Effects of psychoactive agents on the conditioning of the microcirculation in the rat

Normal vascular tonus and permeability of the microcirculatory network is mediated by catecholamines, histamine and serotonin. Following electroconvulsive treatment (ECT), histamine did not provoke local vasodilatation. The inhibition was further potentiated by drugs which prevent the enzymatic or physical inactivarion of free catecholamines and by locally administered norepinephrine. This system became conditioned to a visual stimulus when rats were presented in six consecutive occasions with the visual stimulus preceedingly coincided with the administration of ECT. In the conditioned rats, light alone inhibited the histamine-induced vasodilatation, and this inhibition was potentiated by sub-effective doses of injected norepinephrine and by drugs which prevent the enzymatic or physical inactivation of catecholamines. Sedatives, antidepressants, MAO inhibitors and the chlorpromazine-type agents as well as the psychotomimetic drugs characteristically influence either the acquisition or the extinction of the conditioned reflex. Results suggest that the obtained conditioning of the microcirculatory functions are mediated by tie centrally released catecholamines.     

A model of pavlovian conditioning: Variations in representations of the unconditional stimulus

We present a model of Pavlovian excitatory conditioning in which associative strength and malleable central representations of unconditional stimuli determine the strength of conditional responding. Presentation of a conditioned stimulus acts through an experientially determined associative bond to activate a representation of the unconditional stimulus. The activation of the representation produces a conditioned response. A striking feature of the model is its ability to describe changes in conditioned response magnitude in terms of alterations of representations of the unconditional stimulus. Another is its acknowledgement of the capacity of associative bonds to survive behavioral extinction. The model describes much of the data reported from excitatory conditioning experiments and predicts counterintuitive phenomena. This work was supported by Natural Sciences and Engineering Research Council grant #U0262 awarded to the first author.     

Conceptually driven pharmacologic approaches to acute trauma

Secondary prevention of posttraumatic stress disorder (PTSD) entails intervening in the aftermath of a traumatic event to forestall the development of PTSD. There has been little psychopharmacologic research in this area. This is surprising, given that PTSD is the mental disorder with the most clearly identified cause and onset. In a translational model of PTSD's pathogenesis presented herein: A traumatic event (unconditioned stimulus) overstimulates endogenous stress hormones (unconditioned response); these mediate an overconsolidation of the event's memory trace; recall of the event in response to reminders (conditioned stimulus); releases further stress hormones (conditioned response); these cause further overconsolidation; and the overconsolidated memory generates PTSD symptoms. Noradrenergic hyperactivity in the basolateral amygdala is hypothesized to mediate this cycle. Preventing pre-synaptic norepinephrine release with alpha2-adrenergic agonists or opioids, or blocking post-synaptic norepinephrine receptors with beta-adrenergic antagonists such as propranolol, reduces hormonally enhanced memories and fear conditioning. Two controlled studies of trauma victims presenting to emergency rooms suggest that posttrauma propranolol reduces subsequent PTSD, as does one naturalistic clinical study of morphine treatment of burned children. Cortisol both enhances memory consolidation and reduces memory retrieval, leading to mixed predictions. Two controlled studies of intensive care unit patients found that cortisol reduced PTSD. One study did not find benzodiazepines effective in preventing PTSD. Selective serotonin reuptake inhibitors, antiepileptics, and alpha2-adrenergic agonists have yet to be tried.     

Uncertainty, as defined by the contingency between environmental events, and the adrenocortical response of the rat to electric shock

The pituitary-adrenal system is thought to be sensitive to the degree of uncertainty in a situation. In addition, there is some question whether the pituitary-adrenal system can be conditioned in a Pavlovian sense. Three experiments are reported here. The first and third sought to define uncertainty in terms of conditioned stimulus-unconditioned stimulus (CB-US) and US-US contingencies, which vary the amount of information that can be used to predict the occurrence of discrete shocks. The second experiment examined the possibility that the adrenocortical system was subject to the laws of Pavlovian conditioning, by using a conditioned emotional response paradigm. The results showed that the magnitude of the Pituitary-adrenal response varied in a curvilinear manner along the dimension of uncertainty. Very low and very high degrees of uncertainty resulted in greater corticosterone elevations than did moderate levels. No evidence for Pavlovian conditioning of the adrencortical system was found, although behavioral measures showed fear conditioning. The data presented were supportive of the hypothesis that the pituitary-adrenal response reflects the operation of an arousal system.     

L-Dopa repairs deficits in locomotor and investigatory exploration produced by denervation of catecholamine terminal fields in the forebrain of rats.

In a previous study rats were shown to have decreased locomotor and investigatory exploration after bilateral microinjections of 6-hydroxydopamine into the anterolateral hypothalamus. These deficits correlate with the loss of catecholamine terminals in neocortical, limbic, and anteromedioventral striatal brain sites. To test whether this correlation was causal, central catecholamines were increased by the intraperitoneal administration of L-3,4-dihydroxyphenylalanine (L-dopa), 10--40 mg/kg) after inhibition of extracerebral L-amino acid decarboxylase. Such treatment repaired the deficits in locomotor exploration and investigation in 6-hydroxydopamine rats. Pretreatment with the catecholamine antagonist chlorpromazine (1--2 mg/kg) blocked the increase in locomotor exploration and investigation produced by L-dopa in 6-hydroxydopamine rats. The results suggest, but do not prove, that L-dopa produced these behavioral effects by increasing central catecholamines at the denervated catecholamine receptor sites in the forebrain. These data and the data from the previous study are complementary evidence for the hypothesis that forebrain catecholamine synaptic action is necessary for normal exploratory behavior.     

Autoshaping the pigeon's gape response: acquisition and topography as a function of reinforcer type and magnitude.

The pigeon's key-pecking response is experimentally dissociable into transport (head movement) and gape (jaw movement) components. During conditioning of the key-pecking response, both components come under the control of the conditioned stimulus. To study the acquisition of gape conditioned responses and to clarify the contribution of unconditioned stimulus (reinforcer) variables to the form of the response, gape and key-contact responses were recorded during an autoshaping procedure and reinforcer properties were systematically varied. One group of 8 pigeons was food deprived and subgroups of 2 birds each were exposed to four different pellet sizes as reinforcers, each reinforcer signaled by a keylight conditioned stimulus. A second group was water deprived and received water reinforcers paired with the conditioned stimulus. Water- or food-deprived control groups received appropriate water or food reinforcers that were randomly delivered with respect to the keylight stimulus. Acquisition of the conditioned gape response frequently preceded key-contact responses, and gape conditioned responses were generally elicited at higher rates than were key contacts. The form of the conditioned gape was similar to, but not identical with, the form of the unconditioned gape. The gape component is a critical topographical feature of the conditioned key peck, a sensitive measure of conditioning during autoshaping, and an important source of the observed similarities in the form of conditioned and consummatory responses.     

Varying temporal location of a conditioned stimulus in heart rate conditioning ofMacaca mulatta

The several functions that a stimulus can assume were investigated in a Pavlovian conditioning procedure. The subjects were six rhesus monkeys; the response under observation was heart rate. The conditioning began with a temporal separation of zero between a signal and a regularly repeating electric shock; the signal was then moved to a series of earlier locations in the inter-shock interval. After six sessions at each location, two sessions followed in which only the shock was delivered periodically. The findings included: (1) A two-phased conditioned cardiac rate response seen at the first location became more multiphasic and irregular during longer intervals between signal and shock; (2) the location where the conditioned response peaked became increasingly variable as the signal was moved back, but this variability maintained a constant proportion to the signal-shock interval; and, (3) heart rate during a presignal period, and during a comparable period in shock only sessions, was generally deceleratory early in training and acceleratory thereafter. Sessions with the signal showed heart rate in the presignal period to have become acceleratory earlier in training than sessions with shock only. The data pertain to stimulus control over heart rate as a function of: (A) the temporal proximity of a signal to an aversive stimulus; and, (B) the presence or absence of the signal. The use of appropriate response units in cardiac conditioning is also discussed.     

Acquisition of the classically conditioned eyeblink response in humans over the life span

Human subjects ranging in age from 18 to 85 years underwent classical conditioning of the eyeblink response to a tone conditioned stimulus (CS) and an air-puff unconditioned stimulus (UCS). There was a decline in percentage of conditioned responses with age. This decline was most noticeable in subjects over age 50. These conditioning deficits were not due to age-related changes in sensitivity to the tone CS or the air-puff UCS, nor could the conditioning deficits be attributed to an age-related decline in general cognitive abilities or to changes in spontaneous blink rates. The results are discussed in terms of using the classically conditioned eyeblink in humans in conjunction with the classically conditioned nictitating membrane response in rabbits as a model system for studying the neurobiology of age-related conditioning deficits.     

The role of the nucleus basalis magnocellularis in fear conditioning consolidation in the rat

The nucleus basalis magnocellularis (NBM) is known to be involved in the memorization of several conditioned responses. To investigate the role of the NBM in fear conditioning memorization, this neural site was subjected to fully reversible tetrodotoxin (TTX) inactivation during consolidation in adult male Wistar rats that had undergone fear training to acoustic conditioned stimulus (CS) and context. TTX was stereotaxically administered to different groups of rats at increasing intervals after the acquisition session. Memory was assessed as the conditioned freezing duration measured during retention testing, always performed 72 and 96 h after TTX administration. In this way, there was no interference with normal NBM function during either acquisition or retrieval phases, allowing any amnesic effect to be due only to consolidation disruption. The results show that for contextual fear response memory consolidation, NBM functional integrity is necessary up to 24 h post-acquisition. On the other hand, NBM functional integrity was shown to be necessary for memory consolidation of the acoustic CS fear response only immediately after acquisition and not 24-h post-acquisition. The present findings help to elucidate the role of the NBM in memory consolidation and better define the neural circuits involved in fear memories.     

Autoshaping in the rat: The effects of localizable visual and auditory signals for food

Two experiments investigated autoshaping in rats to localizable visual and auditory conditioned stimuli predicting response-independent food. In Experiment 1 considerable conditioned-stimulus approach behavior was generated by a localizable visual conditioned stimulus that was situated approximately 35 cm from the food tray. Using the same apparatus in Experiment 2 we found that the conditioned-stimulus approach was generated only to a visual conditioned stimulus and not to a localizable auditory conditioned stimulus even though subjects (1) could discriminate presentations of the auditory conditioned stimulus, (2) had associated it with food, (3) could localize it, and (4) would approach the auditory stimulus if this behavior constituted an instrumental response to food. The predominant conditioned responses to the auditory stimuli were goal tracking (entering the food tray) and orienting towards the food-paired conditioned stimulus by head turning and rearing and turning. These results imply that rats do not invariably approach a localizable appetitive Pavlovian conditioned stimulus but that stimulus-approach responses depend on the nature and modality of the conditioned stimulus.     

The peripheral unconditioned stimulus pathway in a model learning system involving defensively conditioned heart rate change in the pigeon.

The peripheral pathway transmitting the unconditioned stimulus information is described in a vertebrate model system for studying learning-visually conditioned heart rate change in the pigeon. In this system footshock serves as the unconditioned stimulus, and it is shown that the effective stimulation field of this stimulus, defined with respect to the unconditioned cardioacceleratory response, includes cutaneous dermatomes 21-25 (L1-Sl). The stimulus information is then transmitted by Group III and IV fibers in portions of the femoral and sciatic nerves which enter the spinal cord over segments 21-25. Further, it is shown that interrupting this pathway by section of dorsal roots 21-25 precludes establishing conditioned heart rate change with footshock as the unconditioned stimulus.     

The effect of on‐ or off‐line extinction of a first‐order conditioned stimulus on a second‐order conditioned response in rats

In a water‐licking experiment with rats, the effects of the extinction of a first‐order conditioned stimulus (CS1) on the suppression of licking established for a second‐order conditioned stimulus (CS2) were explored. Extinction of the first‐order conditioned response (CR1) attenuated the conditioned suppression induced by CS2 when the rats had been allowed to lick water during the CR1 extinction phase. However, if water had been unavailable during the CR1 extinction phase, suppression by CS2 was not affected. The latter result is consistent with other studies of rats' conditioned suppression and suggests that the underlying mechanism of second‐order conditioning in this experiment is a connection between CS2 and the response elicited by CS1 rather than a CS2‐CS1 connection. The former result was interpreted as the CR1 extinction phase encouraging the rats to lick water despite the fear elicited by CS1, and thus, in testing, they licked despite the fear elicited by CS2.     

Conditioning,sensations, and the ergotropic-trophotropic balance

Analysis of Pschonik’s work on conditioning and sensation, in the light of Gellhorn’s studies on the tuning of the central nervous system through changes in the ergotropic-trophotropic balance, leads to the following results. Vasomotor and sensory reactions (VSR) induced by stimulation of cutaneous warmth and pain receptors (US), or by the conditional stimulus (CS) reinforced by the US, show parallel changes in a variety of circumstances: 1) anesthesia of the skin abolishes the effect of the US but not that of the CS; 2) various procedures lead to a reversal of VSR in the conditioned state in response to the US; 3) in a near-neurotic state VSR may be abolished while the plethysmogram gives evidence that ergotropic and trophotropic discharges occur at the same time. Changes in the ergotropic-trophotropic balance at the hypothalamic level alter VSR quantitatively and qualitatively. In an ergotropicallytuned state not only ergotropically-acting stimuli, but also trophotropically-acting stimuli lead to vasoconstriction and pain. Thus, stimulation of pain receptors, as well as stimulation of warmth receptors, produces vasoconstriction and pain. Similarly, these stimuli effect vasodilatation and warmth in the trophotropically-tuned state. It is concluded that the ergotropic-trophotropic balance has a profound influence on sensations and perceptions. It is of clinical significance that this balance can be altered through a conditional reflex mechanism,i.e., on the basis of individual experience.     

The Rescorla-Wagner model: losses in associative strength in compound conditioned stimuli

This series of experiments demonstrated that compound conditioned stimuli (CSs) highly conditioned in isolation lose conditioned response strength when compound-CS-unconditioned stimulus (US) pairings are given. This loss in conditioned responding was a positive function of the number of compound-CS-US pairings and was greater for the more salient stimulus. Finally, if a previously neutral stimulus was compounded with two previously conditioned cues, the neutral stimulus could acquire conditioned inhibitory properties with only compound-CS-US pairings. These results provide support for some aspects of the Rescorla-Wagner model.     

Conditioning of successive adaptive responses to the initial effects of drugs

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.     

Conditioned suppression and conditioned enhancement with the same positive UCS: an effect of CS duration

Previous experiments have shown that positively reinforced operant responding is suppressed during a conditioned stimulus terminated with an electric shock (conditioned suppression). In the present experiment, the conditioned stimulus was terminated with a positive unconditioned stimulus, and it was found that the duration of the conditioned stimulus was a key factor in determining whether response suppression or response enhancement was observed during the stimulus. The lever-pressing responses of rats were maintained by a variable-interval schedule of food reinforcement. While the rats were pressing the lever, a light was occasionally turned on, its offset coincident with a brief period of access to a sucrose solution. In consecutive blocks of sessions, the light duration was 40 sec, 12 sec, or 120 sec. Results showed that the rate of lever pressing was substantially suppressed during the 12-sec stimulus, slightly suppressed during the 40-sec stimulus, and enhanced during the 120-sec stimulus.     

Central cannabinoid receptors modulate acquisition of eyeblink conditioning

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex, particularly the molecular layer, contains a high density of cannabinoid receptors (CB1R). The CB1Rs are located on the axon terminals of parallel fibers, stellate cells, and basket cells where they inhibit neurotransmitter release. The present study examined the effects of a CB1R agonist WIN55,212-2 and antagonist SR141716A on the acquisition of delay eyeblink conditioning in rats. Rats were given subcutaneous administration of 1, 2, or 3 mg/kg of WIN55,212-2 or 1, 3, or 5 mg/kg of SR141716A before each day of acquisition training (10 sessions). Dose-dependent impairments in acquisition were found for WIN55,212-2 and SR141716A, with no effects on spontaneous or nonassociative blinking. However, the magnitude of impairment was greater for WIN55,212-2 than SR141716A. Dose-dependent impairments in conditioned blink response (CR) amplitude and timing were found with WIN55,212-2 but not with SR141716A. The findings support the hypothesis that CB1Rs in the cerebellar cortex play an important role in plasticity mechanisms underlying eyeblink conditioning.     

Potentiation of the acoustic startle response by a conditioned stimulus paired with acoustic startle stimulus in rats

The hypothesis that the standard acoustic startle habituation paradigm contains the elements of Pavlovian fear conditioning was tested. In a potentiated startle response paradigm, a startle stimulus and a light conditioned stimulus (CS) were paired. A startle stimulus then was tested alone or following the CS. Freezing behavior was measured to index conditioned fear. The startle response was potentiated on CS trials, and rats froze more in CS than in non-CS periods. In Experiment 1, response to a previously habituated, weak startle stimulus was potentiated. In Experiment 2, response to the same stimulus used as the unconditioned stimulus (US) in training was potentiated. This CS-potentiated response retarded the course of response decrements over training sessions as compared with an explictly unpaired control group. Conditioned fear is a standard feature of this habituation paradigm, serves to potentiate the startle response, and provides an associative dimension lacking in the habituation process per se.     

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.