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A simple and reliable method for the positive identification of pavlovian conditioned cocaine effects in open-field behavior.

The identification of the Pavlovian conditioning of the behavioral effects of cocaine using open-field behavior is often confounded by the concurrent occurrence of behavioral habituation in control animals. Thus, differences in spontaneous activity between cocaine conditioned animals vs. control can be explained either by Pavlovian conditioning of the psychostimulant effects of cocaine or by anti-habituation effects of cocaine. In a series of experiments we demonstrate that location of the animal within the open-field permits a positive identification of cocaine conditioning independent from habituation factors. In three separate experiments, five daily paired 10 mg/kg cocaine treatments induced both increased locomotion as well as increased entries into the central zone in the open-field as compared with saline and cocaine unpaired control groups. Critically, in three experimental replications, animals which received the paired cocaine treatment exhibited statistically significant increases in central zone entries in non-drug tests for conditioning both with respect to the saline and cocaine unpaired groups as well as to pre-conditioning levels. In contrast, the spontaneous locomotor behavior in the cocaine paired group on the conditioning test did not reliably increase above pre-conditioning levels but rather was only increased when compared with the reduced habituated activity levels in the saline and cocaine unpaired groups. The conditioned increase in central zone entries induced by cocaine was equally robust at 4 and 9 days post-conditioning but yet could be extinguished with repeated non-cocaine exposures to the open-field environment.

Animals↗

Conditioned immunomodulation: investigations of the role of endogenous activity at mu, kappa, and delta opioid receptor subtypes.

The present investigations were designed to determine the role of activity at mu, kappa, and delta opioid receptor subtypes in conditioned immunomodulation by evaluating the effects of selective opioid receptor antagonists on conditioned stimulus-induced alterations in immune status. Lewis rats were exposed to an aversive conditioned stimulus that was developed through pairings with electric footshock. This aversive conditioned stimulus induces a reduction in splenic natural killer cell activity, splenocyte proliferation in response to mitogens, and diminished levels of interferon-gamma (IFN-gamma) production by splenocytes. Intracerebroventricular (i.c.v.) administration of the opioid antagonist naltrexone or the mu 1-selective antagonist naloxonazine blocked conditioned alterations of immune status, indicating that activity at mu-opioid receptors is involved in conditioned immunomodulation. Further support for the involvement of mu-opioid receptors within the central nervous system is provided by data showing that peripheral administration of naloxonazine, at doses shown to be effective when administered i.c.v., had no effect on conditioned alterations of immune status. Ventricular administration of the kappa receptor antagonist nor-binaltorphimine (nor-BNI) did not antagonize the immunomodulatory effects of the conditioned stimulus. Administration of the delta receptor antagonist naltrindole also did not antagonize the conditioned alterations of immune status. Collectively, the results of this study indicate that the alterations of immune status produced by an aversive conditioned stimulus require activity at mu-opioid receptors, possibly mu 1, within the central nervous system.

Animals↗

Behaviorally conditioned immunosuppression using cyclosporine A: central nervous system reduces IL-2 production via splenic innervation.

Bi-directional interactions between the central nervous system (CNS) and immune system are demonstrated by the modification of immune function using behavioral conditioning. However, the mechanisms by which the CNS achieves conditioned immunomodulation are still in question. Here, we report that the immunosuppressive effects of cyclosporine A (CsA) can be behaviorally conditioned in rats using saccharin as a gustatory conditioned stimulus. The conditioned effects were compared to control groups that received CsA paired with water (sham-conditioned), CsA injection on test days (CsA-treated), and unhandled rats (untreated). In conditioned animals, the mitogen-induced lymphocyte proliferation in the spleen is significantly suppressed, and the survival time of heterotopic heart allografts prolonged. These effects are paralleled by conditioned inhibition of IL-2 and IFN-gamma synthesis by splenocytes. Furthermore, the CNS-induced immunosuppression is mediated neuronally and not via the blood, since the conditioned reduction of proliferation and cytokine production is completely abrogated after surgical denervation of the spleen. Thus, during conditioning, the CNS learns to reinstate at demand a CsA-like immunosuppression via splenic innervation. This might be used as a supportive therapy for controlling immune functions.

Animals↗

Cocaine conditioning and cocaine sensitization: what is the relationship?

With repeated cocaine use, cocaine conditioned behavior develops to associated stimuli, and in addition, sensitization can occur to the unconditioned stimulant effects of cocaine. To investigate the relationship between the conditioned and unconditioned behavioral effects of repeated cocaine use, two groups of rats (n = 7) were given five daily paired cocaine treatments (10 mg/kg i.p.) immediately before a 20-min placement in an open-field environment. Other groups received either saline before testing or cocaine unpaired which was administered 30 min after testing in the homecage. When tested in the open-field with saline for conditioned effects, the two cocaine paired groups selectively exhibited substantial and equivalent cocaine conditioned responses. One of these groups was subjected to an extinction procedure which was effective in eliminating the cocaine conditioned responses. Subsequently, all the rats which had received cocaine in the first phase of the experiment, paired and unpaired, along with a subset of saline animals were given a cocaine (10 mg/kg i.p.) challenge test. The paired cocaine animals exhibited an earlier onset of the cocaine induced behavioral response (sensitization) as compared with the saline and the unpaired cocaine animals. Critically, the sensitization effects were unaffected by extinction, and in addition, the conditioned response did not contribute to the sensitization effect. It is suggested that the cocaine drug response occludes the cocaine conditioned response. Subsequent to this sensitization test, the animals were retested for conditioning. In this test, the paired cocaine animals which had not been subjected to the extinction procedure still exhibited a conditioned cocaine response, whereas, the paired cocaine group subjected to extinction was indistinguishable from saline controls. Although the present results show that Pavlovian conditioned responses to exteroceptive contextual cues do not directly contribute to cocaine induced behavioral sensitization effects, the sensitization effects were context-specific, and therefore, were tied to associative processes. It is suggested that context specificity is mediated by a compound stimulus complex comprised of exteroceptive stimuli and interoceptive cocaine drug cues. Furthermore, these exteroceptive and interoceptive cues associated with cocaine effectively expedite the onset of cocaine effects, and thereby, facilitate the addictive potency of cocaine.

Animals↗

Operant conditioning of antennal movements in the honey bee.

An operant learning protocol was developed for honeybees that are fixed in small tubes. The bees had to touch one or two small silver plates within the range of one antenna. The contacts of the antenna with the silver plates were registered electronically. Three conditioning protocols were analysed. In the first series the conditioned increase of the contact frequency was tested. The animals could touch one plate and received a reward (a small drop of sucrose) whenever the instantaneous frequency at this plate was more than one or two standard deviations above the spontaneous frequency. After conditioning the bees showed a significant increase of the contact frequency. No significant changes were found in a group of yoked controls. In the second series differential conditioning was tested. The animals could touch two silver plates. The spontaneous behaviour was measured and the animals received the reward upon touching the plate with the lower spontaneous frequency. The rewards were only applied whenever the instantaneous frequency exceeded a defined threshold. After ten conditioning trials the animals showed a significant increase in contact frequency for the conditioned plate compared to spontaneous behaviour. No significant changes were found in a group of yoked controls. In the third series reversal learning was tested. The animals were able to touch two silver plates. They were first conditioned to touch the plate which had the lower spontaneous contact frequency. After these conditioning trials they were tested for 10 min and subsequently conditioned to the alternative plate. The experiments demonstrated significant reversal learning compared to yoked controls. This new operant conditioning paradigm for the bee offers the possibility to analyse at the physiological level the mechanisms underlying different forms of learning in this insect.

Animals↗

Behavioural correlates of conditioned ventilatory responses to hypoxia in rats.

To examine the possible contribution of behavioural arousal to ventilatory conditioning, we performed a differential conditioning experiment using two odours as the paired conditioned stimulus (CS + ) and unpaired conditioned stimulus (CS-) and a hypoxic mixture (7.5% O2) as the unconditioned stimulus (US) in 24 adult male rats. Vanillin was the CS + and rose the CS - in half the rats, and vice versa in the other half. Each rat underwent 26 paired CS + /hypoxia trials and 26 CS - trials in alternation, followed by two CS + only and two CS - trials to test for conditioning. Analysis of breathing variables and behavioural scores during the test showed two qualitatively different conditioned responses. The initial conditioned response was characterised by short breath durations (TT), frequent sniffing episodes, and arousal responses. Following this, a specific, conditioned increase in tidal volume (VT) and levelling off of sniffing and motor activities occurred. The early TT-response and late VT-response to CS + both contributed to an increase in ventilation (VI). The present data show that the association of an odour and hypoxia elicits a biphasic ventilatory conditioned response, of which the first component is integrated into conditioned arousal.

Animals↗

Induction of NGFI-B mRNA following contextual fear conditioning and its blockade by diazepam.

Expression of the immediate-early gene, NGFI-B (nerve growth factor inducible gene B), was examined in the amygdala, hippocampus, and neocortex following contextual fear conditioning. Rats were either handled, placed within the testing context without receiving the footshock, received a footshock immediately upon placement within the context, or received a footshock after a 3-min delay (delayed-shock). Only the delayed-shock group displayed a fear response (freezing) in the post-shock period and in a retention test 24 h after fear conditioning. Expression of NGFI-B mRNA was increased in the dorsolateral part of the lateral nucleus of the amygdala (LaDL) and the neocortex 30 min following conditioning in the delayed-shock group compared to the other three groups. In addition, following a retention test conducted 24 h after fear conditioning, NGFI-B mRNA expression was increased in the neocortex of the delayed-shock group compared to the handled group. In a subsequent experiment, the effects of pretreatment with the anxiolytic drug, diazepam, on fear conditioning and the concomitant increases in NGFI-B mRNA were investigated. Rats administered a 2.5 mg/kg, i.p. dose of diazepam before fear conditioning did not acquire contextual fear as demonstrated by a lack of freezing in a retention test. Although diazepam blocked fear conditioning while the 40% propylene glycol, 10% ethanol vehicle solution did not, both diazepam and the vehicle reduced the conditioning-induced increase in NGFI-B expression in the LaDL. In contrast, the fear-conditioning-induced NGFI-B increase in the neocortex was blocked by diazepam, but not by the vehicle. The data suggest that the transcriptional factor NGFI-B in the LaDL and neocortex may play a functional role in learning and memory of contextual fear, but blocking the increase in NGFI-B expression in the LaDL is not essential for diazepam to interfere with fear conditioning.

Amygdala↗

Aims of conditioning.

Nuclear warfare research and treatment of radiation accident victims uncovered the potential of hemopoietic stem cell transplants. Prior to transplantation of hemopoietic stem cells patients receive "conditioning" agents: high-dose total-body irradiation and/or high-dose chemotherapy. High-dose conditioning causes at least 20% procedure-related mortality. Recent efforts to reduce procedure-related mortality by the use of low-dose conditioning included low-dose total-body irradiation, immunosuppressive agents, and the replacement of high-dose chemotherapy by donor lymphocytes for graft-vs-tumor effects. Procedure-related mortality remains high (10-30%). Tumor recurrence at 1 year is over 50%. In this review, the aims of conditioning (creation of space, prevention of hemopoietic stem cell rejection, eradication of immune memory, and eradication of tumor cells) are reexamined in those patient and animal studies that explore quantitative and mechanistic conditioning issues. Translational experimental animal models provide the best opportunities for the development of less toxic conditioning agents for human patients and require an analysis of the consequences of the effects of new conditioning agents on host-vs-graft as well as graft-vs-host reactions. Total-body irradiation or other forms of radiation create space, prevent rejection of histocompatible stem cells, and can eliminate immune memory to autoimmune antigens at modest, nontoxic doses. The transplantation of histoincompatible stem cells and the eradication of large loads of tumor cells remain problematic. The therapeutic index of allogeneic stem cell transplants will increase if new conditioning agents are targeted only to those host tissues that need conditioning: hemopoietic system, immune system, and tumor masses. Radiolabeled immunoglobulins are among the most promising new, low-toxicity conditioning agents.

Animals↗

Pretraining tetanic fimbrial stimulation impairs the expression but not the acquisition of contextual fear conditioning in mice.

We recently reported that the pretraining induction of long-term potentiation in the lateral septum by fimbrial tetanic stimulation altered contextual fear conditioning in mice. The aim of the present study was to examine at which stage of fear conditioning (i.e. either acquisition or expression) this impairment takes place. Mice implanted with stimulating electrodes in the fimbria and recording electrodes in the lateral septal were conditioned to acquire fear towards a novel context using a footshock procedure. Twenty-four hours after conditioning, animals were re-exposed to the conditioning environment and the level of freezing behavior served as the measure of conditioned fear. The level of fimbrial-lateral septal synaptic neurotransmission was manipulated using either fimbrial tetanic stimulation (which induced septal long-term potentiation) alone, or followed by fimbrial low-frequency stimulation producing depotentiation of the previously established long-term potentiation. The results showed that (i) septal long-term potentiation induced either prior to acquisition or only prior to retention testing impaired conditioned freezing; and (ii) the impairing effect of pretraining induction of long-term potentiation on conditioned freezing was not only abolished by fimbrial low-frequency stimulation administered prior to retention testing but actually produced enhanced conditioned freezing with respect to controls. These data suggest that the level of fimbrial-lateral septal synaptic neurotransmission may influence the expression, but not the acquisition, of contextual fear conditioning.

Animals↗

Inhibition of premature ventricular extrastimuli by subthreshold conditioning stimuli.

The purpose of this study was to determine whether trains of subthreshold high frequency conditioning stimuli (333 Hz, 1 ms duration, 2 ms interval) delivered to the canine ventricle inhibited the response to a premature stimulus (S2) more effectively than did a single subthreshold conditioning stimulus. It was found that trains of conditioning stimuli (mean 1.21 mA) inhibited the response to S2 152 ms beyond expiration of the ventricular effective refractory period, whereas a single conditioning stimulus inhibited S2 only 20 ms or less beyond the ventricular effective refractory period. In late diastole, trains of conditioning stimuli failed to inhibit S2 when the train of stimuli caused ventricular depolarization or the latter occurred in response to the next sinus impulse. Trains of conditioning stimuli did not induce ventricular arrhythmias. Lidocaine or autonomic blockade did not alter the response to trains of conditioning stimuli. Trains of conditioning stimuli or a single conditioning stimulus inhibited the response to S2 only when they were delivered at the same electrode site. By lengthening the ventricular effective refractory period, trains of conditioning stimuli could prevent or terminate tachycardias, but this possibility is constrained, at present, by the spatial limitations of the technique.

Animals↗

Altered ambient temperature and ethanol-induced conditioned place preference in mice.

Previous studies with rats exposed to altered ambient temperature (Ta) or with mice selectively bred for their thermal response to ethanol have shown that a reduced hypothermic response is correlated with decreased place aversion and greater place preference, respectively. The present experiment was designed to test whether alterations in Ta would alter ethanol's ability to produce conditioned place preference in genetically heterogeneous mice. Three groups of mice underwent a differential conditioning procedure that paired one distinctive floor texture with ethanol (2.25 g/kg, i.p.) and a different floor texture with saline. During conditioning, each group was exposed to a different Ta: cold (10 degrees C), normal (21 degrees C), or warm (34 degrees C). Each group was further divided and subgroups were tested for preference at either the conditioning temperature or a different temperature. Consistent with previous findings, mice conditioned and tested at normal Ta developed a conditioned preference for the ethanol-paired floor. In contrast, mice exposed to a warm or cold Ta during conditioning or testing failed to show place conditioning. Although exposure to either warm or cold Ta interfered with place conditioning, only the warm Ta had an effect on hypothermia. These findings suggest that altered Ta produced stimuli that may have interfered with the association between floor cues and ethanol during conditioning or interfered with expression of this association during testing.

Animals↗

A pharmacological analysis of the substrates underlying conditioned feeding induced by repeated opioid stimulation of the nucleus accumbens.

It has previously been demonstrated that stimulation of opiate receptors within the nucleus accumbens results in marked hyperphagia, perhaps reflecting enhancement of taste palatability. Rats that have received multiple morphine treatments also increase feeding in response to environmental stimuli that have been associated with the morphine injections. The present investigation further examined this phenomenon. In Experiment 1, it was shown that induction of conditioned feeding was dose-dependent; significant conditioned feeding was obtained with repeated (n = 5) intra-accumbens injections of 5 or 10 microg/microl morphine but not with saline or 1 microg. The conditioned feeding response was blocked by systemic naltrexone (5 mg/kg). In the second experiment, co-treatment with either a D-1 (SCH 23390, 0.1 mg/kg) or D-2 (haloperidol, 0.25 mg/kg) antagonist did not block the development of conditioned feeding, nor did these drugs block morphine-induced feeding. In Experiment 3, it was found that systemic naltrexone blocked the expression of conditioned feeding (confirming Experiment 1), as did SCH-23390, whereas haloperidol did not affect expression of conditioned feeding. In the fourth experiment, we observed that significant conditioned feeding was induced with repeated treatment with the selective mu agonist D-Ala2, NMe-phe4, Glyol5-enkephalin (DAMGO, 2.5 microg), but not with the delta agonist D-Pen2,5-enkephalin (DPEN, 3.1 microg). The final experiment tested the diurnal variability of the expression of conditioned feeding, and it was found that the magnitude of the effect depended on time of day. In summary, the development of opioid-induced conditioned feeding depends on mu opiate receptor stimulation, but not dopamine receptor stimulation. Its expression, however, involves both opiate and D-1 receptor activation. These findings are considered in terms of putative neural mechanisms governing conditioned meal initiation, and implications for compulsive eating and bulimia are also discussed.

Analgesics, Opioid↗

Conditioned locomotion is not correlated with behavioral sensitization to cocaine: an intra-laboratory multi-sample analysis.

Pre-clinical and clinical studies have demonstrated the importance of associative factors in regulating craving for drugs of abuse. To model these conditioned effects, we have examine cue-induced conditioned locomotion in rodents. The present study involved analysis of several of our prior studies to evaluate the relationship between conditioned locomotion and behavioral sensitization using a within-subjects analysis. Both are animal models used to study addiction, so it is important to know if one is predictive of the other, and more generally, if drug effects are predictive of conditioned effects. In all of our studies, Paired subjects received cocaine during presentation of conditioned stimuli while Unpaired subjects received saline with the stimuli and cocaine at the home cages an hour later. Paired subjects typically displayed behavioral sensitization over the course of training. After the completion of training, all subjects were tested with the conditioned stimuli in the absence of drug and conditioned locomotion was measured. The response of Unpaired subjects on the last training day was positively correlated with their response on test day, as expected since both days were nearly identical (stimuli presented without cocaine). However, for Paired subjects, the magnitude of conditioned locomotion on the drug-free test day was not positively correlated with the magnitude of behavioral sensitization. These results underscore the importance of focusing research on drug-free conditioned behaviors when attempting to model conditioned responses to drug related cues in human addicts.

Animals↗

Paradoxical effects of proximal unconditioned stimulus preexposure: interference with and conditioning of a taste aversion.

Taste aversions were conditioned in rats by giving the subjects an injection of lithium following exposure to saccharin. Treatment with lithium shortly (30 to 60 min.) before such a conditioning trial disrupted the taste-aversion learning produced by the postsaccharin drug injection. In Experiment 1, this interference effect was found to be a monotonically decreasing function of the preexposure-to-conditioning interval. The greatest disruption of conditioning was observed with a 30-min. preexposure-to-conditioning interval, and no interference occurred if the preexposure was administered 1 or 2 days before conditioning. These results suggest that in addition to the more durable effects of unconditioned stimulus (US) preexposure emphasized by previous investigators, US preexposure also activates temporary mechanisms that likewise attenuate subsequent conditioning. Experiment 2 demonstrated that lithium given before saccharin exposure disrupts the conditioning produced by a postsaccharin drug injection even if the presaccharin injection would itself otherwise be effective in producing a "backward" conditioned saccharin aversion. This outcome indicates that proximal US preexposure can have two opposite and paradoxical effects: It can interfere with as well as condition a taste aversion.

Animals↗

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.

Animals↗

Transfer and counterconditioning of conditional control in the rabbit nictitating membrane response.

Two experiments using the rabbit nictitating membrane response investigated whether training in one conditional discrimination (A-->X+, B-->X-), enabled the feature cues (A and B) to modulate responding to another CS (Y) trained as a target stimulus in a second conditional discrimination (C-->Y+, D-->Y-). There was near-complete transfer of the feature cue's conditional control, indicating that the feature cue's ability to modulate responding is not based on an association specific to the training target. Experiment 2 also revealed that the role of a stimulus to act as a conditional cue is affected by its ability to act as a simple conditioned excitor or inhibitor. Following initial acquisition of two conditional discriminations, two feature cues were reinforced in a pattern consistent with the initial conditional discrimination (A-->+, B-->-), where as the other two feature cues were reinforced in the reverse pattern to that of the original conditional discrimination (C-->-, D-->+). Subsequent tests revealed that the reversed training of the feature cues interfered with the original conditional discriminations. The results are consistent with theories that the feature cue gains an association with a representation of the emotional attributes of the US, which acts to modulate responding to the target stimulus through a diffuse change in motivational level. However, hierarchical theories of conditional discriminations that assume a lack of CS-specificity may also be able to explain the findings.

Analysis of Variance↗

Operant conditioning of H-reflex in spinal cord-injured rats.

Operant conditioning of the spinal stretch reflex or its electrical analog, the H-reflex, is a new model for exploring the mechanisms of supraspinal control over spinal cord function. Both rats and primates can gradually increase (HRup conditioning mode) or decrease (HRdown conditioning mode) soleus H-reflex magnitude when exposed to an operant conditioning task. This study used H-reflex operant conditioning to assess and modify spinal cord function after injury. Soleus H-reflexes were elicited and recorded with chronically implanted electrodes from rats that had been subjected to calibrated contusion injuries to the spinal cord at T8. From 18 to 140 days after injury, background EMG, M response amplitude, and initial H-reflex amplitude were not significantly different from those of normal rats. HRdown conditioning was successful in some, but not all, spinal cord-injured rats. The H-reflex decrease achieved by conditioning was inversely correlated with the severity of the injury as assessed histologically or by time to return of bladder function. It was not correlated with the length of time between injury and the beginning of conditioning. The results confirm the importance of descending control from supraspinal structures in mediating operantly conditioned change in H-reflex amplitude. In conjunction with recent human studies, they suggest that H-reflex conditioning could provide a sensitive new means for assessing spinal cord function after injury, and might also provide a method for initiating and guiding functional rehabilitation.

Animals↗

Sensitization to apomorphine in pigeons is due to conditioning, subject to generalization but resistant to extinction.

Apomorphine (Apo) administration induces a persistent bout of pecking in pigeons and other birds. Repeated injections of Apo in pigeons lead to sensitization, i.e. the pecking response to a particular dose increases up to a dose-dependent asymptotic level. It is also known that Apo-induced pecking can be classically conditioned to the cage environment where the animals experience the effect of the drug. Here we address the question of whether, and to what extent, the sensitization effect arises as a consequence of a conditioning or of a pharmacological process. An extinction experiment demonstrated that an extinction procedure supposed to be effective in inhibiting the conditioned pecking response was not effective in suppressing the sensitization to Apo, thus casting provisional doubt on the conditioning hypothesis. However, a conditioning experiment demonstrated that the sensitization effect undoubtedly involved an important component of conditioning to an experimental cage environment, but also suggested that there was an additional component possibly not due to learning. A generalization experiment, however, showed that this second component was very probably due to a stimulus generalization effect deriving from conditioning to the home cage, suggesting that learning can account for most, if not all, of the increase in Apo-induced pecking and that an exclusively pharmacological sensitization process plays, at best, a minor role. The apparent contrast between the results of the first experiment, indicating that the sensitization is not affected by inhibitory conditioning, and the results of the last two experiments, suggesting that the sensitization is due to excitatory conditioning, can be resolved by assuming that Apo induces a drug-state-dependent conditioning. These results are related to findings and arguments concerning the sensitization to psychostimulant drugs in mammals.

Animals↗