Biomedical subjects

R F Westbrook

Publications and source records attributed to R F Westbrook.

At least 19 recordsLinked to original sources

PubMed2006

Carbachol injections into the nucleus accumbens disrupt acquisition and expression of fear-potentiated startle and freezing in rats.

The nucleus accumbens is involved in different types of emotional learning, ranging from appetitive instrumental learning to Pavlovian fear conditioning. In previous studies, we found that temporary inactivation of the nucleus accumbens blocked both the acquisition and expression of conditioned fear. This was not due to altered dopaminergic activity as we have also found that intra-nucleus accumbens infusions of the dopamine agonist amphetamine do not affect either the acquisition or the expression of conditioned fear. Therefore, in the present study we examined whether cholinergic activity in the nucleus accumbens is involved in the acquisition and expression of conditioned fear. Specifically, the effect of intra-nucleus accumbens infusions of the unselective cholinergic agonist carbachol on the acquisition and expression of conditioned fear was assessed. Across several experiments, we measured fear to visual and acoustic conditioned stimuli and to the experimental context. Further, two different measures of conditioned fear were recorded: fear potentiation of startle and freezing. Intra-nucleus accumbens carbachol infusions disrupted acquisition as well as expression of conditioned fear, regardless of the modality of the fear-eliciting stimulus or of the specific measure of conditioned fear. This disruption of conditioned fear was not simply a by-product of enhanced motor activity which also occurred after intra-nucleus accumbens carbachol infusions. Interestingly, despite the substantial effect of intra-nucleus accumbens carbachol on expression of conditioned fear, the results of the final experiment suggest that these rats extinguish similarly to control rats. Taken together, the present results indicate that acetylcholine within the nucleus accumbens is important for the learning and retrieval of conditioned fear.

Acetylcholine↗

PubMed2001

Contextual control over the expression of fear in rats conditioned under a benzodiazepine.

RATIONALE: Benzodiazepines disrupt fear conditioning, but this disruption is context-specific; if rats have been conditioned under a benzodiazepine, their fear is recovered if they are tested in a different context. The present experiments investigated how the conditioning context controls fear in rats conditioned under a benzodiazepine. OBJECTIVES: The experiments had three aims: (1) to replicate the finding that fear is recovered when rats are tested in a different context, (2) to test whether the conditioning context reduces fear generally or only for the specific stimulus conditioned in that context and (3) to test whether latent inhibition of the conditioning context reduces its control over fear. METHODS: Rats were injected with the benzodiazepine midazolam (1.25 mg/kg) or saline and exposed to a conditioned stimulus (CS) and shock in a distinctive chamber. Latent inhibition of the chamber was induced by extensively preexposing the rats to the chamber. The day after conditioning, fear was assessed by presenting the CS while rats were in either the conditioning chamber or a different chamber. RESULTS: The midazolam-induced reduction of fear was reversed (i.e. fear was partially recovered) if rats were tested in the different context, and was completely prevented if the conditioning context had been latently inhibited. These two effects were not additive since, when the conditioning context had been latently inhibited, rats showed less fear in the different context than in the conditioning context. CONCLUSIONS: We argue that midazolam does not disrupt conditioning, but imbues the conditioning context with control over retrieval of the CS-shock association. In this regard, the effects of midazolam closely parallel those of extinction.

Animals↗

PubMed2000

Acute exposure to saccharin reduces morphine analgesia in the the rat: evidence for involvement of N-methyl-D-aspartate and peripheral opioid receptors.

RATIONALE: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug's peripheral effect, while learned tolerance involves activation of N-methyl-D-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. OBJECTIVES: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. METHODS: Six experiments used the rat's tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the noncompetitive NMDA receptor antagonist MK-801 on this modulation of analgesia. RESULTS: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment la), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. CONCLUSIONS: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.

Analgesia↗

PubMed2000

Motivational state regulates the content of learned flavor preferences.

Rats acquired a preference for an aqueous odor (almond) presented in simultaneous compound with sucrose. Separate presentations of saccharin reduced this preference in rats with ad-lib access to food during training or at test, but not in rats that were hungry during both training and test. In contrast, separate presentations of sucrose reduced the preference for the almond irrespective of deprivation state during training and test. We interpret the results to mean that a hungry rat forms odor-taste and odor-calorie associations, and its motivational state on test determines which of these associations controls the preference. In contrast, a rat that is not hungry during training only forms an odor-taste association, and its performance on test is independent of its level of hunger.

Animals↗

PubMed2000

Contextual control over conditioned responding in a latent inhibition paradigm.

We used 1-, 2-, and 3-context designs to study the control exerted by contexts over freezing in rats exposed to a conditioned stimulus (CS) in advance of its pairing with a shock unconditioned stimulus. The latent inhibition observed when preexposure, conditioning, and testing occurred in the same context was attenuated if preexposure occurred in a different context to conditioning and testing. Latent inhibition (i.e., attenuated performance) was restored in a CS-specific manner if preexposure and testing occurred in the same context and conditioning in a different one. Latent inhibition was also reduced by a long retention interval but remained specific for a particular context-CS relation. Finally, CS preexposure resulted in contextual control over the expression of excitatory conditioned performance. The results are discussed in terms of memory, associative, and associative-performance models of CS-preexposure effects.

Animals↗

PubMed2000

Contextual control over conditioned responding in an extinction paradigm.

Four experiments studied contextual control over rats' freezing to conditioned stimuli (CSs) that had been paired with shock and were then extinguished. In Experiment 1, rats were exposed to a CS A-shock and a CS B-shock pairing in Context C. CS A was then extinguished in Context A, and CS B in Context B. Freezing was renewed when each CS was presented in the context where the other CS had been extinguished. In Experiments 2-4, rats were exposed to a CS A-shock pairing in A and a CS B-shock pairing in B. They were then exposed to Context C where one, both, or neither of the CSs were extinguished, or where both CSs continued to be reinforced. On test, the rats froze more to CS A than to CS B in Context A, and more to CS B than to CS A in Context B, but only if the CSs had been extinguished. Thus, after extinction, rats use contexts to regulate retrieval not only of their memory for extinction, but also of their memory for the original conditioning episode.

Aged↗

PubMed2000

A peripheral, intracerebral, or intrathecal administration of an opioid receptor antagonist blocks illness-induced hyperalgesia in the rat.

We used the tail-flick response of rats to study the role of opioid receptors in illness-induced hyperalgesia. An intraperitoneal injection of lithium chloride (LiCl) produced hyperalgesia that was blocked in a dose-dependent manner by subcutaneous injection of the opioid antagonist naloxone. Neither hyperalgesia nor its blockade by naloxone were due to variations in tail-skin temperature induced by LiCl. Hyperalgesia was also blocked when opioid receptor antagonism was restricted to (a) the periphery, by intraperitoneal administration of the quaternary opioid receptor antagonist naloxone methiodide; (b) the brain, by intracerebroventricular microinjection of naloxone; or (c) the spinal cord, by intrathecal microinjection of naloxone. These results document a pain facilitatory role of opioid receptors in both the peripheral and central nervous systems and are discussed with reference to their analgesic and motivational functions.

Animals↗

PubMed1999

The benzodiazepine midazolam does not impair Pavlovian fear conditioning but regulates when and where fear is expressed.

Rats were injected with a benzodiazepine (midazolam) and shocked after presentation of an auditory conditioned stimulus (CS). They were then tested for fear reactions (freezing) to the CS in either the original context or a 2nd context after either a short (1-day) or long (21-day) retention interval. Rats tested in the original context froze less after 1 day than rats tested after that interval in the 2nd context or rats tested after 21 days. Moreover, rats tested after the long interval in the original context froze less than rats tested after that interval in the 2nd context. Therefore, midazolam does not impair the acquisition of conditioned fear but regulates when and where that fear is expressed. These effects of midazolam were interpreted as a contextually controlled deficit in the expression of conditioned fear that is similar to that associated with latent inhibition and extinction (M. E. Bouton, 1993).

Animals↗

PubMed1999

An infusion of bupivacaine into the nucleus accumbens disrupts the acquisition but not the expression of contextual fear conditioning.

An infusion of the local anesthetic bupivacaine into the nucleus accumbens (Acb) impaired the acquisition but not the expression of fear responses (freezing) to a shocked context but spared both the acquisition and expression of these responses to an auditory conditioned stimulus (CS) paired with the shock. In contrast, an infusion of bupivacaine into the amygdala impaired the acquisition and the expression of fear responses to both the CS and the context. The results demonstrate a critical role for the Acb in the acquisition but not the expression of contextual fear conditioning and are consistent with the view that this structure is involved in the processes by which rats represent a context.

Acoustic Stimulation↗

PubMed1999

Bacterial lipopolysaccharide induces a conduction block in the sciatic nerves of rats.

A single injection of Escherichia coli lipopolysaccharide (LPS; intraperitoneally [i.p.] and intravenously [i.v.]) reliably induces peripheral nerve disturbances in the hindlimbs of inbred Australian albino Wistar (AaW) rats. In the series of experiments presented here, we aimed to characterize this syndrome by examining electrophysiologic, immunologic, and immunochemical features. The LPS-induced neurologic sequelae in AaW rats were transient, at least partly reversible by drug treatment, and were not associated with any detectable neuropathologic findings by light microscopy. Neurologic sequelae were prevented by administration of dexamethasone and by pretreatment with the macrophage inhibitor gadolinium chloride, suggesting that they were caused by LPS-induced activation of peripheral macrophages. Sequelae were associated with early decreases in compound muscle-action potential amplitudes, indicating impaired functioning of either proximal sciatic nerve axons and/or neuromuscular synapses. Spinal somatosensory-evoked potential latencies also were increased, indicating impaired somatosensory function at the sciatic nerve, dorsal roots, spinal cord, and/or postsynaptic interneurons, although the precise location of impairment could not be delineated. Similarities between this syndrome and immune-mediated polyneuropathies in humans are discussed.

Animals↗

PubMed1998

Evidence that GABA transmission mediates context-specific extinction of learned fear.

Six experiments used rats to study the effects of the beta-carboline FG 7142 on extinction of fear responses (freezing) to an auditory cue that had signalled footshock. Subcutaneous injection of FG 7142 interfered with the development of extinction without having any detectable effect on the rats' levels of fear prior to extinction. Injection of FG 7142 also reversed extinction, partially reinstating fear responses that had been extinguished previously. A similar reinstatement of extinguished fear was seen when rats were tested for fear of the cue in a different chamber. The reinstatement produced by FG 7142 and that caused by context shift were not additive: FG 7142 did not increase extinguished fear if rats were tested in the different chamber. Finally, FG 7142 had no detectable effect on the latent inhibition of fear produced by repeatedly presenting the cue alone before conditioning with shock, even though this inhibition, like extinction, was affected by a shift in context. The present findings indicate that GABA transmission at GABA(A) receptors is involved in the inhibition of extinguished fear, and that this effect of GABA is regulated by those cues that constitute the extinction context.

Animals↗

PubMed1998

Test type influences the expression of lithium chloride-induced hyperalgesia.

The hyperalgesic properties of the emetic drug lithium chloride (LiCl) were examined in eight experiments. At a dose of 63.6 mg/kg, LiCl produced hyperalgesia in the radiant-heat (Experiment la) and immersion (Experiment 1b) tail-flick tests. At doses of 15.9, 31.8, 63.6, and 127.2 mg/kg, LiCl failed to produce hyperalgesia during the delayed behavioral response in the formalin test (Experiments 2a and 2b), but 63.6 mg/kg LiCl did produce hyperalgesia during the normally quiescent, interphase period of formalin responding (Experiment 2c). At the dose of 63.6 mg/kg, LiCl did not produce hyperalgesia in the hotplate test (Experiments 3a and 3b) and did not exert significant motoric effects in a step-down passive-avoidance task (Experiment 4). The results were discussed with reference to the behavioral effects of LiCl and their implications for demonstrations of associatively mediated morphine analgesic tolerance.

Animals↗

PubMed1998

Benzodiazepine-induced amnesia in rats: reinstatement of conditioned performance by noxious stimulation on test.

A benzodiazepine (midazolam), injected either systemically or directly into the basolateral amygdala (BLA), differentially affected the acquisition of fear responses to a shocked context: Administration of the drug before conditioning impaired subsequent freezing to the context but spared analgesic responses in rats tested there for sensitivity to formalin pain. Moreover, the pain test not only revealed evidence for analgesic responses but also served to reinstate conditioned freezing that was otherwise absent in rats conditioned under midazolam. The results were interpreted as showing that the presence of noxious stimulation on test serves either (a) to assist in retrieval of the context-shock association whose storage had been modified by midazolam's action in the BLA, or (b) to enable performance of the context-shock association whose affective properties had been blocked by midazolam's action in the BLA.

Amygdala↗

PubMed1998

Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms.

2-Amino-5-phosphonovalerate↗

PubMed1998

Effects of retention interval on latent inhibition and perceptual learning.

Repeated, non-reinforced preexposure to a context slowed development of conditioned freezing to that context when it was subsequently paired with footshock (latent inhibition) and enhanced discriminability of that context from a similar context (perceptual learning) whether assessed by a generalization test or by explicit discrimination training. Latent inhibition was eliminated by a delay between conditioning sessions and test (Experiments 1a and 1b) and reduced by a delay between preexposure and conditioning (Experiment 2). However, perceptual learning was unaffected by either of these intervals (Experiments 1b and 2). These results are discussed in terms their impact on theories that have latent inhibition as a possible mechanism of perceptual learning, and on theories of latent inhibition that consider the retardation of conditioned responding to be the result of an acquisition failure.

Animals↗

PubMed1998

Loss of latent inhibition of contextual conditioning following non-reinforced context exposure in rats.

Three experiments with rats demonstrated that preexposure to an experimental environment retarded the level of conditioned freezing observed on a test in that environment after it had been paired with mild footshock. Furthermore, Experiment 1 demonstrated that this latent inhibition effect could be abolished if preexposed rats were exposed to a second experimental environment following conditioning to the preexposed environment. Experiments 2 and 3 demonstrated that this second environment had to be similar, but not identical, to the preexposed environment, and that the influence of exposure to the second environment on latent inhibition could be abolished by exposure to that environment prior to footshock conditioning. These results are considered in terms of the Dickinson-Burke (1996) theory of retrospective revaluation, and their implications for experiments demonstrating a loss of latent inhibition across a delay are considered.

Animals↗

PubMed1997

Context dependency of conditioned aversions to water and sweet tastes.

Three experiments exposed rats (Rattus norvegicus) to a discriminative conditioning procedure whereby a specific fluid was followed by lithium in one environment but not in another. This produced context-specific aversion to water, as detected by 2-bottle tests in Experiment 1, and a context-dependent saccharin aversion, which was unaffected by context extinction, in Experiment 2. Experiment 3 found that sucrose preexposure increased contextual control over the aversion established by sucrose-lithium pairings but had no effect on the target context. By contrast, target context exposure during conditioning reduced aversion to this context but did not affect contextual control of the sucrose aversion. In conclusion, depending on the conditioning procedures, contextual control of a taste aversion can be independent of the context's Pavlovian properties.

Animals↗

PubMed1997

Microinjection of morphine into the nucleus accumbens impairs contextual learning in rats.

A unilateral microinjection of morphine into the amygdala impaired fear conditioning to both a conditioned stimulus (CS) paired with shock and the context where shock occurred, whereas a microinjection of morphine into the nucleus accumbens (NA) spared fear conditioning to the CS but impaired, in a dose-dependent and receptor-specific manner, fear conditioning to the context. Morphine in the NA also spared extinction and latent inhibition of a CS but abolished the context specificity of these effects and eliminated the increase in discriminability that results from preexposure to a to-be-shocked context. The results identify a role for the NA in the processes by which rats learn about a context and are discussed in terms of an opioid disruption of either within-context associations or of attentional processes that contribute to such associations.

Animals↗