Saccharin's rewarding, conditioned reinforcing, and memory-improving properties: mediation by isomorphic or independent processes?

Unconditioned reward and conditioned reinforcing effects may reflect an isomorphic motivational process because increased conditioned reinforcing effects were seen with increased amounts of saccharin consumed in taste and place conditioning. Reinforcing effects in place conditioning leveled off as saccharin unconditioned consumption reached maximum amounts of approximately 140 mg/rat. Posttrial consumption, but not intraperitoneal injection, of saccharin significantly enhanced conditioned place and taste preferences as well as conditioned taste aversions. Saccharin's memory-improving effects in both aversive and appetitive conditioning suggest a process separate from the reward-reinforcement process. Independent of effects on blood glucose, the motivational property of saccharin's sweet taste undergoes differential central processing to mediate reward-reinforcement versus memory improvement processes.     

Synergism of a compound unconditioned stimulus in taste aversion conditioning

Anti-lymphocyte serum (ALS) and lithium chloride have both previously been used successfully as unconditioned stimuli in taste aversion conditioning paradigms in rats. This report substantiates those findings but shows that when the two stimuli are given as a compound unconditioned stimulus in association with saccharin flavoured drinking solution, the conditioned taste aversion response following a second exposure to saccharin alone is more profound than that following conditioning with either ALS or LiCl alone. These results demonstrate synergism between the two stimuli when given together.     

Naloxone induces multiple effects on aversive Pavlovian conditioning in rabbits

A series of experiments examined the effects of intravenous naloxone treatment on aversive Pavlovian conditioning of eye-blink and heart rate responses, and related unconditioned behaviors, in rabbits. Naloxone treatment before testing attenuated bradycardiac orienting responses to tones used as conditioning stimuli. Naloxone also attenuated conditioned bradycardia when administered either before or after training sessions, but it potentiated conditioned bradycardia during extinction of discriminative conditioning. Naloxone did not influence acquisition or extinction of discriminative eye-blink conditioning or somatic or cardiac responses to shocks used as unconditioned stimuli, but it did decrease locomotor activity. Naloxone treatment immediately after training sessions facilitated acquisition of eye-blink responses. It was concluded that naloxone influences aversive Pavlovian conditioning in more than one way: (a) During training, it appears to alter reception and processing of signals but does not affect subsequent development of somatic responses to the Pavlovian conditioning contingency. (b) After training sessions, naloxone apparently affects consolidation of both somatic and autonomic conditioning. (c) Naloxone also appears to delay extinction of Pavlovian conditioning; this effect may similarly involve changes in a stimulus-processing mechanism or in memory functions, but it apparently does not involve changes in somatomotor responsitivity.     

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

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

Air puff versus shock unconditioned stimuli in rabbit heart rate conditioning.

The present study examined whether corneal air puff can be used as an unconditioned stimulus to elicit reliable classically conditioned heart rate (HR) responses in rabbits. The conditioned and unconditioned HR responses were assessed during Pavlovian conditioning with different intensities of paraorbital shock (2.7, 1.2, or 0.5 mA) or corneal air puff (18.3, 5.9, or 2.2 N/cm2) unconditioned stimuli (UCSs). Each experimental group was given one acquisition session during which an acoustic conditioned stimulus was paired with either the high, medium, or low intensity of a shock or air puff UCS. The results suggest that: a) HR is reliably conditioned with a high-intensity air puff UCS, and with medium- or high-intensity paraorbital shock stimuli; and b) only UCSs that elicit a tachycardiac unconditioned HR response reliably support HR conditioning. It was concluded that either air puff or paraorbital shock can serve as an effective UCS for HR conditioned responses.     

Conditioned increase of natural killer cell activity (NKCA) in humans.

Cumulating evidence suggests that immune parameters can be modified by behavioral conditioning processes in animals. The present results suggest that this also holds true for a human immune parameter. Healthy subjects were exposed to a conditioning procedure in which a neutral sherbet sweet (conditioned stimulus) was repeatedly paired with a subcutaneous injection of 0.2 mg epinephrine (unconditioned stimulus). After epinephrine administration an increase of natural killer (NK) cell activity could be observed (unconditioned response). On the conditioning test day the conditioned group showed increased NK cell activity after reexposure of the sherbet sweet combined with saline injection. No increase was found in control groups that previously received the sherbet sweet in combination with saline (saline control) or with epinephrine in an unpaired manner (unpaired control). This study supports previous findings of conditioned modulation of immune responses and represents a model to investigate conditioning processes of a human immune function.     

Once is too much: conditioned changes in accumbens dopamine following a single saccharin-morphine pairing

The present study tested whether presentation of a taste cue would support conditioned suppression of dopamine in the nucleus accumbens (NAcc) following a single taste-drug pairing. Nondeprived male Sprague-Dawley rats were given 20-min access to a 0.15% saccharin conditioned stimulus (CS). Immediately thereafter, experimental rats were injected with morphine (15 mg/kg ip); standard controls were injected with saline; and explicitly unpaired controls were injected with morphine, but approximately 24 hr later. All rats were then given one 20-min CS-only test. Microdialysis samples from the NAcc were measured over 20-min intervals before, during, and after CS access on the conditioning and test trial. The results showed that a single saccharin-morphine pairing led to a marked reduction in CS intake, and the reduction in intake was accompanied by a conditioned blunting of the accumbens dopamine response to the saccharin reward cue. In turn, a single exposure to the saccharin cue also blunted the unconditioned dopamine response to morphine. Reward comparison effects, then, are cross-modal, bidirectional, and immediate, resulting in both unconditioned and conditioned changes in brain and behavior.     

Early Pavlovian conditioning impairs later Pavlovian conditioning

Four experiments tested the effects in the rat of very early experience with stimuli to be used later for Pavlovian conditioning. Beginning on postnatal Day 12, prior to the development of substantial detection and effective perception of visual and auditory stimuli, rats were given five daily experiences with either lights or tones and a footshock known to be an effective unconditioned stimulus at these ages. Twenty-four hours after the last of these experiences, pairings of either the light or tone and the unconditioned stimulus were given with parameters established to yield a moderate degree of conditioning in untreated preweanlings (Experiment 1). Experiment 2 determined that early experience with paired or unpaired presentations of either the light or tone and the unconditioned stimulus resulted in a failure to condition to these same lights or tones on postnatal Day 17, although nontreated pups from the same litters conditioned quite effectively. Experiment 3 determined that this early conditioning experience with either paired or unpaired presentations of the lights or tones and the unconditioned stimulus yielded impaired conditioning on postnatal Day 17 in the alternative sensory modality as well, although again nontreated siblings conditioned quite effectively. Experiment 4 replicated the results of each of Experiments 2 and 3 and determined in addition that despite the impairment in conditioning that resulted from early paired or unpaired experience with the stimuli of conditioning, early experience with the individual stimuli of conditioning—with only the CS, the US, or the context—did not result in a similar impairment in conditioning. Although the results were unexpected, they may be understood in part in terms of intersensory competition during development, and there is precedent in the literature for similar interfering effects of early learning on later learning in a variety of species. © 1996 John Wiley & Sons, Inc.     

Cerebellar cortex and eyeblink conditioning: A reexamination

Summary We examined the effects of cerebellar cortical lesions upon conditioned nictitating membrane responses in rabbits. Using extended postoperative conditioning and unpaired presentations of the conditioned stimuli (CSs), we confirmed that combined lesions of lobules HVI and ansiform lobe abolished conditioned responses (CRs) established to light and white noise CSs. Extended retraining enabled some slight recovery of CR frequencies. Less extensive cortical lesions produced initial abolition of CRs but allowed more complete recoveries. Although CR frequencies and amplitudes were profoundly depressed by cortical lesions, unconditioned response (UR) amplitudes to periorbital electrical stimulation were enhanced. The dissociation of lesion effects upon conditioned and unconditioned responses is consistent with the suggestion that cerebellar cortical mechanisms are important for the learning and execution of eyeblink conditioning.     

Classical conditioning and conditioning-specific reflex modification of rabbit heart rate as a function of unconditioned stimulus location

Heart rate conditioning is used as an index of conditioned fear and is important for understanding disorders of anxiety and stress, including post traumatic stress disorder (PTSD). One important feature of PTSD is that patients generalize conditioned fear from danger signals to safety signals especially when the two signals have overlapping features. What has not been determined is whether generalization occurs between unconditioned stimuli with overlapping features. In the current experiment, heart rate conditioning and conditioning-specific reflex modification of rabbit heart rate were examined as a function of two different unconditioned stimulus locations. Heart rate conditioning occurred at identical terminal levels whether electrical stimulation was presented near the eye or on the back. Despite different heart rate response topographies to electrical stimulation at the two locations, conditioning-specific reflex modification was detected near the eye and on the back and appeared to generalize between the locations. Interestingly, only conditioning-specific reflex modification detected on the back persisted for a week after heart rate conditioning. This persistence may be a model for some features of post traumatic stress disorder. Overgeneralization of unconditioned responses to unconditioned stimuli similar to the trauma may also be an important aspect of PTSD modeled here.     

Behavioural endocrine immune-conditioned response is induced by taste and superantigen pairing

Administration of bacterial superantigen, such as staphylococcal enterotoxin B (SEB), induces in vivo stimulation of T cell proliferation and cytokine production such as interleukin-2 (IL-2). It has been previously reported that SEB administration induces fever, c-Fos expression in the brain, and hypothalamus-pituitary-adrenal axis activation, demonstrating that the brain is able to sense and respond to SEB. Previously it had been shown that immune functions can be behaviourally conditioned pairing a novel gustatory stimulus together with an immunomodulatory drug or an antigen. We designed an experimental protocol using Dark Agouti rats in which saccharin taste, as conditioned stimulus, was paired with an i.p. injection of SEB (2 mg/kg), as unconditioned stimulus. Six days later, when conditioned animals were re-exposed to the conditioned stimulus they displayed strong conditioned taste avoidance to the saccharin. More importantly, re-exposure to the conditioned stimulus significantly increased IL-2, interferon-gamma and corticosterone plasma levels, in comparison with conditioned animals which had not been re-exposed to saccharin taste. These results demonstrate a behavioural-immune-endocrine conditioned response using a superantigen as unconditioned stimulus. In addition, they illustrate the brain abilities to mimic the unconditioned effects of a superantigen by yet unknown mechanisms.     

Latent Inhibition and Conditioning in Rat Strains Which Show Differential Prepulse Inhibition

Latent inhibition (LI) is the retardation of associative conditioning resulting from preexposure of the conditioned stimulus (CS) alone prior to conditioning. Schizophrenic patients show deficient prepulse inhibition (PPI) and, at least acutely, deficient LI as well. We recently found that Brown Norway (BN) rats show a PPI deficit compared to Wistar-Kyoto (WKY) rats. If PPI and LI depend on neural processes with common genetic substrates, then LI should be deficient in BN rats as well. Here, LI of a conditioned taste aversion was examined in BN and WKY rats. One group from each strain was preexposed to a saccharin-flavored solution (CS) the day prior to conditioning. For taste aversion conditioning, these two groups again consumed saccharin and were injected with lithium chloride (unconditioned stimulus) 10 min later. A second group from each strain was not preexposed to the CS and was treated identically during conditioning, while a third group was not conditioned (injected with sodium chloride). To test for taste aversion conditioning, saccharin was offered for 20 min/day for 3 days. Nonconditioned BN and WKY rats consumed equal amounts of saccharin on test days. In both strains, conditioned rats showed a saccharin aversion. However, conditioning was less robust in BN than in WKY rats. WKY rats showed good LI of the conditioned taste aversion in that preexposed WKY rats consumed significantly more saccharin on test days than conditioned, nonpreexposed WKY rats. Preexposed BN rats did not consume significantly more saccharin on test days than conditioned, nonpreexposed BN rats. The previously reported deficiency in PPI in the BN rats was confirmed here 1 week after the taste aversion experiment. These results suggest that BN rats show deficient LI as well as PPI and display poor associative learning, a trait also reported in schizophrenia.     

Dissociation of autonomic and behavioral components of conditioned fear during development in the rat

Classical conditioning of heart rate (HR) was examined in unrestrained preweanling and weanling (16-, 19-, 21-, 25-, and 28-day-old) rats, with tone and light as the conditioned stimuli (CS) and electric shock as the unconditioned stimulus. The conditioned cardiac response was a sustained deceleration in HR which did not emerge until Day 21 for the tone CS and until Day 28 for the light CS. In contrast, when suppression of a behavioral response (running in a straight alley for dry suckling as reward) was used as the index of conditioning, the suppressive effects of the CS were evident around Day 16 for the tone and around Day 19 for the light. These findings indicate that during ontogenesis (a) the behavioral and autonomic responses to the same conditioned stimulus do not develop at the same pace, (b) the emergence of conditioned responses to tone and light stimuli parallel the sequential order in which the relevant sensory modalities achieve maturity (first audition, next vision), and (c) there is no clear-cut interdependence between development of the HR orienting response and conditionability of HR because unconditioned cardiac deceleration to both auditory and visual stimuli first appears about Day 16 in the developing rat, well before conditioned HR responses can be established to either stimulus.     

Generalization of appetitive conditioned responses

A stimulus (conditioned stimulus, CS) associated with an appetitive unconditioned stimulus (US) acquires positive properties and elicits appetitive conditioned responses (CR). Such associative learning has been examined extensively in animals with food as the US, and results are used to explain psychopathologies (e.g., substance‐related disorders or obesity). Human studies on appetitive conditioning exist, too, but we still know little about generalization processes. Understanding these processes may explain why stimuli not associated with a drug, for instance, can elicit craving. Forty‐seven hungry participants underwent an appetitive conditioning protocol during which one of two circles with different diameters (CS+) became associated with an appetitive US (chocolate or salty pretzel, according to participants’ preference) but never the other circle (CS?). During generalization, US were delivered twice and the two CS were presented again plus four circles (generalization stimuli, GS) with gradually increasing diameters from CS? to CS+. We found successful appetitive conditioning as reflected in appetitive subjective ratings (positive valence, higher contingency) and physiological responses (startle attenuation and larger skin conductance responses) to CS+ versus CS?, and, importantly, both measures confirmed generalization as indicated by generalization gradients. Small changes in CS‐US contingency during generalization may have weakened generalization processes on the physiological level. Considering that appetitive conditioned responses can be generalized to non‐US‐associated stimuli, a next important step would be to investigate risk factors that mediate overgeneralization.     

Classical conditioned learning using transcranial magnetic stimulation

This study examined whether brain responses to transcranial magnetic stimulation (TMS) would be amenable to classical conditioning. Motor cortex in human participants was stimulated with TMS pulses, which elicited a peripheral motor response in the form of a motor evoked potential (MEP). The TMS pulses were paired with audio-visual cues that served as conditioned stimuli. Over the course of training, MEPs following the conditioned stimuli decreased in amplitude. Two experiments demonstrated that the attenuated response only occurred when the TMS was preceded by the conditioned stimulus. Unsignaled TMS and TMS preceded by a cue that was not previously paired did not attenuate the response. The experiments demonstrate that the modulation of the motor response depended on the prior pairings of the conditioned stimuli and TMS and that the effects were stimulus specific. Thus we demonstrate here, for the first time, that TMS can serve as the unconditioned stimulus in Pavlovian conditioning.     

Impact of healthy aging on awareness and fear conditioning

Fear conditioning has provided a useful model system for studying associative emotional learning, but the impact of healthy aging has gone relatively unexplored. The present study investigated fear conditioning across the adult life span in humans. A delay discrimination task was employed using visual conditioned stimuli and an auditory unconditioned stimulus. Awareness of the reinforcement contingencies was assessed in a postexperimental interview. Compared with young adult participants, middle-aged and older adults displayed reductions in unconditioned responding, discriminant conditioning, and contingency awareness. When awareness and overall arousability were taken into consideration, there were no residual effects of aging on conditioning. These results highlight the importance of considering the influence of declarative knowledge when interpreting age-associated changes in discriminative conditioned learning.     

Lithium chloride and immunomodulation in taste aversion conditioning.

Lithium chloride has been used in many studies of conditioning to induce taste aversion behaviour, and in some experiments investigating conditioning effects on immunity it has been used on the assumption that it is immunologically neutral. The studies reported here, however, indicate that LiCl is not immunologically neutral and when used to endow a UCS with noxious properties to enhance the behavioural response in taste aversion conditioned immunosuppression, it may antagonize the residual immunosuppression following initial UCS administration and also the conditioned immunosuppression occurring after CS reexposure. Therefore, conclusions drawn from studies of behaviourally conditioned immunomodulation where LiCl is used as part of either the CS or UCS may require reevaluation.     

Dynamics of single unit activity in the association cortex of waking cats during defensive conditioning

Responses of neurons in association area 5 during defensive conditioning to acoustic stimulation were studied in chronic experiments on cats. As a rule the neurons responded by excitation to presentation of conditioned and unconditioned stimuli. During the conditioned reflex unit responses usually appeared in the first 50 msec after the beginning of acoustic stimulation,i.e., they were connected with the action of the conditioned stimulus and not with manifestations of conditioned-reflex motion. The most significant changes in responses of cortical association units were observed in the initial period of conditioning. During stabilization of the conditioned reflex, responses of some neurons became stabilized, whereas in other neurons the spontaneous activity and intensity of responses increased, and in a third group the response to one of the stimuli disappeared. This last result indicates a switch during conditioning from polysensory unit responses to monosensory specialized responses. Extinctive inhibition was found to consist of a gradual decrease in the level of the spike discharge and its approximation to spontaneous activity, i.e., to be passive in character.Translated from Neirofiziologiya, Vol. 10, No. 6, pp. 563–572, November–December, 1978.     

Mechanisms and mediators of psychological stress-induced rise in core temperature

OBJECTIVE: Despite numerous case reports on "psychogenic fever," it remains uncertain how psychological stress raises core temperature and whether the rise in core temperature is a real fever or a hyperthermia. This article reviews studies on the psychological stress-induced rise in core temperature (PSRCT) in animals with the aim to facilitate studies on the mechanisms of so-called psychogenic fever in humans. METHODS: To address this question, we reviewed the mechanisms and mediators of the PSRCT and classic conditioning of the fever response in animals. RESULTS: The PSRCT is not due to the increased locomotor activity during stress, and the magnitude of the PSRCT is the same in warm and cold environments, indicating that it is a centrally regulated rise in temperature due to an elevated thermoregulatory "set point." The PSRCT caused by conventional psychological stress models, such as open-field stress, is attenuated by cyclooxygenase inhibitors, which block prostaglandin synthesis. On the other hand, the PSRCT elicited by an "anticipatory anxiety stress" is not inhibited by cyclooxygenase inhibitors but by benzodiazepines and serotonin Type 1A receptor agonists. The febrile response can be conditioned to neutral stimuli after paired presentation with unconditioned stimuli such as injection of lipopolysaccharide, a typical pyrogen. CONCLUSIONS: Most findings indicate that the PSRCT is a fever, a rise in the thermoregulatory set point. The PSRCT may occur through prostaglandin E2-dependent mechanisms and prostaglandin E2-independent, 5-HT-mediated mechanisms. The febrile response can be conditioned. Thus, these mechanisms might be involved in psychogenic fever in humans.     

Changes in the motor pattern of learned and unlearned responses following cerebellar lesions: a kinematic analysis of the nictitating membrane reflex.

Kinematic and dynamic analyses were employed to study the effects of cerebellar lesions on conditioned and unconditioned nictitating membrane responses in the rabbit. It was found that conditioned responses acquired to an auditory stimulus accelerated in two bursts as indicated by two distinct peaks of acceleration. The second peak of acceleration was very weak during the early portions of conditioning but became a prominent feature of the conditioned response over 16 sessions of conditioning. The second peak of acceleration in the conditioned response was more sensitive to cerebellar damage than was the first peak. When lesions of the cerebellum permanently reduced the amplitude of conditioned responses, but did not affect their frequency, the second peak of acceleration was nearly abolished while the first peak was unaffected. When cerebellar lesions profoundly impaired both the amplitude and frequency of conditioned responses, large and permanent impairments occurred in both peaks of acceleration. Lesions of the anterior interpositus nucleus most severely impaired both peaks of acceleration in the conditioned response and significantly reduced the acceleration of unconditioned responses across a wide range of intensities of corneal air puff. The deficit in the acceleration of unconditioned responses became manifest only after membrane extension exceeded 0.12 mm. The impairment in the amplitude of the unconditioned response after cerebellar lesions more closely approximated the impairment in the amplitude of the conditioned response when the force-generating properties of the conditioned and unconditioned stimuli were equated. It was hypothesized, therefore, that one reason why conditioned responses are so easily disrupted by cerebellar lesions is because they are of low force and not simply because they are learned. It was proposed that the two peaks of acceleration that characterize the conditioned response represent the function of two distinct anatomical systems. The first, a short-latency system, initiates the response and is most likely mediated by circuits that traverse the pontomedullary reticular formation. The second, a longer-latency system, amplifies response amplitude and its neural basis remains to be elucidated. The two components of the conditioned response may reflect two sequential bursts of activity in the accessory abducens nucleus, the principal site of the motoneurons for the retractor bulbi muscle, or may reflect the synergistic activity of the accessory abducens nucleus and the motor nuclei of the other extraocular muscles. It was concluded that the vulnerability of the second component of the conditioned response to cerebellar damage reflects an important role for the cerebellum in modulating the degree to which long-latency neural systems contribute to the ongoing performance of learned and unlearned behaviors.