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Morphine-conditioned changes in locomotor activity: role of the conditioned stimulus.

When a multisensory environment was reliably paired with morphine (2 mg/kg) in rats, that environment, in a drug-free test, evoked a hyperactive conditioned response (CR). When an olfactory cue (banana odor) was the only stimulus element reliably paired with morphine, it also elicited a hyperactive CR. However, a gustatory cue (saccharin solution) evoked a hypoactive CR. This taste-elicited decrease in activity was dose dependent; morphine at 2 and 4 mg/kg conditioned hypoactivity, whereas a higher dose (8 mg/kg) did not. A robust conditioned saccharin aversion occurred only at the highest dose of morphine, suggesting disassociation between the hypoactive CR and taste aversion. A taste cue present during context conditioning also prevented either acquisition or expression of the hyperactive CR to the context. The modality of the conditioned stimulus is a critical determinant of the form of the CR in a morphine locomotor conditioning paradigm.

Animals↗

Medial prefrontal lesions and Pavlovian eyeblink and heart rate conditioning: effects of partial reinforcement on delay and trace conditioning in rabbits (Oryctolagus cuniculus).

Effects of continuous (100%) versus partial (25%) reinforcement were studied on Pavlovian delay and trace eyeblink conditioning in rabbits (Oryctolagus cuniculus) with either lesions to the medial prefrontal cortex (mPFC) or sham lesions. Concomitant heart rate changes evoked by the conditioned stimulus were also assessed. Partial reinforcement retarded eyeblink conditioning in both the trace and delay paradigm, but this impairment was greater during trace conditioning and in rabbits with mPFC lesions. Accompanying conditioned stimulus-evoked heart rate slowing was attenuated under all conditions by the mPFC lesions, although this result was not always statistically significant.

Animals↗

Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance.

Rats administered 5 mg/kg morphine SO4, through subcutaneously implanted catheters, during each of several daily sessions in an open field showed a progressive increase in locomotor activity measured in the open field prior to each morphine administration. Since the increases in activity were not observed in rats given morphine in a different environment (home cage) and saline in the open field, it is concluded that the increases were due to conditioning. In addition, the increases in activity were retained over a 7-day rest period; they were also produced when a second opiate (5 microgram/kg etorphine HCl) was substituted for morphine, were not seen when 2 mg/kg naloxone HCl (ip) was administered during treatment, and were present in rats showing tolerance to opiate-produced hypoactivity. Morphine's direct effect on activity is believed to have a biphasic dose-response curve; therefore, the relation of dose to conditioning was also studied. Increases in activity were the only conditioned behaviors observed; they were present only at the higher doses (16, 4, and 1 vs. .25, .065, and 0 mg/kg), and they occurred whether or not the dose was associated with unconditioned hypoactivity. The discussion deals with the relation of conditioning and morphine tolerance, the question of whether the unconditioned stimulus of morphine conditioning is a compensatory or a direct effect of morphine, and the similarity of conditioned increases in activity produced by morphine and by other stimuli that are reinforcing.

Animals↗

MK-801 disrupts acquisition of contextual fear conditioning but enhances memory consolidation of cued fear conditioning.

The effects of pre-training or post-training subcutaneous injections of multiple doses of the non-competitive NMDA-receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) on cued and contextual fear conditioning were examined in F344 rats. Pre-training injections of MK-801 (0.3 and 1.0 mg/kg) disrupted contextual fear conditioning but not cued fear conditioning. Post-training injections of MK-801 did not disrupt cued or contextual fear conditioning. In fact, the 0.3 mg/kg dose of MK-801 enhanced cued fear conditioning. Finally, rats were tested for MK-801-induced alterations in sensitivity to pain using the formalin test for nociception. MK-801 did not reduce sensitivity to pain. These results suggest that NMDA receptors are involved in acquisition of contextual fear conditioning but not in memory consolidation of the learned response.

Animals↗

Fear-potentiated startle conditioning in humans: explicit and contextual cue conditioning following paired versus unpaired training.

Conditioned fear in response to explicit and contextual cues was examined using the startle reflex in three groups of participants over two sessions separated by 4-5 days. The conditioned stimulus (CS) was paired with an aversive unconditioned stimulus (US) (shock) during conditioning in the paired but not in the unpaired group. In the reaction time (RT) group, the US was a nonaversive visual signal for an RT task. In the paired group, the CS potentiated startle in the postconditioning phase. This conditioned response was fully retained over the retention interval. There was no substantial change in baseline startle (startle delivered in the absence of CS). By contrast, startle was not potentiated by the CS in the unpaired group, but baseline startle was increased from Session 1 to Session 2. In the RT group, startle was not affected by the CS, and baseline startle was reduced from Session 1 to Session 2. These results suggest that paired presentations of a CS and an aversive US result in conditioned fear in response to the CS but little contextual fear, whereas unpaired presentations of a CS and US leads to poor explicit cue conditioning but substantial contextual fear.

Adolescent↗

Sensorimotor cortex ablation prevents H-reflex up-conditioning and causes a paradoxical response to down-conditioning in rats.

Operant conditioning of the H-reflex, a simple model for skill acquisition, requires the corticospinal tract (CST) and does not require other major descending pathways. To further explore its mechanisms, we assessed the effects of ablating contralateral sensorimotor cortex (cSMC). In 22 Sprague-Dawley rats, the hindlimb area of left cSMC was ablated. EMG electrodes were implanted in the right soleus muscle and a stimulating cuff was placed around the right posterior tibial nerve. When EMG remained in a specified range, nerve stimulation just above the M response threshold elicited the H-reflex. In control mode, no reward occurred. In conditioning mode, reward occurred if H-reflex size was above (HRup mode) or below (HRdown mode) a criterion value. After exposure to the control mode for > or = 10 days, each rat was exposed for another 50 days to the control mode, the HRup mode, or the HRdown mode. In control and HRup rats, final H-reflex size was not significantly different from initial H-reflex size. In contrast, in HRdown rats, final H-reflex size was significantly increased to an average of 136% of initial size. Thus like recent CST transection, cSMC ablation greatly impaired up-conditioning. However, unlike recent CST transection, cSMC produced a paradoxical response to down-conditioning: the H-reflex actually increased. These results confirm the critical role of cSMC in H-reflex conditioning and suggest that this role extends beyond producing essential CST activity. Its interactions with ipsilateral SMC or other areas contribute to the complex pattern of spinal and supraspinal plasticity that underlies H-reflex conditioning.

Animals↗

Hippocampal pyramidal cell activity encodes conditioned stimulus predictive value during classical conditioning in alert cats.

We have recorded the firing activities of hippocampal pyramidal cells throughout the classical conditioning of eyelid responses in alert cats. Pyramidal cells (n = 220) were identified by their antidromic activation from the ipsilateral fornix and according to their spike properties. Upper eyelid movements were recorded with the search coil in a magnetic field technique. Latencies and firing profiles of recorded pyramidal cells following the paired presentation of conditioned (CS) and unconditioned (US) stimuli were similar, regardless of the different sensory modalities used as CS (tones, air puffs), the different conditioning paradigms (trace, delay), or the different latency and topography of the evoked eyelid conditioned responses. However, for the three paradigms used here, evoked neuronal firing to CS presentation increased across conditioning, but remained unchanged for US presentation. Contrarily, pyramidal cell firing was not modified when the same stimuli used here as CS and US were presented unpaired, during pseudoconditioning sessions. Pyramidal cell firing did not seem to encode eyelid position, velocity, or acceleration for either reflex or conditioned eyelid responses. Evoked pyramidal cell responses were always in coincidence with a beta oscillatory activity in hippocampal extracellular field potentials. In this regard, the beta rhythm represents a facilitation, or permissive time window, for timed pyramidal cell firing. It is concluded that pyramidal cells encode CS-US associative strength or CS predictive value.

Acoustic Stimulation↗

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↗

Auditory fear conditioning and conditioned stress raise NO(3) level in the Amygdala.

BACKGROUND: The conditioned fear response is considered to be acquired by experimental animals when tone information is combined with that of an electrical foot shock (unconditioned stimulus) in the amygdala. Nitric oxide biosynthesized in the brain is reportedly involved in several kinds of learning. METHODS: In this study, we continuously monitored the NO(3)(-) level, as a marker of nitric oxide production, in the amygdala starting before the application of tone and electrical foot shock stimuli together (conditioned group) or the tone stimulus alone (control group) on day 1, until after the tone information was given (both groups) on day 2, using the in vivo microdialysis method. RESULTS: The NO(3)(-) level of the conditioned group was increased on both day 1 and day 2, while that of the control group was not elevated on either day. Freezing behavior was observed in the conditioned but not the control rats. CONCLUSIONS: Although the sources of NO(3)(-) remain uncertain, these results suggest that nitric oxide is associated with auditory fear conditioning and the response to a conditioned stimulus.

Acoustic Stimulation↗

Conditioning reaction time: evidence for a process of conditioned automatization.

The classical conditioning of the standard, simple reaction time (RT) in 140 college men and women is described. Consequent to an anticipatory instructed conditioning procedure, two experimental and two control groups acquired voluntary, controlled US(light)-URTR (unconditioned reaction-time response) associations which then served as the foundation for subsequent classical conditioning when a novel CS (auditory click) was simultaneously paired with the US. Conditioned reaction-time responses (CRTRs) occurred significantly more often during test trials in the two experimental groups than in the two control groups. Statistical and introspective findings support the notion that observed CRTRs may be products of cognitively unconscious conditioned automatization whereby the conditioning of relatively slow, voluntary, and controlled US-URTR associations leads to the acquisition of relatively fast, involuntary, and automatic CS-CRTR associations.

Adult↗

Outcome-specific conditioned inhibition in Pavlovian backward conditioning.

In the present experiments, the outcome specificity of learning was explored in an appetitive Pavlovian backward conditioning procedure with rats. The rats initially were administered Pavlovian backward training with two qualitatively different unconditioned stimulus conditioned-stimulus (US-CS) pairs of stimuli (e.g., pellet --> noise or sucrose --> light), and then the effects of this training were assessed in Pavlovian-to-instrumental transfer (Experiment 1) and retardation-of-learning (Experiment 2) tests. In the transfer test, it was shown that during the last 10-sec interval, the CSs selectively reduced the rate of the instrumental responses with which they shared a US, relative to the instrumental responses with which they did not share a US. The opposite result was obtained when the USs (in the absence of the CSs) were presented noncontingently. In the retardation test, conditioned magazine approach, responding to the CSs was acquired more slowly when the stimulus-outcome combinations in the backward and the forward conditioning phases were the same, as compared with when they were reversed. These results are collectively in accord with the view that Pavlovian backward conditioning can result in the formation of outcome-specific inhibitory associations. Alternative views of backward conditioning are also examined.

Animals↗

Learning with arbitrary versus ecological conditioned stimuli: evidence from sexual conditioning.

Laboratory investigations of Pavlovian conditioning typically involve the association of an arbitrary conditioned stimulus (CS) with an unconditioned stimulus (US) that has no inherent relation to the CS. However, arbitrary CSs are unlikely to become conditioned outside the laboratory, because they do not occur often enough with the US to result in an association. Learning under natural circumstances is likely only if the CS has a preexisting relation to the US. Recent studies of sexual conditioning have shown that in contrast to an arbitrary CS, an ecologically relevant CS is resistant to blocking, extinction, and increases in the CS-US interval and results in sensitized responding and stronger second-order conditioning. Although the mechanisms of these effects are not fully understood, these findings have shown that signature learning phenomena are significantly altered when the kinds of stimuli that are likely to become conditioned under natural circumstances are used. The implications of these findings for an ecological approach to the study of learning are discussed.

Conditioning, Classical↗

Enhanced behavioral conditioning to context and impaired behavioral and neuroendocrine responses to conditioned stimuli following ceruleocortical noradrenergic lesions: support for an attentional hypothesis of central noradrenergic function.

This study tested the hypothesis that cortical noradrenaline (NA) depletion induced by 6-hydroxydopamine (6-OHDA) widens attentional span, impairing the acquisition of conditioning to an explicit stimulus while enhancing conditioning to contextual stimuli. Sham-operated and NA-depleted rats were exposed to pairings of an auditory (clicker) CS and (footshock) US in a distinctive environment. Half of the lesioned and half of the control animals were trained with a short trace interval between presentations of clicker and shock, and half with a long trace. Associative learning theory predicts that a long trace interval should bias intact animals towards stronger contextual conditioning and, in contrast, a short trace interval should bias controls towards stronger CS conditioning. During testing, NA-depleted animals showed impaired fear conditioning to explicit cues, compared with controls, indicated by their reduced suppression of drinking when the CS was introduced into a separate, lick-operant chamber. In contrast, the same animals exhibited enhanced fear of contextual cues, as shown by their greater preference for a "safe" environment over the one in which they were shocked. The behavioral and plasma corticosterone responses of individual animals to the CS were positively correlated in both the lesion and sham groups. Corticosterone levels corroborated the impairment in CS conditioning caused by the lesion. In contrast, behavioral and corticosterone responses to contextual stimuli were not significantly correlated in either group, and there was no enhancement of the corticosterone response to contextual stimuli in the lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

Contextual conditioning with massed versus distributed unconditional stimuli in the absence of explicit conditional stimuli.

Rats received unsignaled shocks in an observation chamber, with different groups varying with respect to time between shocks. Twenty-four hours later the rats were returned to the observation chamber for a test of conditioning to contextual stimuli. The freezing response served as the dependent variable. In Experiment 1 we found that distributed shock trials (60 s) resulted in more context conditioning than did massed trials (3 s or 16 s). Experiment 2 replicated this intertrial interval (ITI) effect when total time in the context was equated for the massed and distributed groups. The observed beneficial effect of distributed practice for conditional stimuli arises because of decreased contextual conditioning with longer ITIs (e.g., Gibbon & Balsam, 1981; Rescorla & Wagner, 1972). Although the basic effect of enhanced performance with longer ITIs is consistent with Wagner's rehearsal model (e.g., 1978), three findings argue against such an account. First, posttrial stimulation did not reduce the benefit obtained from distributed trials (Experiment 3). Second, intertrial distractors did not improve performance of the animals subjected to massed trials (Experiment 4). And third, the ITI effect was not eliminated when conditioning was brought to its asymptote (Experiment 5). The overall pattern of data is consistent with an opponent-process account suggesting that in addition to supporting conditioning, the unconditional stimulus (US) activates a B-state capable of reducing the impact of the next US and that this B-state lasts longer than 16s but decays before 60 s.

Animals↗

Training of conditioned enhancement and conditioned suppression in rats.

Stable conditioned enhancement of barpressing in rats was elicited by darkness stimulus signaling continuous food reinforcement (CRF) component of a multiple schedule in which 2.5 min variable interval reinforcement (VI) constituted the second component. Conditioned enhancement was rapidly acquired and resistant to extinction. In some groups concurrent alimentary and defensive training was conducted in which darkness signaled food CRF and acoustic white noise signaled inescapable foot shock, both presented against the 2.5 min VI food reinforcement schedule. The continuous reinforcement schedule and/or conditioned enhancement showed a decremental effect on conditioned suppression, but only when defensive trials were less frequent than trials with continuous reinforcement of barpresses. Residual enhancement of barpressing after termination of the stimulus eliciting conditioned enhancement, observed at early stages of training, was then changed to a slight decrease of the barpressing rate. Opposite changes were observed after the offset of the stimulus eliciting conditioned suppression. Changes in intertrial response rates are considered as reflecting the summation of stimuli possesing oposite motivational values.

Animals↗

Glutamine and glutamate metabolism in normal and heat shock conditions in Drosophila Kc cells: conditions supporting glutamine synthesis maximize heat shock polypeptide expression.

We have previously reported that Drosophila Kc cells require glutamine for maximal expression of heat shock proteins in stressed conditions (Sanders and Kon: J. Cell. Physiol. 146:180-190, 1991). The mechanism of this effect has been investigated by comparing the metabolic utilization of glutamine in conditions which support hsp expression with that of glutamate in conditions where up to 100-fold less hsp is synthesized. This comparison showed that free ammonia was generated by cells incubated in the presence of glutamine in 37 degrees C (heat shock) conditions, but not at 25 degrees C, and not in the presence of glutamate in either normal or heat shock conditions. There was no difference in the amount of [14C]O2 generated from either [14C]-labeled amino acid in the tricarboxylic acid cycle, but three- to four-fold more alanine was synthesized in cells incubated in glutamine than in glutamate. Treating the cells with aminotransferase inhibitors to artificially increase NH3 release raised hsp expression in the presence of glutamate to maximal levels characteristic of glutamine. This potentiation correlated with inhibition of alanine aminotransferase. Since only NH3 production correlated with hsp expression in heat shock conditions in the presence of glutamine, and NH3 addition to glutamate also resulted in maximal hsp expression, we measured glutamine production in glutamate plus NH3 and observed net glutamine synthesis. The supposition that glutamine itself is responsible for the regulatory changes supporting maximal hsp expression was supported by the finding that the glutamine analog, 6-diazo-5-oxo-L-norleucine (DON), mimicked the effects of glutamine. We conclude that glutamine imposes regulatory changes which alter nitrogen metabolism and support hsp expression in Kc cells.

Amino Acids↗

Length-force characteristics of the aponeurosis in the passive and active muscle condition and in the isolated condition.

Length behaviour of the entire and designated parts of the proximal aponeurosis of the unipennate gastrocnemius medialis (GM) muscle of the rat was examined at muscle lengths ranging form muscle slack length to 4 mm above muscle optimum length in the passive and active (isometric contractions) muscle condition (n = 13). In addition, length-force characteristics of the aponeurosis in the isolated condition were determined (n = 6). Going from muscle slack length to 4 mm above muscle optimum length, the relative extension (relative to the length at muscle slack length) yielded the following results: 14.3% for the entire aponeurosis, 9.8% for the most proximal 25% of the aponeurosis, 3-5% for the middle 50% of the aponeurosis and 52.3% for the most distal 25% of the aponeurosis. Aponeurosis length as a function of aponeurosis force was significantly shorter in the active compared to the passive or isolated condition for force values within the range of force encountered in all three conditions (0.3-1.0 N); no significant difference was observed between the passive or isolated condition. It is concluded that the extension of the aponeurosis is heterogeneously distributed along its length. Differences in aponeurosis length-force curves between the conditions may be explained in terms of a heterogeneous force distribution within the muscle.

Animals↗