Effect of number of conditioning trials on the development of associative tolerance to morphine

The acquisition of associative tolerance to the analgesic effects of morphine was investigated by giving independent groups of rats 1, 3, 5, 8, 14, 20, or 30 administrations of drug either explicitly paired or unpaired with a distinctive context. Tolerance, assessed on a tail-flick device using dose-response curve (DRC) methodology, developed more rapidly and reached greater magnitude when morphine and the distinctive context were explicitly paired rather than explicitly unpaired. Tolerance magnitude in both conditions reached a maximum at eight conditioning sessions. It is argued that the tolerance found in both treatment groups was associatively controlled. The function of handling and injection cues as conditioned stimuli, and the deleterious effects of latent inhibition and partial reinforcement on conditioned excitation and conditioned inhibition are discussed.     

Enhanced conditioned inhibition following repeated pretreatment with d-amphetamine

We have shown that prior repeated exposure to d-amphetamine facilitates appetitive Pavlovian conditioning. However, animals sensitised in this manner also show elevated levels of stimulated activity. To investigate whether enhanced conditioning was dependent upon increased activity, a conditioned inhibition task was employed in the present study. Rats received d-amphetamine (2 mg/kg, IP) or vehicle once per day for 7 days. After a 7-day drug-free period, an activity assay confirmed that repeated d-amphetamine treatment markedly elevated the locomotor response to a subsequent challenge with 0.5 mg/kg d-amphetamine. Conditioning began 6 days later. In phase 1, stimulus A+ (light or tone) immediately preceded sucrose availability (excitatory conditioning). In phase 2, sucrose again was presented after A+ alone, but not after presentation of a compound of A+ with a second stimulus (AB−). Sensitisation enhanced the acquisition of conditioned approach behaviour to the excitatory stimulus A+ in phase 1. Furthermore, acquisition of conditioned inhibition to the stimulus compound, AB−, was also facilitated. Thus, sensitised rats showed reduced levels of responding to the stimulus compound far sooner than controls. Finally, a retardation test was carried out in stage 3, in which the inhibitory stimulus B- was paired alone with sucrose reward. Sensitised rats initially showed retarded acquisition of excitatory conditioned responding relative to controls, suggesting that B possessed stronger inhibitory associations in these animals. However, sensitised animals again exhibited higher levels of responding in later sessions, consistent with the enhanced excitatory conditioning shown in phase 1. These findings suggest that prior repeated d-amphetamine enhanced the acquisition of inhibitory and excitatory Pavlovian associations; a propensity not readily attributable to stimulated locomotor hyperactivity. Received: 29 December 1997/Final version: 21 July 1998     

Development of both conditioning and sensitization of the behavioral activating effects of amphetamine is blocked by the non-competitive NMDA receptor antagonist,MK-801

The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, has been shown to block the development of sensitization of the behavioral activating effects of amphetamine. Three experiments were designed to determine in rats whether MK-801 had its effects through interference with long-term changes underlying sensitization, per se, or through interference with the development of conditioning of the drug effect to the environment where the drug was given. In experiment 1, conditioning was promoted by explicitly pairing amphetamine (1.5 mg/kg, IP) with the testing environment. In experiment 2, a random-pairing procedure was used to eliminate the possibility of association between the drug and a specific context. Experiment 3 was carried out to assess the duration of the blockade of sensitization by MK-801. The effect of MK-801 (0.25 mg/kg, IP) during amphetamine pre-exposure was studied in tests for conditioning (following saline injections, experiment 1) and in tests for sensitization (following 0.75 mg/kg amphetamine, experiments 1, 2 and 3). It was found in experiment 1 that MK-801 given with amphetamine during the amphetamine pre-exposure phase blocked the development of both conditioning activity and environment-specific sensitization to amphetamine. The results of experiment 2, showing that sensitization to amphetamine was blocked by MK-801 even when conditioning was prevented, suggest that the two effects of MK-801 are independent, and may implicate different sites of action. Experiment 3 showed that the blockade of sensitization by MK-801 was evident in tests made 10 days after pre-exposure to amphetamine, supporting the view that MK-801 interferes with long-term changes underlying sensitization to amphetamine.     

Apomorphine conditioning and sensitization: The paired/unpaired treatment order as a new major determinant of drug conditioned and sensitization effects

Repeated treatments with psychostimulant drugs generate behavioral sensitization. In the present study we employed a paired/unpaired protocol to assess the effects of repeated apomorphine (2.0 mg/kg) treatments upon locomotion behavior. In the first experiment we assessed the effects of conditioning upon apomorphine sensitization. Neither the extinction of the conditioned response nor a counter-conditioning procedure in which we paired an inhibitory treatment (apomorphine 0.05 mg/kg) with the previously established conditioned stimulus modified the sensitization response. In the second experiment, we administered the paired/unpaired protocol in two phases. In the second phase, we reversed the paired/unpaired protocol. Following the first phase, the paired group alone exhibited conditioned locomotion in the vehicle test and a sensitization response. In the second phase, the initial unpaired group which received 5 paired apomorphine trials during the reversal phase did not develop a conditioned response but developed a potentiated sensitization response. This disassociation of the conditioned response from the sensitization response is attributed to an apomorphine anti-habituation effect that can generate a false positive Pavlovian conditioned response effect. The potentiated sensitization response induced by the treatment reversal protocol points to an important role for the sequential experience of the paired/unpaired protocol in behavioral sensitization.     

Same-sex cohabitation under the effects of quinpirole induces a conditioned socio-sexual partner preference in males, but not in female rats

The effects of the dopamine D2-type receptor agonist quinpirole (QNP) were examined on the development of conditioned same-sex partner preference induced by cohabitation in rats. In Experiment 1, males received either saline or QNP (1.25 mg/kg) and cohabited during three trials with almond-scented stimulus males that were sexually naïve. In Experiment 2, males received six trials, and in Experiment 3 received three trials with sexually expert stimulus males. During a final drug-free preference test, males chose between the familiar or a novel male partner. In Experiments 1, 2 and 3 only QNP-treated males displayed a social preference for the familiar male, observed with more time spent together. In Experiment 3 males also displayed a sexual preference observed with more non-contact erections when were exposed to their male partner. In Experiment 4 we tested the effects on OVX, E+P primed females that received 1 systemic injection of either saline or QNP during three conditioning trials. In Experiment 5, females received 2 injections 12-h apart during each trial. Results indicated that both saline and QNP-treated females failed to develop partner preference. These data demonstrate that enhanced D2-type receptor activity during cohabitation facilitates the development of conditioned same-sex partner preference in males, but not in female rats. We discuss the implications for same-sex partner preferences.     

Effect of 5-HT<Subscript>3</Subscript> antagonists and a 5-HT<Subscript>1A</Subscript> agonist on fluoxetine-induced conditioned gaping reactions in rats

Rationale  The effect of manipulation of the serotonin (5-HT) system on conditioned gaping (presumably reflective of nausea in rats) was evaluated. Objective  The potential of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (which produces nausea in the clinic), to produce conditioned gaping in rats and of the 5-HT₃ antagonists (ondansetron and palonosetron) and the 5-HT_1A autoreceptor agonist (8-OH-DPAT) to reverse this effect were evaluated. Materials and methods  In each of four experiments, rats received three pairings of intraorally delivered 17% sucrose solution and fluoxetine (0, 2, 10 or 20 mg/kg) and 72 h later were given a drug-free test trial. In experiment 2, rats were pretreated with the 5-HT₃ antagonists, ondansetron (0, 0.1 or 1.0 mg/kg) or the longer acting palonosetron (0.1 mg/kg), 30 min before each of three sucrose–fluoxetine (20 mg/kg) pairings. In experiment 3, rats were injected with palonosetron (0.1 mg/kg) 2 h before each of three sucrose–fluoxetine (20 mg/kg) or sucrose–lithium chloride (LiCl, 25 mg/kg) pairings. In experiment 4, rats were pretreated with the 5-HT_1A autoreceptor agonist, 8-OH-DPAT (DPAT, 0.1 mg/kg) 30 min before each of three sucrose–fluoxetine (20 mg/kg) pairings. Results  After two sucrose–fluoxetine pairings, the highest dose of fluoxetine tested (20 mg/kg) produced conditioned gaping reactions. These conditioned gaping reactions were prevented by pretreatment with DPAT, but not with the 5-HT₃ antagonists. On the other hand, palonosetron administered 2 h prior to sucrose–LiCl pairings attenuated conditioned gaping reactions. Conclusions  These results suggest that the conditioned nausea produced by SSRIs, but not LiCl, may be resistant to treatment with 5-HT₃ antagonists, but not 5-HT_1A autoreceptor agonists.     

Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA

The conditionability of increases in locomotor activity induced by morphine administration into the ventral tegmental area was studied in rats. Morphine produced a clear increase in locomotor activity that was reversed by the opiate receptor blocker, naloxone, and blocked by the neuroleptic, pimozide, suggesting the mediation of this effect by the ascending mesolimbic dopamine system. The increase in locomotor activity showed sensitization with repeated morphine administrations and this sensitization was found to be specific to the environment in which morphine was administered. Conditioning tests also revealed that, in the absence of morphine, increased locomotor activity was elicited by the administration environment. Pimozide blocked the development of the conditioned sensitization. These data demonstrate that a learned association developed between this excitatory action of morphine and the administration environment. These results have important implications for the role of conditioning factors in relapse to drug use and may provide an explanation for conditioning data obtained when morphine is administered systemically.     

On the importance of placebo timing in rTMS studies for pain relief

The efficacy of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex for neuropathic pain relief is founded on double-blind studies versus placebo. In these studies, however, the analgesic effect of active interventions remained modest compared with the placebo effect. This observation led us to re-evaluate the intrinsic placebo action on pain relief according to the relative timing of active and sham rTMS interventions. In a randomized controlled study including 45 patients, we compared the analgesic effect of sham rTMS that either preceded or followed an active rTMS, which could be itself either successful or unsuccessful. Placebo analgesia differed significantly when the sham rTMS session followed a successful or an unsuccessful active rTMS. Placebo sessions induced significant analgesia when they followed a successful rTMS (mean pain decrease of 11%), whereas they tended to worsen pain when following an unsuccessful rTMS (pain increase of 6%). Only when the sham intervention was applied before any active rTMS were placebo scores unchanged from the baseline. These results probably reflect an unconscious conditioned learning. The timing of placebo relative to active interventions should be taken into account in rTMS studies for pain relief, and possibly in other conditions too. The fact that placebo effects could be enhanced by a previous rTMS with an analgesic effect as low as 10% suggests that a 30% pain decrease threshold in therapeutic trials may be too severe because smaller analgesic effects may have a clinical significance too.     

Arousal response to hypoxia in newborns: Insights from animal models

In newborns, the inability to initiate an arousal response to hypoxia is associated with apnea of prematurity, sudden infant death syndrome, and rare genetic disorders of respiratory control. Despite intensive research, the mechanisms of this response are poorly understood. This paper provides an overview of studies investigating the arousal response to hypoxia, with special emphasis on newborn mouse models. Mutant mouse models can provide valuable information regarding the pathogenesis of genetically determined disorders affecting arousal response to hypoxia, although data remain sparse. In mice, the arousal response to hypoxia emerges immediately after birth, when the ventilatory response to hypoxia is still immature. Habituation of the arousal response occurs after repeated hypoxic episodes. Newborn mice can learn to associate novel odors to hypoxia and respond to those odors by producing alerting responses, suggesting that the arousal response to hypoxia may be shaped by learning processes.     

Can patient–provider interaction increase the effectiveness of medical treatment or even substitute it?—An exploration on why and how to study the specific effect of the provider

Objective

Numerous studies demonstrate the impact of high-quality patient–provider interaction (PPI) on health outcomes. However, transformation of these findings into clinical practice is still a crucial problem. One reason might be that health communication research rarely investigated whether PPI can increase the effectiveness of medical treatment and/or even substitute it. Therefore, our objective was to provide empirical and methodological background of why and how to investigate the specific effect of the provider on patients’ health outcomes.

Methods

This is a debate paper based on a narrative (non-systematic) literature review in Medline and PsycINFO without any year limitation.

Results

Neurobiological evidence based on expectation and conditioning theory indicates that PPI is able to increase the effectiveness of medical treatment. Moreover, the use of creative RCT study designs described in this paper enables health communication researchers to investigate whether PPI is able to substitute medical treatment.

Conclusion

This paper exemplifies that there exist an evidence-based knowledge from neurobiology as well as creative RCT designs which enable researcher to investigate the specific effects of PPI.

Practice implications

Research on the specific effects of PPI requires intense reflection on which patient groups or types of illness are reasonable, suitable, and ethically justifiable for interventions.