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PubMed2003

Effects of apomorphine and clozapine on conditioned freezing and latent inhibition.

Consistent evidence has shown that learning may be produced in paradigms using electrical stimulation of the inferior colliculus as unconditioned stimulus (US). Much evidence has also been provided for the involvement of dopamine in the setting up of adaptive responses to aversive states generated at this mesencephalic level. The aim of the present study was to determine whether dopaminergic mechanisms are involved in the conditioned freezing behavior and latent inhibition (LI) using either foot shocks (Experiment 1) or inferior colliculus stimulation (Experiment 2) as US and light as conditioned stimulus (CS). To this end, the authors examined the effects of the dopaminergic agonist apomorphine (AP; 0, 0.5, 1.0, and 2.0 mg/kg) and the atypical antipsychotic clozapine (CLZ 0, 1.0, 2.5, and 5.0 mg/kg) on the acquisition of conditioned freezing and LI. Rats were either simply placed in the experimental chamber non-preexposed (NPE) or preexposed (PE) to 50 light presentations. Next, they were submitted to 10 light plus foot shock (or inferior colliculus stimulation) pairings. In the testing session, conditioned freezing under the CS was measured. In both experiments, conditioned freezing was highly significant in the NPE group while previous exposure to nonreinforced light (PE) weakened the strength of the conditioning. Although weaker than that caused by foot shock/light pairings, the occurrence of freezing and LI with the use of inferior colliculus stimulation as US gives additional support to the participation of this structure in the filtering processes of relevant information to higher brain regions. The drug effects depended on whether foot shock or inferior colliculus stimulation was used as US. In Experiment 1, AP produced a dose dependent increase in conditioned freezing without changing LI. On the other hand, CLZ did not change freezing and LI. In Experiment 2 while AP did not change freezing and LI, CLZ clearly increased freezing without changing LI with the use of inferior colliculus as US. The selective effect of AP on conditioned freezing due to light/foot shocks association is consistent with the heightened attentional and cognitive functions of dopaminergic mechanisms of the mesocorticolimbic systems in the setting up of adaptive responses aimed at coping with or signaling the presence of stimuli of aversive nature. The selective effect of CLZ on conditioned freezing is due to light/IC stimulation and may also be due to the known antagonism of 5-HT(2) receptors produced by low doses of this atypical antipsychotic.

Animals↗
PubMed1997

Reversal of spinal cord non-opiate analgesia by conditioned anti-analgesia in the rat.

The spinal cord contains endogenous substances (such as cholecystokinin, FMRFamide, etc.) that can block the analgesic effects of opiates. Anti-opiate actions have been most commonly studied by exogenous administration of receptor agonists and receptor antagonists of these substances. However, we have recently demonstrated that anti-analgesia can be brought under environmental control through Pavlovian conditioning. Whereas analgesia can be conditioned to signals for danger, anti-analgesia can be conditioned to signals for safety. Using this paradigm, we have previously demonstrated that conditioned anti-analgesia can reverse a variety of opiate analgesic states, including those produced by conditioned danger signals, systemic morphine, and intrathecal mu- and delta-opiate receptor agonists. These data raise the question of the generality of anti-analgesia actions. The present series of experiments examined the ability of conditioned anti-analgesia to affect non-opiate analgesic states induced by spinal delivery of GABA(A), GABA(B), 5HT2 + 5HT1, and 5HT3 receptor agonists. While conditioned anti-analgesia had no effect on GABA(A) or 5HT2 + 5HT1 non-opiate analgesias, conditioned anti-analgesia completely blocked GABA(B) and 5HT3 non-opiate analgesias. These findings clearly demonstrate that conditioned anti-analgesia can powerfully modulate non-opiate as well as opiate analgesias and bring into question whether putative anti-opiate neuroactive substances may have broader actions than previously suggested.

Analgesia, Epidural↗
PubMed2000

Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats.

Although the amygdala is known to be crucial for fear conditioning, little is known about the molecular and cellular mechanisms in the amygdala that are important for fear conditioning. One possible mechanism may be the activation of immediate-early genes, which function as regulatory factors of transcriptional processes. To investigate whether one of the major immediate-early gene families is involved in the learning and memory of fear, we examined the effects of fear conditioning on the expression of the four members of the early growth response (EGR) gene family, EGR-1, EGR-2, EGR-3, and EGR-4. Image analysis of in situ hybridization of messenger RNA of the four family members was performed in the amygdala, hippocampus, and neocortex 15, 30 and 60min following one-trial contextual fear conditioning. Rats were either handled, placed within the testing context without receiving the footshock, and received a footshock immediately upon placement within the context, or received a footshock after a 3-min delay (delayed-shock). Of the four groups, only the delayed-shock group exhibited a fear response (freezing). EGR-1 messenger RNA expression in the dorsolateral part of the lateral amygdaloid nucleus was significantly greater in the delayed-shock group compared with the other groups 15 and 30min following the conditioning. The increased expression of EGR-1 was specifically localized to the lateral nucleus of the amygdala; expression in the hippocampus and cortex was not increased by fear conditioning. In contrast, the expression of EGR-2, EGR-3, and EGR-4 messenger RNA was not increased in the amygdala, hippocampus or cortex following fear conditioning. In addition, following a retention test conducted 24h after fear conditioning, no increases were found in the expression of EGR-1 messenger RNA expression in the amygdala, hippocampus or cortex. The results demonstrate that of the four genes of the EGR family of transcription-regulatory factors, only EGR-1 messenger RNA in the dorsolateral portion of the lateral nucleus of the amygdala was specifically increased with contextual fear conditioning. It is suggested that EGR-1 plays a functional role during learning, but not retrieval, of contextual fear within the lateral nucleus of the amygdala.

Amygdala↗
PubMed2001

Selective responding of nucleus accumbens core and shell dopamine to aversively conditioned contextual and discrete stimuli.

Dopamine transmission within the nucleus accumbens has been implicated as a neurochemical substrate of associative learning processes. It has been suggested that the acquisition of classically conditioned fear to a specific environment, or context, differs fundamentally from the development of conditioned fear to a discrete stimulus, such as a light or a tone. In this study, we assessed extracellular dopamine in the rat nucleus accumbens shell and core during the expression of a conditioned fear response. Animals were aversively conditioned to either a context or a tone and extracellular dopamine was measured in the nucleus accumbens shell and core by in vivo microdialysis over the next 2 days as animals were returned first to the conditioning chamber (day 1: context test), and subsequently as animals were again returned to the chamber and presented with the conditioned tone stimulus (day 2: tone test). Dopamine levels in the core were significantly higher in the Context-Shock group compared to the Tone-Shock group during the 30-min exposure to context while dopamine levels in the nucleus accumbens shell did not differ significantly during the context test between groups. In contrast, extracellular dopamine in the shell but not the core of Tone-Shock animals increased significantly during presentation of the tone. Dopamine in both the shell and core remained unchanged during the tone test in the Context-Shock groups.These data suggest distinct roles for shell and core dopamine transmission in the expression of a conditioned emotional response. While dopamine increased in the shell primarily during the presentation of a discrete tone conditioned stimulus, core dopamine responded more to a contextual conditioned stimulus. These results may reflect differences in either the type of information acquired or the salience of the learned associations which are formed to a context vs. a discrete tone cue.

Acoustic Stimulation↗
PubMed1997

Salient responsiveness of parabrachial neurons to the conditioned stimulus after the acquisition of taste aversion learning in rats.

The pontine parabrachial nucleus is considered to be one of the most critical regions for the acquisition of conditioned taste aversion which is an associative learning of taste and illness. To further clarify the possible involvement of the parabrachial nucleus in conditioned taste aversion, we recorded neuronal responses to taste stimuli from the parabrachial nucleus of rats under deep urethane anaesthesia. Animals were separated into two groups: the conditioned taste aversion group that had acquired a taste aversion to 0.1 M NaCl (conditioned stimulus) after paired presentations of the taste stimulus with intraperitoneal injection of LiCl (unconditioned stimulus), and the control group that had received only the unconditioned stimulus before experiments. Taste-responsive neurons in the conditioned taste aversion group showed larger responses to NaCl at below 0.1 M, but similar responses to 0.3 M and 0.5 M NaCl when compared with those in the control group. Furthermore, hierarchical cluster analyses revealed a strong similarity among responses to sodium salts in neurons of the conditioned taste aversion group compared with the control group. These results suggest that the aversive conditioning to NaCl modified parabrachial units so that the sodium taste was more salient than other tastes. This modification may reflect a long-term plastic change persisting without support of forebrain structures, and would facilitate the gustatory discrimination of the conditioned stimulus, which is required by conditioned animals.

Animals↗
PubMedDate not supplied

The paradoxical hedonic valence of acute ethanol withdrawal (hangover) states in rats: place and taste conditioning.

The hedonic valence of EtOH's delayed effects, usually referred to as "hangover," was assessed 18 h after a 4 g/kg injection using both place and taste learning tasks. In the place conditioning task two CS-,CS+ intervals were used (48 h and 144 h); within each treatment interval, experimentally induced "hangover" was paired with the initially nonpreferred conditioning compartment for half of the experimental group (N = 10 rats) and with the initially preferred conditioning compartment for the half (N = 10 rats). Saline injections were paired with placement in the alternate conditioning compartment. A third group (N = 10 rats) was conditioned with milliliter equivalent volumes of saline on both sides. A conditioned place preference was conditioned with the hangover state-induced interoceptive stimuli. Attempts were made to taste condition 24 rats with the interoceptive stimulus attributes of hangover. Experimentally induced hangover was associated with an adipsogenic state, defined as a significant decline in voluntary intake of both saccharin and water, which prevented taste conditioning.

Animals↗
PubMedDate not supplied

Effects of prenatal ethanol exposure and early experience on radial maze performance and conditioned taste aversion in mice.

C57BL/6 mice were intubated on gestational days 14-18 twice daily with 1.58 g/kg ethanol, 4.2 g/kg sucrose, or remained untreated. Offspring of ethanol-treated or lab chow control groups were raised either by group-housed dams and weaned on postnatal day (PND) 28 (enriched condition), or by individually housed dams and weaned on PND 21 (standard condition). Offspring of the sucrose control group were raised by individually housed dams and weaned on PND 21. Groups did not differ in pup weight or litter size. Male and female offspring were assessed for performance in an unbaited radial maze (PND 45-52) and male offspring only were tested for conditioned taste aversion (PND 54-59). As hypothesized, mice prenatally exposed to ethanol and raised under standard conditions failed to develop the conditioned taste aversion response. In contrast, subjects with in utero ethanol exposure that were raised under enriched preweaning conditions developed the taste aversion response. Maze performance improved significantly over days, but no significant effects were detected for either prenatal treatment or preweaning rearing conditions. In conclusion, enriched preweaning rearing conditions abolished the detrimental effects of prenatal ethanol exposure on conditioned taste aversion, but radial maze performance remained unaffected by any treatment in this study.

Analysis of Variance↗
PubMed1998

Clonidine blocks acquisition but not expression of conditioned opiate withdrawal in rats.

Previous studies in rodents have reported that clonidine, an alpha 2-adrenergic receptor agonist, attenuated conditioned aversions to naloxone-precipitated opiate withdrawal when administered prior to each withdrawal conditioning episode. The current study was designed to determine whether clonidine could modify the expression of previously established conditioned place aversions and conditioned suppression of operant responding. Dose- and time-dependent effects of clonidine on activity and suppression of operant responding for food identified appropriate treatment parameters for subsequent studies in which rats rendered dependent on opiates through implantation of morphine pellets were tested for: (1) conditioned place aversion; and (2) conditioned suppression of operant responding for food (fixed ratio-15 schedule), in a paradigm wherein rats received four pairings of naloxone with a distinct tone and odor stimulus. Clonidine dose-dependently blocked the acquisition of both conditioned behaviors when administered prior to naloxone on each conditioning trial, but was ineffective in blocking the expression of these conditioned withdrawal signs when administered prior to the test session.

Adrenergic alpha-Agonists↗
PubMed1982

Allocation of cognitive processing capacity during human autonomic classical conditioning.

In each of two experiments, allocation of cognitive processing capacity was measured in college-student subjects during autonomic discrimination classical conditioning. A 7.0-sec delay paradigm was used to establish classically conditioned responses to a reinforced visual conditioned stimulus (CS+). Electrodermal responses were the primary measures of autonomic classical conditioning. Allocation of processing capacity was measured by monitoring performance on a secondary reaction-time (RT) task. The auditory secondary-task RT signal was presented before, and 300, 500, 3500, 6500, and 7500 msec following CS onset. The RT signal was also presented following properly and improperly cued shock unconditioned stimuli (UCSs). Significant discrimination classical conditioning was obtained in both experiments. Comparison with control subjects who did not receive the RT signals indicated that the presence of the RT signals did not interfere with the development of classical conditioning. Four principal findings were obtained with the secondary-task RT measure. First, RTs to signals presented during CS+ were consistently slower than RTs to signals presented during CS-. This finding indicates that greater capacity allocation occurred during CS+ than CS- and is consistent with recent cognitive interpretations of classical conditioning. Second, the largest capacity allocation (i.e., slowing of RTs) occurred 300 msec following CS+ onset. This finding is consistent with the notion that subjects are actively processing the signal properties of the CS+ at 300 msec following CS+ onset. Third, presentation of the UCS when improperly cued (following CS-) significantly increased capacity allocation, whereas presentation of the same UCS when properly cued (following CS+) did not affect capacity allocation. These findings indicate that subjects were actively prepared for the UCS following CS+ but not following CS- and that a surprising UCS elicits greater capacity allocation than does an expected UCS. Fourth, large electrodermal responders to the CSs exhibited patterns of capacity allocation during the CSs, particularly during the CS+, different from those of small electrodermal responders. In particular, they exhibited significantly longer RTs at 300 msec after CS+ onset than did the small responders, followed by a shortening of RT at 500 msec relative to the small responders. This finding suggests that large electrodermal responders devote greater processing capacity to significant environmental stimuli than do small responders and that their processing may begin and be completed more rapidly. All in all, the data indicate the complexity of the cognitive processes that occur during human classical conditioning and the usefulness of the secondary-task technique in integrating conditioning theories and psychophysiology with cognitive psychology.

Animals↗
PubMed1985

Conditioned suppression tests of the context-blocking hypothesis: testing in the absence of the preconditioned context.

Two experiments are reported that use rats in a conditioned suppression situation. The experiments, designed to remove confounds that have complicated interpretations of prior research, tested the context-blocking hypothesis, the proposition that static apparatus cues or conditioning contexts can block conditioning to discrete conditioned stimuli (CSs). Experiment 1, like previous work, tested for conditioning to the target CS in the same context that had been preconditioned and in which target conditioning had occurred; the experiment demonstrated a context-blocking like effect. Experiment 2 tested for conditioning not only in the preconditioned context but also in a nonpreconditioned context. Evidence for context blocking appeared similar in the two test situations. This suggests that conditioned contexts block the acquisition of associative strength by discrete CSs at the time of target conditioning (e.g., Rescorla & Wagner, 1972) and not through performance factors at the time of testing (e.g., Gibbon & Balsam, 1981).

Animals↗
PubMed1995

Role of stimulus ambiguity in conditional learning.

Three experiments using rats and the conditioned emotional response procedure examined the notion that when a conditioned stimulus (CS) is paired with a reinforcer (US), that CS must be ambiguous if the CS-US association is to become the target of conditional control. CS ambiguity was manipulated by varying whether the CS had been preexposed prior to conditioning. In Experiments 1 and 2, it was demonstrated that a cue that accompanied pairings of a CS and shock acquired conditional control over the CS-shock association when that CS had been preexposed, but not when it was novel. The measure of conditional control in Experiments 1 and 2 was the ability of the (conditional) cue to enhance responding to the target CS. Experiment 3 used a blocking procedure to show that this enhancement reflected an amplification of the target CS's effective associative strength. These findings extend existing knowledge of the conditions required for conditional cue formation.

Animals↗
PubMed1990

Lesions of the cerebellar vermis and cerebellar hemispheres: effects on heart rate conditioning in rats.

The effects of lesions of the cerebellum on the acquisition of heart rate (HR) conditioned responses (CRs) were examined in rats. Large lesions of the cerebellar vermis severely attenuated the acquisition of differentially conditioned bradycardic responses in restrained rats without affecting unconditioned HR responses to the tone conditioned stimuli (CSs) or the shock unconditioned stimulus (UCS). In a second experiment, rats were trained unrestrained, and under these conditions the CR was tachycardia in control animals. Lesions of the vermis again severely attenuated acquisition of this CR without affecting unconditioned responses to the CSs or UCS. Bilateral lesions of the cerebellar hemispheres did not affect HR conditioning in either test procedure. It is concluded that the vermis of the cerebellum is an essential component of an HR conditioning circuit in the rat. The cerebellar hemispheres, which are critically involved in some discrete somatomotor CRs, apparently have no essential functional contribution to HR conditioning. The results of these experiments implicating the midline cerebellar vermis in autonomic conditioning are discussed in relation to contributions from a forebrain system involved in HR conditioning and in relation to lateral cerebellar contributions to discrete somatomotor CRs.

Animals↗
PubMed1992

Stimulation at a site of auditory-somatosensory convergence in the medial geniculate nucleus is an effective unconditioned stimulus for fear conditioning.

The medial division of the medial geniculate nucleus (MGm) and the posterior intralaminar nucleus (PIN) are necessary for fear conditioning to an auditory conditioned stimulus (CS), receive both auditory and somatosensory input, and project to the amygdala, which is involved in production of fear conditioned responses. If CS-unconditioned stimulus (US) convergence in the MGm-PIN is critical for fear conditioning, then microstimulation of this area should serve as an effective US during classical conditioning, in place of standard footshock. Guinea pigs underwent conditioning (40-60 trials) using a tone as the CS and medial geniculate complex microstimulation as the US. Conditioned bradycardia developed when the US electrodes were in the PIN. However, microstimulation was not an effective US for conditioning in other parts of the medial geniculate or for sensitization training in the PIN or elsewhere. Learning curves were similar to those found previously for footshock US. Thus, the PIN can be a locus of functional CS-US convergence for previously for footshock US. Thus, the PIN can be a locus of functional CS-US convergence for fear conditioning to acoustic stimuli.

Amygdala↗
PubMed1994

Ontogeny of contextual fear conditioning in rats: implications for consolidation, infantile amnesia, and hippocampal system function.

The authors present developmental evidence that contextual fear conditioning is supported by a short-term memory system that supports conditioning immediately after a shock and by a long-term memory system that supports contextual conditioning 24 hr after training. This is based on the finding that after 1 conditioning trial, rats 18 to 32 days old show the same amount of conditioned freezing when tested immediately after conditioning but 18-day-old rats show much less conditioned freezing than the older rats when the retention interval is 24 hr. The data also suggest that the long-term memory representation of context that mediates conditioned fear is not available until several hours after the conditioning trial. Implications of these findings for memory consolidation processes, infantile amnesia, and hippocampal formation development are discussed.

Aging↗
PubMed2003

Conditional discrimination learning in patients with bilateral medial temporal lobe amnesia.

The ability of bilateral medial temporal lobe amnesic patients (MT; n=8) and normal participants (NC; n=8) to acquire a conditional discrimination in trace and delay eyeblink conditioning paradigms was investigated. Experiment 1 assessed trace conditional discrimination learning by using a light conditional stimulus (S+/S-) and tone conditioned stimulus (CS) separated by a 1-s trace. NCs responded differentially on S+ trials (mean percent conditioned responses=66) versus S- trials (30). Whereas MTs were impaired in their acquisition of the conditional discrimination (S+ =51, S- =43). In Experiment 2, the temporal separation was eliminated. NCs acquired the conditional discrimination (S+ =70, S- =29). MTs were unable to respond differentially (S+ =42, S- =37). The findings indicate that the hippocampal system is essential in acquiring a conditional discrimination, even in a delay paradigm.

Adult↗
PubMed1980

Flavor preexposures in a conditioned taste aversion situation: a dissociation of behavioral and endocrine effects in rats.

A series of experiments examined the effects of flavor preexposures on pituitary-adrenal/behavior relations in a conditioned taste aversion paradigm. It was found that reexposure to a novel milk solution paired earlier with lithium chloride (LiCl) elicited conditioned activation of the pituitary-adrenal system (Experiment 1). The unconditioned response to LiCl (measured by changes in plasma levels of corticosterone) did not vary as a function of prior (2 and 5 vs. 10) exposures to the milk solution (Experiment 2). Increased familiarity with the substance (resulting from 10 prior exposures) rendered the conditioning of a taste aversion to this substance less effective. Further, reexposure to this familiar substance after its pairing with LiCl was not accompanied by the characteristic conditioned pituitary-adrenal activation (Experiment 3). By titrating the number of conditioned stimulus (CS) preexposures (Experiment 4) it was found that within the range of preexposures manipulated (5-10), subjects exhibited (a) a coupling of behavioral and pituitary-adrenocortical responses when the conditioned taste aversion to the milk solution was paralleled by elevated plasma corticosterone (5-6 preexposures), (b) a coupling of these two response systems when flavor consumption was accompanied by suppressed plasma titers of corticoids (9-10 preexposures), or (c) a dissociation of the two system when the conditioned taste aversion was not accompanied by conditioned adrenocortical activity (7-8 preexposures). These data are discussed in terms of a dissociation in the effects of CS preexposures on conditioned adrenocortical and behavioral response systems.

Adrenocorticotropic Hormone↗
PubMed1981

Septal correlates of conditioned inhibition and excitation in rats.

Multiple-unit activity was recorded in the lateral septum of rats during Pavlovian differential conditioning. In Experiment 1, one group of animals received a classical aversive discrimination paradigm, while another group was presented with a control procedure in which the unconditioned stimuli (shocks) were administered randomly with regard to the conditioned stimuli. Septal unit activity increased during presentations of the conditioned inhibitor and was markedly suppressed during presentations of the conditioned excitor in the conditioning-group animals and not in the control animals. Baseline activity remained unchanged in the conditioning group but was suppressed in the random control group. Furthermore, termination of the aversive stimuli was marked by a burst of firing in the conditioning group, but no such rebound was seen in the control group. In Experiment 2, a classical appetitive discrimination paradigm was given, in which septal unit activity was found to increase in the presence of the conditioned excitor and was suppressed in the presence of the conditioned inhibitor. The results are interpreted as indicating a role for the septum in the relief of aversive states.

Animals↗
PubMed2003

Trace eyeblink conditioning in decerebrate guinea pigs.

We investigated the trace eyeblink conditioning in decerebrate guinea pigs to elucidate the possible role of the cerebellum and brainstem in this hippocampus-dependent task. A 350-ms tone conditioned stimulus was paired with a 100-ms periorbital shock unconditioned stimulus with a trace interval of either 0, 100, 250 or 500 ms. Decerebrate animals readily acquired the conditioned response with a trace interval of 0 or 100 ms. Even in the paradigm with a 500-ms trace interval, which is known to depend critically on the hippocampus in all animal species examined, the decerebrate guinea pigs acquired the conditioned response, which had adaptive timing as well as in the other paradigms with a shorter trace interval. However, it took many more trials to learn in the 500-ms trace paradigm than in the shorter trace interval paradigms, and the conditioned response expression was unstable from trial to trial. When decerebrate animals were conditioned step by step with a trace interval of 100, 250 and 500 ms, sequentially, they easily acquired the adaptive conditioned response to a 500-ms trace interval. However, the frequency of conditioned responses decreased after the trace interval was shifted from 250 ms to 500 ms, which was not observed after the shift from 100 ms to 250 ms. These results suggest that the cerebellum and brainstem could maintain the 'trace' of the conditioned stimulus and associate it with the unconditioned stimulus even in the 500-ms trace paradigm, but that the forebrain might be required for facilitating and stabilizing the association.

Adaptation, Psychological↗