure to the tone/click compound also resulted in an attenuation of latent inhibition to the click relative to a group that was pre-exposed to the click in isolation. Experiment 2 demonstrated that latent inhibition to the tone was left intact following pre-exposure to the tone in compound with a light. This pattern of results seems to be most plausibly explained in terms of the presence and absence of generalization decrement following compound pre-exposure.