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PubMed2006

Drugs, sweat, and fears: a comparison of the effects of diazepam and methylphenidate on fear conditioning.

RATIONALE: Classical conditioning of a fear response involves the formation of an association between a stimulus and an emotional response and can be seen as a basic form of emotional memory. While both benzodiazepines and stimulant drugs may influence the formation of episodic memories for emotional events, their effects on fear conditioning are less clear. OBJECTIVES: This study compared the effects of diazepam with methylphenidate on fear conditioning. MATERIALS AND METHODS: In a single-session between groups design with three conditions [placebo, diazepam (10 mg), and methylphenidate (40 mg)], classical conditioning of a skin conductance response to a visual stimulus previously paired with a 100-db white noise was tested in 45 healthy volunteers. RESULTS: Diazepam blocked fear conditioning, despite responses to the unconditioned aversive stimulus and neutral control stimulus being unimpaired. Conditioning remained intact after methylphenidate. Conditioned responses were not extinguished completely by the end of the experiment, and it was not possible to draw conclusions about the effects of the drugs on extinction. CONCLUSIONS: Although diazepam has well-documented amnesic effects, it has not been found to affect implicit forms of memory like perceptual and conceptual priming. As the present study found impaired fear conditioning after diazepam, it adds weight to recent findings that emotional memories are disproportionately impaired by the benzodiazepines.

Adult↗
PubMed2003

Auditory-evoked spike firing in the lateral amygdala and Pavlovian fear conditioning: mnemonic code or fear bias?

Amygdala neuroplasticity has emerged as a candidate substrate for Pavlovian fear memory. By this view, conditional stimulus (CS)-evoked activity represents a mnemonic code that initiates the expression of fear behaviors. However, a fear state may nonassociatively enhance sensory processing, biasing CS-evoked activity in amygdala neurons. Here we describe experiments that dissociate auditory CS-evoked spike firing in the lateral amygdala (LA) and both conditional fear behavior and LA excitability in rats. We found that the expression of conditional freezing and increased LA excitability was neither necessary nor sufficient for the expression of conditional increases in CS-evoked spike firing. Rather, conditioning-related changes in CS-evoked spike firing were solely determined by the associative history of the CS. Thus, our data support a model in which associative activity in the LA encodes fear memory and contributes to the expression of learned fear behaviors.

Action Potentials↗
PubMed2004

Behavioural and cardiovascular responses during latent inhibition of conditioned fear: measurement by telemetry and conditioned freezing.

This study assessed freezing behaviour and cardiovascular responses during the expression of latent inhibition of conditioned fear. Animals that were either repeatedly preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (non-preexposed; NPE) subsequently experienced three presentations of the tone paired with footshock. Animals were tested 24 h later in the context of the footshock chamber, and on the following day, in the presence of the tone CS. Changes in heart rate and blood pressure were recorded by radio-telemetry. The PE rats spent more time freezing to the conditioned contextual cues and exhibited higher blood pressures during the last half of the context test session than did the NPE animals. During the tone test, the PE rats exhibited less conditioned freezing to the tone CS compared with the NPE animals, i.e. expression of the latent inhibition. This behavioural effect was associated with a significant increase in heart rate, but not blood pressure, in the PE but not the NPE animals. Our results suggest that the increased blood pressures of the PE rats during the context test directly reflect their greater fear of the conditioning context. In contrast, the increased heart rate response but decreased freezing shown by PE rats in response to the tone CS may be due to the fact that lower stress levels (e.g. PE condition) elicit sympathetically-mediated increases in heart rate, whereas higher stress levels (e.g. NPE condition) activate both sympathetic and parasympathetic systems, thus eliminating any CS-induced increase in heart rate in the NPE rats.

Animals↗
PubMedDate not supplied

Body temperature as a conditional response measure for pavlovian fear conditioning.

On six days rats were exposed to each of two contexts. They received an electric shock in one context and nothing in the other. Rats were tested later in each environment without shock. The rats froze and defecated more often in the shock-paired environment; they also exhibited a significantly larger elevation in rectal temperature in that environment. The rats discriminated between each context, and we suggest that the elevation in temperature is the consequence of associative learning. Thus, body temperature can be used as a conditional response measure in Pavlovian fear conditioning experiments that use footshock as the unconditional stimulus.

Animals↗
PubMed2005

Lesions of the basal amygdala block expression of conditioned fear but not extinction.

Although the role of the amygdala in acquisition of conditioned fear is well established, there is debate concerning the intra-amygdala circuits involved. The lateral nucleus of the amygdala (LA) is thought to be an essential site of plasticity in fear conditioning. The LA has both direct and indirect [via the basal nuclei; basal amygdala (BA)] projections to the central nucleus (Ce) of the amygdala, an essential output for fear behaviors. Lesions of the LA or Ce prevent acquisition of conditioned freezing to a conditioned stimulus, but BA lesions do not, suggesting that the BA is not normally involved in fear conditioning. If true, posttraining BA lesions should also have no effect. Replicating previous studies, we found that rats given electrolytic BA lesions before training acquired conditioned fear normally. They also showed normal long-term retention and extinction of conditioned fear. Unexpectedly, BA lesions made after training completely blocked expression of conditioned fear. Despite this deficit, lesioned rats were able to learn a new tone-shock association. Thus, although the LA-Ce system is sufficient for fear acquisition in the absence of the BA, it is not sufficient when the BA is present, suggesting that the BA is an important site of plasticity in fear conditioning. The pattern of lesion deficits we observed (after but not before training) might be explained by homeostatic mechanisms that balance plasticity over multiple inputs, regulating the influence of the BA and LA onto Ce output neurons.

Amygdala↗
PubMed2001

Conditioned fear stimuli reinstate cocaine-induced conditioned place preference.

These studies examined the ability of a conditioned stimulus previously paired with footshock to reinstate cocaine-induced conditioned place preference. Male rats were given either odor or tone in a paired (PRD group) or explicitly unpaired (random, RND group) manner with footshock. All rats were subsequently trained in a cocaine conditioned place preference (CPP) task. Cocaine CPP was demonstrated in all groups. After CPP extinction, presentation of the conditioned fear stimulus produced a greater degree of reinstatement in PRD rats compared to the RND group. This was true whether the conditioned stimulus was odor or tone, but when odor was used as the conditioned stimulus, the RND group also partially reinstated cocaine CPP. In rats trained with tone as the conditioned stimulus, presentation of the tone during the test for reinstatement produced robust reinstatement of cocaine CPP only in the PRD, but not RND, group. In contrast, a subsequent priming injection with cocaine reinstated cocaine CPP equally in both RND and PRD groups. These studies indicate for the first time that conditioned fear stimuli induce reinstatement of cocaine CPP, and suggest that stimuli associated with prior stress may produce relapse in humans.

Animals↗
PubMedDate not supplied

Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice.

Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear conditioning mice with three pairings of a white noise conditional stimulus (CS) with moderate footshock, we injected the D2 antagonist, sulpiride, the D2 agonist, quinpirole, or vehicle, just before repeated CS presentations to generate extinction. We assayed fear by measuring behavioral freezing during extinction presentations and then drug-free during CS presentations 1 d later. We found that sulpiride injections before extinction training facilitated extinction memory 24 h later, while quinpirole partially blocked extinction memory compared with vehicle-injected controls. Notably, sulpiride treatment yielded significant extinction after spaced CS presentations, which yield no extinction at all in vehicle-treated mice. These findings suggest that dopamine D2-mediated signaling contributes physiological inhibition of extinction, and that D2 antagonists may be useful adjuncts to behavior therapy of human anxiety disorders.

Animals↗
PubMed1993

A dissociation between the proactive ECS effects on inhibitory avoidance learning and on classical fear conditioning.

This study investigated if the nature of the task is a determinant factor of whether or not a series of electroconvulsive shock (ECS) will proactively affect learning in animals. Rats were administered one daily ECS for 7 days. A day after the last administration they were concomitantly trained on an inhibitory avoidance task and on classical conditioning of fear response to a brief tone. Twenty-four hours later they were exposed for 8 min to an open-field arena and the freezing reaction was measured both before and after tone presentation (classical fear conditioning test). On the subsequent day the step-through latency (without presentation of the tone) was measured on the avoidance apparatus (inhibitory avoidance test). Impairment of inhibitory avoidance was seen in ECS-administered animals in comparison to controls, but the freezing reaction to the tone was equally high in both groups. Additional groups of rats were trained in order to control for ECS alone-induced freezing and pseudoconditioning. Also, it was demonstrated that the differential ECS effects on the two tasks were not due to the order of testing since similar dissociation was obtained when inhibitory avoidance test was conducted before the open-field test.

Animals↗
PubMed2002

Slow late component in conditioned stimulus-evoked potentials from the amygdala after fear conditioning in the rat.

Male Wistar rats were subjected to a differential Pavlovian fear conditioning procedure in which one of two tones (6 or 10 kHz) was followed by an electric shock (CS+) and the other was not (CS-). Before and after fear conditioning, we recorded the evoked potentials elicited by CS+ and CS- from electrodes aimed at the lateral nucleus of the amygdala. Before conditioning, a slow, negative component with peak amplitude around 150 ms was present in the evoked potentials. This component was sensitive to habituation. After fear conditioning, both CS+ and CS- elicited the same late component, albeit with a larger amplitude. This enhancement was temporary: decreasing amplitude was observed in the course of CS test presentations under extinction. Prior research revealed a comparable slow component in the amygdala of the cat under similar experimental conditions. The collective results indicate that the large late component in the amygdala is enhanced by fear conditioning, suggesting that such enhancement reflects the anticipation of a biologically significant event.

Acoustic Stimulation↗
PubMed2003

Nicotine enhances contextual fear conditioning in C57BL/6J mice at 1 and 7 days post-training.

Nicotine has been demonstrated to enhance learning processes. The present experiments extend these results to examine the effects of nicotine on acquisition and consolidation of contextual and cued fear conditioning, and the duration of nicotine's enhancement of conditioned fear. C57BL/6 mice were trained with two pairings of an auditory CS and a foot shock US. Multiple doses of nicotine were given before or immediately after training and on testing day (0.0, 0.050, 0.125, 0.250, and 0.375 mg/kg, i.p). Freezing to both the context and auditory CS was measured 24h after training and again 1 week after training. Mice did not receive nicotine for the 1-week retest. Nicotine (0.125 and 0.250 mg/kg) given on both training and testing days enhanced freezing to the context at 24h. In addition, elevated freezing to the context was seen 1 week post-training in mice previously treated with 0.125 and 0.250 mg/kg nicotine. Thus, nicotine-treated mice did show elevated levels of freezing when retested 1 week later, even though no nicotine was administered at the 1-week retest. Mice that received nicotine on training day or testing day only and mice that received nicotine with mecamylamine, a nicotinic receptor antagonist, were not different from saline-treated mice. In addition, post-training administration of nicotine did not enhance fear conditioning. The present results indicate that nicotine enhancement of contextual fear conditioning depends on administration of nicotine on training and test days but results in a long-lasting enhancement of memories of contextual fear conditioning that remains in the absence of nicotine.

Age Factors↗
PubMed1996

Conditioned stimulus determinants of conditioned response form in Pavlovian fear conditioning.

Four experiments using barpress conditioned suppression in rats found that tone evoked more freezing (immobility) than did light. Still, tone and light appeared to have similar conditioned value as assessed by suppression in Experiments 1, 2, and 3, and by blocking, second-order conditioning, and overconditioning assays in Experiments 1, 2, and 3, respectively. Experiment 4 arranged for tone to evoke less suppression than light but more freezing. Results suggest that in fear conditioning, the nature of the conditioned stimulus affects the form of conditioned responding (strong vs. weak freezing). This conclusion extends one drawn by P. C. Holland (1977) on the basis of his work in appetitive conditioning.

Animals↗
PubMed2007

Amygdala upregulation of NCAM polysialylation induced by auditory fear conditioning is not required for memory formation, but plays a role in fear extinction.

There is much interest to understand the mechanisms leading to the establishment, maintenance, and extinction of fear memories. The amygdala has been critically involved in the processing of fear memories and a number of molecular changes have been implicated in this brain region in relation to fear learning. Although neural cell adhesion molecules (NCAMs) have been hypothesized to play a role, information available about their contribution to fear memories is scarce. We investigate here whether polysialylated NCAM (PSA-NCAM) contributes to auditory fear conditioning in the amygdala. First, PSA-NCAM expression was evaluated in different amygdala nuclei after auditory fear conditioning at two different shock intensities. Results showed that PSA-NCAM expression was increased 24 h post-training only in animals subjected to the highest shock intensity (1mA). Second, PSA-NCAM was cleaved in the basolateral amygdaloid complex through micro-infusions of the enzyme endoneuraminidase N, and the consequences of such treatment were investigated on the acquisition, consolidation, remote memory expression, and extinction of conditioned fear memories. Intra-amygdaloid cleavage of PSA-NCAM did not affect acquisition, consolidation or expression of remote fear memories. However, intra-amygdaloid PSA-NCAM cleavage enhanced fear extinction processes. These results suggest that upregulation of PSA-NCAM is a correlate of fear conditioning that is not necessary for the establishment of fear memory in the amygdala, but participates in mechanisms precluding fear extinction. These findings point out PSA-NCAM as a potential target for the treatment of psychopathologies that involve impairment in fear extinction.

Acoustic Stimulation↗
PubMed1998

Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning.

A role for corticosterone in the consolidation of contextual fear conditioning has previously been proposed. In this study, physiological evidence was found to support this view. The extent of conditioned fear and the levels of plasma corticosterone in rats, after context exposure at training and at different posttraining times (24 hr and 7 days), depended on the intensity of the unconditional stimulus (footshock). In each experimental session, a positive correlation was found between the magnitude of corticosterone levels and the fear-related behavioral inhibition exhibited in the context. Results support the involvement of corticosterone on the processes that occur during consolidation in determining the strength at which the contextual fear conditioning is stored as a long-term memory.

Analysis of Variance↗
PubMed1989

The effect of hypocapnia on extinction of conditioned fear responses.

Conditioning models have been very helpful in the understanding of the etiology and maintenance of anxiety. Such laboratory models, however, leave unexplained why in many cases of naturally occurring anxiety, as in the case of agoraphobia, the fear responses do not extinguish. Literature on experimental anxiety provocation suggests that a systemic alkalosis might play a role in the maintenance of phobic fear. It was hypothesized that a subject in a state of respiratory alkalosis would show delayed extinction to classical conditioned anxiety. In a differential classical conditioning paradigm, consisting of a habituation-, an acquisition-, and an extinction-phase, slides and electric shocks were used as conditioned stimuli (CS) and unconditioned stimuli (US) respectively. The skin conductance response was taken as (U)CR. Subjects were randomly assigned to two groups: hyperventilation or control. It was shown that the extinction was not delayed when subjects were hypocapnic during the extinction. These data support the view that a respiratory alkalosis per se is not a sufficient condition for the maintenance of neurotic fears. The data of the present study are discussed in the context of existing literature on a psychological interpretation of the maintenance of anxiety.

Adult↗
PubMed2006

Behavioral, central monoaminergic and hypothalamo-pituitary-adrenal axis correlates of fear-conditioned analgesia in rats.

Fear-conditioned analgesia is an important survival response which is expressed upon re-exposure to a context previously paired with a noxious stimulus. The aim of the present study was to characterize further the behavioral, monoaminergic and hypothalamo-pituitary-adrenal axis alterations associated with expression of fear-conditioned analgesia. Rats which had received footshock conditioning 24 h earlier, exhibited reduced formalin-evoked nociceptive behavior upon re-exposure to the footshock chamber, compared with non-footshocked formalin-treated rats. Intra-plantar injection of formalin reduced the duration of contextually-induced freezing and 20-40 kHz ultrasound emission. Intra-plantar injection of formalin to non-footshocked, non-conditioned rats did not induce ultrasonic vocalizations. Intra-plantar injection of formalin to footshock-conditioned rats, significantly increased tissue levels of 3,4-dihydroxyphenylacetic acid and the 3,4-dihydroxyphenylacetic acid:dopamine ratio in the periaqueductal gray and reduced levels of dopamine in the thalamus, compared with saline-treated footshocked controls. Non-footshocked, non-conditioned rats were capable of mounting a robust formalin-evoked increase in plasma corticosterone levels. Moreover, plasma corticosterone levels were significantly higher in saline-treated, footshock conditioned rats compared with saline-treated non-footshocked rats and levels did not differ between saline- and formalin-treated footshock conditioned rats. Assessment of the effects of the intra-plantar injection procedure revealed an attenuation of short-term extinction of contextually-induced freezing in rats anesthetized for intra-plantar injection of saline compared with non-anesthetized, non-injected rats as well as discrete effects on monoamines, their metabolites and plasma corticosterone levels. These data extend behavioral characterization of the phenomenon of fear-conditioned analgesia and suggest that measurement of ultrasound emission may be used as an ethologically relevant index of the defense response during fear-conditioned analgesia. Ultrasonic vocalization may also be a useful behavioral output to aid separation of nociception and aversion. The data provide evidence for discrete alterations in dopaminergic activity in the periaqueductal gray and thalamus and for altered hypothalamo-pituitary-adrenal axis activity following expression of defensive behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning.

Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, egr-1, is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that egr-1 and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To directly test this hypothesis, an egr-1 antisense oligodeoxynucleotide (antisense-ODN) was injected bilaterally into the amygdala prior to contextual fear conditioning. The antisense-ODN reduced Egr-1 protein in the amygdala and interfered with fear conditioning. A 250-pmole dose produced an 11% decrease in Egr-1 protein and reduced long-term memory of fear as measured by freezing in a retention test 24 h after conditioning, but left shock-induced freezing intact. A larger 500-pmole dose produced a 25% reduction in Egr-1 protein and significantly decreased both freezing immediately following conditioning and freezing in the retention test. A nonsense-ODN had no effect on postshock or retention test freezing. In addition, 500 pmole of antisense-ODN infused prior to the retention test in previously trained rats did not reduce freezing, indicating that antisense-ODN did not suppress conditioned fear behavior. Finally, rats infused with 500 pmole of antisense-ODN displayed unconditioned fear to a predator odor, demonstrating that unconditioned freezing was unaffected by the antisense-ODN. The data indicate that the egr-1 antisense-ODN interferes with learning and memory processes of fear without affecting freezing behavior and suggests that the inducible transcription factor Egr-1 within the amygdala plays important functions in long-term learning and memory of fear.

Amygdala↗
PubMed1991

N-methyl-D-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning.

The role of N-methyl-D-aspartate (NMDA) receptors in Pavlovian fear conditioning was examined using the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV). Either APV (5 micrograms/rat) or saline was administered before the training phase, the testing phase, or both. APV completely blocked acquisition but not expression of fear conditioning. The L enantiomer of APV did not affect the acquisition of conditional fear. To separate encoding from consolidation processes, APV was administered either before or immediately after the footshock unconditional stimulus (US) during the training phase. The results indicate that APV must be present during the US to produce its effects on fear conditioning. The behavioral effect of the drug is not due to analgesic action because APV did not alter pain sensitivity. The data suggest that NMDA receptors are critical for the acquisition but not expression of fear conditioning. These effects on fear conditioning are parallel to the in vitro effects of APV on the acquisition but not expression of long-term potentiation (LTP) and suggest that endogenously generated NMDA-dependent LTP participates in the neural plasticity underlying fear conditioning.

2-Amino-5-phosphonovalerate↗
PubMed2005

Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate.

Conditioned fear is an artificial stress, induced by a stimulus, such as a tone, that does not elicit fear in nature. This fear response is acquired by experimental animals when tone is combined with an unconditioned stimulus, such as electrical foot shock. The amygdala is considered to be the area involved in acquisition, consolidation and recall of fear. A series of previous pharmacological studies showed antagonists of dopamine D1 and D2, glutamate N-methyl-D-asparatate and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors to prevent the acquisition of conditioned fear. However, little is known about the types of neurotransmitters released when conditioned fear is acquired and recalled. The present study was designed to continuously monitor changes in extracellular levels of glutamate, dopamine and serotonin in the amygdala, at the acquisition of conditioned fear on Day 1 and at fear recall in response to a tone as a conditioned stimulus on Day 2, using the in vivo microdialysis method. Glutamate was elevated only on Day 1, while dopamine and serotonin rose on both days. The periods of elevated dopamine and serotonin were longer on Day 1 than on Day 2. These results suggest that greater amounts of glutamate, dopamine and serotonin are necessary for acquisition than for recall of conditioned fear.

Amygdala↗