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Conditioned taste aversion and conditioned drinking: two independent and opposing effects of 5-hydroxytryptophan?

Four experiments were carried out to examine the effects of 5-HTP in a conditioned taste aversion (CTA) paradigm. Using two-choice tests to measure the CTA, administration of 5-HTP following consumption of a novel flavour caused aversions to saline and saccharin solutions. In single-choice tests 5-HTP reduced consumption of saccharin, sugar cubes and beef-flavoured stock cubes, but only reduced saline consumption if animals had been pretreated with the 5-HTP decarboxylase inhibitor benserazide or the 5-HT receptor antagonist xylamidine, both of which act peripherally. Benserazide did not attenuate the CTA in any experiment. The results are interpreted in terms of two competing behavioural effects of 5-HTP: a centrally-mediated CTA and a peripherally-mediated conditioned drinking response.

5-Hydroxytryptophan↗

Nucleus basalis lesions attenuate acquisition, but not retention, of Pavlovian heart rate conditioning and have no effect on eyeblink conditioning.

Rabbits with lesions of the anterior nucleus basalis of Meynert (nBM) were compared with animals with sham lesions or unoperated control animals on a classical conditioning task in which heart rate (HR) and eyeblink (EB) conditioned responses (CRs) were assessed. The nBM lesions impaired the magnitude of the decelerative HR CR, but had no effect on the EB CR. A second experiment, in which animals were lesioned after acquisition was complete, showed that anterior nBM lesions had no effect on retention of either the HR or EB CR. These data suggest that the anterior nBM may participate in the early stages of information processing in which stimuli are evaluated for their significance based on their association with a reinforcer. However, the anterior nBM is apparently not involved in the selection of a somatomotor response to deal effectively with such changing stimulus contingencies.

Animals↗

Fentanyl-induced conditional place preference: lack of associated conditional neurochemical events.

Three experiments were performed to determine if stimuli previously paired with the reinforcing effects of fentanyl elicit changes in the activity of dopaminergic neurons that are similar to the unconditional effects of the drug. Experiment 1 characterized the unconditional effects of fentanyl (0.04 mg/kg SC) on neurochemical indices of dopaminergic activity in rats. Both acute and repeated fentanyl injections (five injections administered at 48-h intervals) increased the concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) within the striatum (STR), nucleus accumbens (NAS), and olfactory tubercle (OT). Acute injections elicited a greater increase in metabolite concentrations in the NAS than in the STR, suggesting that there are regional differences in the sensitivity of dopaminergic neurons to fentanyl. In experiments 2 and 3, fentanyl (five injections; 0.04 mg/kg SC) was paired with environmental stimuli using a place preference conditioning paradigm. The fentanyl-paired stimuli failed to elicit conditional changes in DOPAC or HVA concentrations within the STR, NAS, or OT even though rats exhibited a preference for the drug-paired compartment of the shuttle box. These results indicate that the secondary reinforcing effects of stimuli previously paired with fentanyl may not reflect the ability of these stimuli to elicit measurable changes in the activity of mesolimbic or nigrostriatal dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗

Formation of the conditioned reflexes to a complex signal in ontogenesis under alternate choice conditions.

The formation of a conditioned reflex to a complex signal, "light + sound," and its components under alternate choice conditions was studied in kittens aged 1.5-10 months. A preference for one of the food dispensers and a low percent of correct reactions (48-57%) was characteristic during the process of training for kittens aged from 1.5 to 5 months. Successful training using the alternate choice method was achieved in kittens whose training began at six months of age. A lesion of the sensorimotor region of the cortex in the same kittens following the achievement of a high level of correct reactions (75-80%) led to a disturbance in the previously developed reflex to the complex signal and its components. The latter was expressed in the manifestation of unidirectional motoric reactions and a sharp decrease in the percent of correct reactions. The question of the confinement of the development of different forms of interaction of the sensory and motor systems to specific age periods and the participation in this process of the sensorimotor region of the cortex is discussed.

Acoustic Stimulation↗

Regional characteristics of electrical responses (in the band 1-225 Hz) in the cerebral cortex to conditioned stimuli in operant conditioning.

Power spectra of short-term (less than 1 sec) electrical responses to conditioned stimuli were studied over the frequency range 1-225 Hz in dogs during food-related operant conditioning. These spectra demonstrated regional characteristics in terms of energy levels and frequency composition. Responses were more marked in the visual and parietal areas of the left hemisphere. Power in responses to a differential stimulus were significantly lower than with responses to positive stimuli, mainly because of the high-frequency range (80-225 Hz); energy levels in these two situations were similar during prestimulus intervals. The frequency composition of responses was defined by a series of discrete frequencies in the gamma (30-80 Hz) and high-frequency ranges.

Analysis of Variance↗

Conditioned approach: an analogue of conditioned avoidance; effects of chlorpromazine and diazepam.

An analogue of the conditioned avoidance test, the conditioned approach test, was designed in which the reinforcing event was eating food rather than avoiding or escaping shock. A response to the approach stimulus resulted in immediate delivery of food. Failure to respond to the approach stimulus for 15 sec resulted in the delivery of a food pellet. Administration of chlorpormazine at 2--4 mg/kg, PO to squirrel monkeys resulted in the failure of the monkeys to respond to many approach stimuli although they promptly responded to the freely delivered food pellet. Diazepam was without effect at doses up to 100 mg/kg, PO.

Animals↗

Cholinergic overstimulation supports conditioned-facilitated startle but not conditioned hyperalgesia.

Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to support odor-potentiated startle responding in rats. Here we conducted 2 sets of experiments that further characterize aspects of this learned association. First we conducted experiments designed to further characterize the learning parameters of the odor-PB association that leads to startle facilitation weeks later. We found that an acute injection of PB causes an increase in startle reactivity that lasts less than 2 h. This is evidence for PB's direct action on the startle response as an enhancing agent. We also delineated the duration of the conditioned enhancement to less than 4 weeks. Second, we conducted similar studies but substituted a nociceptive paw-lick response (thermal pain reflex) for the startle reflex. PB did not have an unconditional action upon the latency to paw-lick to a 48.5 degrees C heated plate nor did any subsequent changes in paw-lick occur in the presence of the previously paired odor. These results suggest that the actions of PB, as an unconditional stimulus, are limited to specific behaviors. Future work examining this compound as a source of conditioned symptoms (as in the case of Gulf War Illness) should focus on those symptoms that are directly influenced by peripheral cholinergic activity.

Animals↗

Reinstatement of both a conditioned place preference and a conditioned place aversion with drug primes.

In two experiments, we report that the place-conditioning paradigm can be used to demonstrate reinstatement of place preference/aversion by a drug prime following extinction training. In Experiment 1, rats were trained to prefer a chamber paired with morphine. Following extinction training, a morphine drug prime reinstated the morphine place preference. In Experiment 2, a lithium-induced conditioned place aversion was reinstated following extinction training by a lithium prime prior to testing. These results indicate that not only do rewarding drug primes produce reinstatement of learned responses (as demonstrated in the drug self-administration paradigm), but also aversive drug primes reinstate aversive learned responses.

Analgesics, Opioid↗

Negative anticipatory contrast and preference conditioning: flavor cues support preference conditioning, and environmental cues support contrast.

In 2 experiments, access to a 0.15% saccharin solution was followed on alternating days by access to a 32% sucrose solution and the same saccharin solution. In Experiment 1, rats increased both intake of and preference for a flavored saccharin solution that predicted sucrose, but neither effect was found using a predictive odor cue alone. Experiment 2 replicated the predictive flavor results but showed suppression of saccharin intake when environmental cues predicted sucrose. When both flavor and environment predicted sucrose, saccharin intake did not change, but preference for the predictive flavor increased. Discriminative taste cues appear to facilitate the development of preference conditioning, but environmental cues favor negative anticipatory contrast effects. Also, preference conditioning and contrast may develop concurrently and compete for expression.

Animals↗

Conditioned antisickness: heat as an internal stimulus in conditioning taste aversion and aversion failure in rats.

Heat was found to be effective as a conditional stimulus in the aversion failure procedure (S. Revusky, H. K. Taukulis, L. A. Parker, & S. Coombes, 1979) and was also found to be effective as an unconditional stimulus using a taste aversion procedure in which rats exposed to high ambient temperature following saccharin consumption showed robust saccharin aversions relative to unpaired and unheated controls. The antisickness and taste aversion conditioning evidence force reexamination of the view that toxic heat effects are referred to the external environment. Together with other recent evidence from this laboratory, these data support the hypothetical antisickness mechanism of aversion failure, which requires that toxic heat serve as an internal stimulus.

Animals↗

Effects of time of testing, stress level, and number of conditioning days on naloxone sensitivity of conditioned stress-induced analgesia in rats.

Controversy exists as to whether conditioned stress-induced analgesia (CSIA) utilizes opioid or nonopioid mechanisms. In two experiments, both an anticipatory conditioned stimulus (CS) and a shock-associated CS were used. The duration of exposure to the anticipatory CS was long, as in studies reporting opioid CSIA, whereas the duration of the shock-associated CS was short, as in studies reporting nonopioid CSIA. In addition, the effects of unconditioned stimulus (UCS) strength were investigated by using three levels of footshock (no, moderate, and high), and the development of CSIA was monitored by using different levels of training (1 to 6 days). CSIA, measured in both anticipatory and postexposure test periods, was found to be relatively stable across tail-flick trials within days and insensitive to strength of shock. As training progressed, CSIA increased with repeated CS-UCS pairings. We tested for opioid involvement using naloxone and found opioid and nonopioid mechanisms underlying CSIA; these mechanisms combined to form a stable level of analgesia. Our data suggest that stress level and amount of training interact to activate opioid and nonopioid mechanisms of CSIA. Apparent discrepancies in previous studies regarding naloxone sensitivity of CSIA may therefore be attributable to differences in stress levels, test periods and durations of exposure to shock-related cues.

Animals↗

Conditioned cyclosporine effects but not conditioned taste aversion in immunized rats.

In 2 experiments, the development of adjuvant arthritis (an experimental autoimmune disease) was inhibited by exposing rats to a flavored solution that had previously been paired with injections of cyclosporine (an immunodepressive drug) compared with rats with the same history but exposed to a flavored solution that had previously not been paired with drug injections. In contrast to earlier experiments on conditioned cyclophosphamide effects, rats did not avoid the taste that had previously been paired with drug administration. Thus, conditioned immunopharmacologic effects were not confounded with taste aversion. These observations are interpreted as reflecting an associative learning process that affected the development of an autoimmune disease.

Animals↗

Conditioned incentive properties of a food-paired conditioned stimulus remain intact during dopamine receptor blockade.

Hungary rats were exposed to a conditioned stimulus (CS) event (either light onset or offset) before food delivery. After several weeks of contingent CS+/food pairings, animals were pretreated with either 0, 0.5, 0.75, or 1.0 mg/kg pimozide and exposed to the CS+ alone. Both vehicle- and neuroleptic-treated rats showed large elevations in locomotor activity immediately after CS+ presentation, in relation to pre-CS+ activity levels. This elevation in activity was apparently due to the conditioned motivational properties of the stimulus because animals that had previously received unpaired presentations of the CS and food failed to show similar responsiveness to the CS. Although pimozide did not affect responsiveness to the CS+, the neuroleptic did produce an overall suppression of locomotor activity during both pre- and post-CS+ periods. The results suggest that neuroleptic treatment produces a suppression of general activity but leaves the motivational properties of food-paired stimuli intact.

Animals↗

NMDA receptor antagonist MK-801 blocks learning of conditioned stimulus-unconditioned stimulus contiguity but not fear of conditioned stimulus in goldfish (Carassius auratus L.).

The blockade of learning of Pavlovian fear conditioning by the N-methyl-D-aspartic acid (NMDA)-receptor antagonist MK-801 was examined in 166 goldfish. In previously untrained fish, MK-801 blocked learning of a light-off or a tone conditioned stimulus (CS) paired with an electrical shock unconditioned stimulus (US). Pretraining on the light-off CS did not affect the rate of learning of the tone CS but protected the tone learning from disruption by MK-801. Switching from the light-off to the tone CS changed the identity of the CS but not its temporal contiguity with the US. Pretraining consisting of pseudoconditioning of the light-off CS did not protect subsequent tone learning from blockade by MK-801. Thus, the NMDA receptor functions are necessary for learning related to the temporal contiguity of the CS and US but not to the identity of the CS as a cue to the occurrence of the fearful effects of the US.

Acoustic Stimulation↗

Classical conditioning with electrical stimulation of cerebellum as both conditioned and unconditioned stimulus.

Stimulating electrodes were implanted in rabbit cerebellum, providing an electrical conditioned stimulus (CS) activating cortical parallel fibers and thence Purkinje and other cells, and an electrical unconditioned stimulus (US) activating underlying white matter and eliciting unconditioned responses. Paired CS-US presentations led to the development of conditioned responses, which showed extinction following CS-alone trials and reacquisition with significant savings on reinstatement of paired trials. Increased local excitability as a result of paired training (but not following unpaired stimulus presentations) was observed in cerebellar cortex, as manifested in substantial decreases in CS threshold for response elicitation in all subjects. This preparation offers a model for the study of plastic neuronal interactions within cerebellar networks critically involved in associative learning.

Animals↗

Mechanisms of Pavlovian conditioning: role of protection from habituation in spinal conditioning.

Conditioned antinociception can be established in spinal rats by pairing stimulation to one hind leg (the conditioned stimulus [CS]) with an intense tailshock (the unconditioned stimulus [US]). After this training, the paired CS (CS+) elicits greater antinociception on the tail-flick test than a CS that was explicitly unpaired (CS-). Five experiments are reported that suggest that this effect reflects protection from habituation. Experiment 1 showed that the CS (legshock) induces antinociception before training. Presenting the CS alone weakened (habituated) its antinociceptive impact (Experiment 2). Less habituation was observed when the CS was paired with the US (Experiment 3). Decreasing habituation to the CS- (by increasing the interval between trials) and facilitating habituation to the CS+ (by increasing the number of trials) effectively eliminated the CS+/CS- difference (Experiments 4 and 5).

Animals↗

Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.

Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network.

Animals↗

Impairments in conditioned stimulus processing and conditioned responding after combined selective removal of hippocampal and neocortical cholinergic input.

Previous studies indicated that changes in attentional processing of conditioned stimuli (CSs) are regulated by the basal forebrain (BF) cholinergic system. In those studies, destruction of BF innervation of the neocortex interfered with enhancements in CS processing, and destruction of BF innervation of the hippocampus prevented reductions in CS processing. In the current experiments, the performance of rats with 192 IgG-saporin lesions of both hippocampal and neocortical cholinergic input was examined. These combined lesions disrupted both enhancements and reductions in CS processing. Lesioned rats also showed more general impairments in conditioned responding. These results indicate that, although the neural systems for increasing and decreasing attentional processing may be largely independent, combined loss of hippocampal and neocortical cholinergic input may produce behavioral impairments that are not apparent after either lesion alone.

Animals↗