Acquisition Of Conditioned Response Research Articles

Effects of Subanesthetic Concentrations of Isoflurane and Their Interactions with Epinephrine on Acquisition and Retention of the Rabbit Nictitating Membrane Response

Evidence concerning the concentrations of volatile anesthetics that prevent learning and recall is limited. Epinephrine is believed to enable learning during anesthesia. We investigated the effects of isoflurane and its interaction with epinephrine on learning and subsequent retention of the rabbit's classically conditioned nictitating membrane response. In experiment 1, a tone (conditioned stimulus, CS) preceded paraorbital shock (unconditioned stimulus, US) during 60-min daily sessions of 60 presentations of these paired stimuli for 6 days of acquisition training under 0, 0.4%, or 0.8% isoflurane (n = 8, 13, and 9, respectively). Responses were recorded as conditioned responses (CRs) if they occurred during the CS and before the onset of the US. After 1 day of rest, the animals were given 3 days of extinction consisting of 60 presentations of CS-alone and without isoflurane to assess the retention of CRs from acquisition training. In experiment 2, epinephrine in a dose of 0, 0.01, or 0.1 mg/kg was injected subcutaneously in rabbits receiving 0.4% isoflurane. Two types of epinephrine were used, a sustained release form and epinephrine hydrochloride. Acquisition and retention were tested in the same way as in experiment 1. No isoflurane or epinephrine was used during retention testing. Learning was significantly suppressed during 0.4% isoflurane (approximately equal to 0.2 MAC) treatment and eliminated during 0.8% (approximately equal to 0.4 MAC). Information learned during administration of 0.4% isoflurane was not retained (P < 0.05). Although the low doses of epinephrine improved learning during the last day of the acquisition phase (P < 0.05), there were no differences between the treatment groups on any of the remaining acquisition or extinction days. There was no learning during treatment with 0.8% concentration. Even a 0.4% concentration, which allowed some learning, abolished CRs in extinction, perhaps because of state-dependent retrieval. Epinephrine did not alter substantially the rates of CR acquisition or resistance to extinction.

MK801 impairs acquisition and expression of conditioned responses in the rabbit nictitating membrane preparation

MK801 is a noncompetitive antagonist to N-methyl-D-aspartate (NMDA) receptors. MK801 (0.1 mg/kg IV) was given to rabbits during classical conditioning of their nictitating membrane response. Administration of MK801 before each training session impaired acquisition of a conditioned response (CR). When MK801 administration was suspended, responding remained at a low level. Control animals were given either MK801 after each training session (Experiment 1) or saline before each session (Experiment 2). The control animals showed high levels of CR acquisition. When the control animals were given the MK801 before a session, they showed a large deficit in responding. Responding returned to its former level when the original control condition was reinstated. In all the animals, tests for motor deficits caused by MK801 proved negative; the magnitude of the UR was not influenced by MK801 at either the beginning or end of training. In conclusion, it appears that MK801 impairs both the formation of associative linkages and the performance of established CRs. A reduction in CS salience caused by MK801 is the most parsimonious explanation of the data. There is a more complex, two-factor alternative that contends that MK801 directly hindered associative formation in the subjects trained with that drug and produced a state-dependent generalization decrement in responding when introduced to the control subjects.

Morphine-conditioned analgesia using a taste cue: dissociation of taste aversion and analgesia

The present study examined the ability of a taste cue to serve as a conditioned stimulus (CS) for conditioning the analgesic effect of morphine. Rats were given three pairings of a taste CS with a morphine unconditioned stimulus (US). As expected, there was a decrease in CS intake across repeated pairings, indicating that a conditioned taste aversion was obtained. More important, presentation of the CS alone also increased paw-lick latencies on a hot plate test (either 50 degrees C or 54 degrees C hot plate), suggesting that an analgesic conditioned response (CR) was obtained. The dose of morphine required to produce conditioned analgesia was higher than the dose of morphine required to produce conditioned taste aversion. Using 15 mg/kg morphine, however, both conditioned taste aversion and conditioned analgesia were present when the morphine US was given immediately following CS intake, but not when given 6 h following CS intake. In contrast to morphine, pairing a taste CS with lithium produced a conditioned taste aversion without any conditioned analgesic response. These results indicate that acquisition of an analgesic CR is not the result of stress induced by an aversion to the taste CS.

Nitrous oxide: Sensory, motor, associative, and behavioral tolerance effects in classical conditioning of the rabbit nictitating membrane response

Experiment 1, of a series of six experiments with the rabbit nictitating memebrane response (NMR) preparation, revealed that nitrous oxide (0%, 33%, 67%) impaired acquisition of conditioned responses (CRs). Subsequent experiments indicated that nitrous oxide (N 2O) had no reliable effects upon nonassociative processes (Experiment 2); impaired unconditioned response (UR) amplitude (Experiment 3); attenuated tone-conditioned stimulus (CS) intensity (Experiment 4); decremented tone-induced reflex modification of the unconditioned NMR (Experiment 5); and demonstrated no reliable evidence of behavioral tolerance (Experiment 6). It was concluded that N 2O's impairment of CR acquisition was attributable to its attenuation of the intensity of tone CSs and shock USs and/or UR amplitude. These findings are consistent with the behavioral laws of conditioning: the attenuation of the intensive sensory properties of the CS and US and/or UR components of conditioning affect their ability to enter into the establishment of CS-CR connections and, therefore, the development of associative learning.

MDA effects on classical appetitive conditioning of the rabbit jaw movement response

We determined MDA's effects on: 1. (a) conditioning of the rabbit's jaw movement response (JMR) (Experiment 1) 2. (b) nonassociative JMRs and unconditioned JMRs (Experiment 2). Rabbits were administered 3,4-methylene-dioxyamphetamine (MDA; 0, 2, or 4 mg/kg) into the marginal ear vein 20–30 min prior to each of 10 daily sessions. Experiment 1 involved 30 daily training trials of 15 tone- and 15 light-conditioned stimuli (CSs) paired with a 1-ml squirt of water, as the unconditioned stimulus (UCS), injected into the oral cavity. The study revealed that MDA impaired conditioned response (CR) acquisition to tone-CS trials while augmenting CRs to light-CSs. In Experiment 2, the animals received 15 tone- and 15 light CS-alone and 30 UCS-alone presentations daily. The study revealed that MDA produced a modest increase in nonassociative responses over days that interacted with CS modality. Accordingly, these nonassociative effects could not account for MDA's influences on CR acquisition. Moreover, MDA's decrementing and enhancing of CRs to tone- and light-CSs, respectively, appears to be attributable to the drug's enhancing or decrementing tone- and light-CS intensity.

A neural model of timed response learning in the cerebellum

A spectral timing model is developed to explain how the cerebellum learns adaptively timed responses during the rabbit's conditioned nictitating membrane response (NMR). The model posits two learning sites that respectively enable conditioned excitation and timed disinhibition of the response. Long-term potentiation of mossy fiber pathways projecting to interpositus nucleus cells allows conditioned excitation of the response's adaptive gain. Long-term depression of parallel fiber-Purkinje cell synapses in the cerebellar cortex allows learning of an adaptively timed reduction in Purkinje cell inhibition of the same nuclear cells. A spectrum of partially timed responses summate to generate an accurately timed population response. In agreement with physiological data, the model Purkinje cell activity decreases in the interval following the onset of the conditioned stimulus, and nuclear cell responses match conditioned response (CR) topography. The model reproduces key behavioral features of the NMR. including the properties that CR peak amplitude occurs at the unconditioned stimulus (US) onset: a discrete CR peak shift occurs with a change in interstimulus interval (ISI) between conditioned stimulus (CS) and US; mixed training at two different ISIs produces a double-peaked CR; CR acquisition and rate of responding depend unimodally on the ISI; CR onset latency decreases during training; and maladaptively timed, small-amplitude CRs result from ablation of cerebellar cortex.

Behavioral effects of a LHRH antagonist in intact and ovariectomized rats

The effects of the LHRH antagonism on the acquisition of conditioned responses (CARs) and spontaneous motility were studied in intact and ovariectomized rats. A synthetic antagonist of LHRH, [N-acetyl-D-p-chloro-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LHRH, was injected in a single dose (10 micrograms/rat, SC) at noon on the day of proestrus in the normally cycling rat, and behavioral experiments were carried out on the morning of estrus or metestrus. Two procedures were followed in the ovariectomized rats: in the first, the antagonist was injected 1 h before estradiol, and in the second, at noon on the day after estradiol replacement. The experiments were carried out 24 and 48 h after estradiol, respectively. The LHRH antagonist facilitated the acquisition of CARs in both experimental groups, thus reversing the impairments observed during estrus and metestrus and those induced by estradiol replacement. The antagonist decreased the number of head shakes during estrus, whereas it induced an increase in total motility and rears in ovariectomized control animals. On the other hand, the antagonist increased the number of rears and reversed the decrease in grooming behavior induced by estradiol. The results led to the idea of a role of LHRH in behaviors not apparently related to sex, which could explain the behavioral changes observed across the estrous cycle and those induced by estradiol replacement in ovariectomized rats.

Concurrent Associative Transfer and Competition in Serial Conditioning of the Rabbit′s Nictitating Membrane Response

Two seemingly contradictory principles describe conditioned response (CR) acquisition when a sequence of two conditioned stimuli (CSA-CSX) signal the unconditioned stimulus (US) for the rabbit′s nictitating membrane (NM) response. For long CSA-CSX intervals, responding to CSA shows facilitation similar to second-order conditioning. For shorter CSA-CSX intervals, responding to CSX shows impairments similar to blocking and overshadowing. Whether and how the two processes interact has been unclear. The present study interpolated extra CSs between CSA and CSX, thus introducing the full range of CS-CS intervals into a single sequence. The interpolated CSs maintained the facilitation of CRs to CSA and progressively impaired CRs to CSX. The interpolated CSs themselves tended to show facilitated CR acquisition. Thus, the two processes can act concurrently. In theoretical terms, the higher-order CSs appear to have a parasitic relationship to the first-order CS, effectively stealing its associative strength.

Evidence for an involvement of the μ-type of opioid receptor in the modulation of learning

Pavlovian conditioning of the rabbit's nictitating membrane response was used to determine whether the retardation of learning produced by enkephalin derivatives was mediated through an action on μ- or δ-opioid receptors. Intraventricular injection of the highly selective μ-agonist, [D-Ala 2, MePhe 4, Gly-ol 5] enkephalin (DAMGO) significantly retarded (2 nmol) or completely blocked (20 nmol) the acquisition of conditioned responses. The retarded or blocked acquisition of conditioned responses produced by DAMGO could still be detected when the rabbits were tested two days after cessation of drug injections, suggesting that DAMGO had affected learning and not simply performance of conditioned responses. Intraventricular injection of a comparable dose (20 nmol) of the highly selective δ-agonist, [D-Pen 2.5] enkephalin (DPDPE) did not retard learning. A higher dose of DPDPE (200 nmol), which would be expected to act at both μ- and δ-receptors, did produce a retardation of acquisition that was comparable to the effects of a 2-nmol dose of DAMGO. However, unlike DAMGO, the retardation of learning produced by this dose of DPDPE appeared to be due, at least in part, to a reduction in the aversive properties of the unconditioned stimulus. The retardation of learning produced by 2 nmol of DAMGO and 200 nmol of DPDPE was due to an action on an opioid receptor because this effect was blocked by a subcutaneous injection of naloxone (2.5 μmol/kg), a specific opioid antagonist. The stereoselective effects of the μ-opioid agonist levorphanol further confirmed that the retarded learning was mediated through actions at the μ-opioid receptor. Autoradiographic studies indicated that a 2-nmol, intraventricular dose of DAMGO achieved contents greater than 1 pmol/mg in tissue lying within 2 mm of the lateral ventricle, third ventricle and cerebral aqueduct. These data suggest that enkephalins produce a retardation of learning through an effect on the μ-type of opioid receptor and that at least one locus of their actions is produced at periventricular sites lying within 2 mm of the ventricles. It was concluded that the μ-type of opioid receptor was normally involved in the modulation of learning and that such modulation would be expected to be most prominent during environmental conditions that have been demonstrated to produce a large release of endogenous enkephalins.

Harmaline-induced impairment of Pavlovian conditioning in the rabbit

In this study we examined the effects of harmaline on Pavlovian conditioning of the rabbit's nictitating membrane response. The acquisition of conditioned responses was determined during a single session consisting of 120 pairings of a tone-conditioned stimulus with a corneal air puff unconditioned stimulus. Harmaline severely retarded (5 mg/kg) or completely blocked (10 and 20 mg/kg) acquisition of conditioned responses. The blocked or retarded acquisition of conditioned responses could still be detected when the rabbits were tested 2 d after cessation of drug injections, suggesting that harmaline was affecting acquisition and not the motoric expression of conditioned responses. Control experiments established that harmaline (5 mg/kg) did not affect (1) baseline levels of responding, (2) the level of non-associative responding to the conditioned stimulus, (3) the amplitude or any of the temporal characteristics of the unconditioned response, (4) the development of habituation to the unconditioned stimulus, and (5) the threshold of the unconditioned stimulus for eliciting the unconditioned response. However, harmaline did produce a 12 dB increase in the intensity threshold of the conditioned stimulus for eliciting conditioned responses. We concluded that the primary effect of harmaline was to impair stimulus processing within brainstem circuits such as to reduce the excitatory properties of the conditioned stimulus, thus retarding its entry into associative learning. The results were discussed with respect to the possible role of the inferior olive in associative learning.

Pre-pulse inhibition of the acoustic startle response and measures of attention in schizophrenic subjects

Sex differences in attentional processing and new motor learning remain controversial, and are complicated by the influence of endogenous and exogenous gonadal hormones. Facilitated acquisition of a classically conditioned eyeblink response in oral contraceptive-using women has been reported, as have menstrual cycle-dependent changes in pre-pulse inhibition (PPI). The current study sought to replicate and extend these findings by comparing acquisition of the conditioned eyeblink response and PPI in women currently taking oral contraceptives (OCs), women not taking OCs, as well as men. Women were assigned to participate either during their follicular or luteal menstrual cycle phase. Acquisition was assessed in a two-tone discrimination delay paradigm (500-ms conditional stimulus (CS); 100-ms airpuff unconditional stimulus (US)). PPI was lower in males and OC-users depending on stimulus intensity. Consistent with early classical conditioning research, females acquired an eyeblink conditioned response faster than males. Faster acquisition was associated with larger unconditional responses. Women taking OCs demonstrated accelerated conditioned response acquisition compared to women not taking OCs and males although unconditional responses were comparable to males. Facilitated acquisition of new motor learning in OC-users was replicated in a college-aged population of women and was not secondary to enhanced reactivity to sensory stimuli.

Selective hippocampal lesions abolish the contextual specificity of latent inhibition and conditioning.

The contextual specificity of the conditioned response (CR) and latent inhibition (LI) was examined in rats with selective hippocampal lesions. Acquisition of the CR to a novel conditioned stimulus (CS) was equally rapid in control and hippocampal rats (Experiments 1 and 2), and CS preexposure disrupted acquisition, (i.e., produced LI) to an equal extent in both groups (Experiment 2). In control subjects, however, the CR established in one context transferred incompletely to a second context (Experiment 1), and LI was attenuated when CS preexposure and conditioning occurred in different contexts (Experiment 3). This context specificity of the CR and LI was not apparent in hippocampal rats--the CR and LI transferred readily from one context to another. In addition, hippocampal rats were impaired in a spatial learning task (Experiment 2) but were unimpaired in learning a Pavlovian contextual discrimination (Experiment 3). These results suggest that a common contextual retrieval process underlies the contextual dependence of the CR and of LI and that this process is mediated by the hippocampus.

Sodium pentobarbital: sensory and associative effects in classical conditioning of the rabbit nictitating membrane response.

Four experiments were conducted to determine the effects of sodium pentobarbital (0, 3, 9, and 15 mg/kg) on the acquisition of the rabbit's classically conditioned nictitating membrane response (NMR) and to determine the locus of the drug's effects on sensory, motor, associative, and nonassociative processes. In experiment 1, classical conditioning of the NMR was accomplished by pairing tone and light conditioned stimuli (CSs) with paraorbital shock as the unconditioned stimulus (US). The experiment revealed that pentobarbital retarded the acquisition of conditioned responses (CRs) to both tone and light CSs. Experiment 2, employing unpaired CS, UCS presentations, indicated small but significant drug effects on NMR base rate and nonassociative NMRs to the CS. Experiment 3 revealed no significant drug effect on the psychophysical functions relating UCS intensity to UCR frequency or amplitude, nor on the UCS intensity threshold for eliciting UCRs. On the other hand, in experiment 4, the drug significantly impaired CR frequency over an extended range of CS intensities and raised CS intensity threshold. It was concluded that pentobarbital's attenuation of CS intensity also operated to impair CR acquisition.

6-Hydroxydopamine induced impairment of Pavlovian conditioning in the rabbit.

This study employed bilateral, intraventricular injections of 6-hydroxydopamine (6-HDA) to examine the effects of monoamine depletion on Pavlovian conditioning of the rabbit's nictitating membrane response. 6-HDA produced dose-dependent and highly correlated decreases in the rate of acquisition of conditioned responses and in the telencephalic content of 5-HT, DA, and NE. At the highest dose of 6-HDA (1340 micrograms), 5-HT, DA, and NE were reduced by 42, 48, and 89%, respectively, and the number of trials required to achieve criterion acquisition was increased by 123%. Control experiments established that the highest dose of 6-HDA: 1) had no effect on the unconditioned nictitating membrane reflex; 2) had no effect on the threshold of the conditioned stimulus for eliciting conditioned responses; and 3) produced only a small, less than 5%, decrease in nonassociative responding. It was concluded that decreases in 5-HT, DA, and NE can impair associative learning without altering sensory or motor function.

Excitatory amino acids and memory: Evidence from research on Alzheimer's disease and behavioral pharmacology

The excitatory amino acid transmitter (EAA) system is believed to play a crucial role in a variety of physiological processes related to neuronal plasticity. Substantial neurophysiological evidence suggests that, under normal physiological conditions. EAAs may be involved in mechanisms underlying learning and memory. However, overactivity of this system produces excitotoxic damage to neurons which is believed to be an etiological factor in various neurological conditions, such as epilepsy, and stroke-induced impairments. The fact that EAAs have been implicated in both, normal cognitive function and in degenerative neurological conditions suggests that they may contribute to the etiology of Alzheimer's disease (AD), because AD is characterized by memory deficits and specific histopathological signs of neuronal damage. This paper summarizes information regarding 1) the involvement of EAAs in Alzheimer's disease and 2) results from psychopharmacological studies of EAAs in laboratory animal models of learning. Investigations of the pathophysiology of AD indicate that glutamatergic deficits are associated with this syndrome. However, there is controversy concerning the nature of this defect. As a result, it is unclear whether it is a consequence of excitotoxic changes produced by glutamatergic overactivity or result from a decrease in glutamatergic function. Evidence from behavioral studies is consistent with the conclusion that EAAs may be involved in the acquisition of conditioned responses. However, in parallel with the clinical findings, learning impairments have been produced by treatments which either increase or decrease activity within this transmitter system. Therefore, although present results suggest that the EAAs play a role in cognition and in clinical syndromes in which such function is compromised, the specific nature of that role needs to be elucidated by future research.

Effects of amygdala lesions on reflex facilitation and conditioned response acquisition during nictitating membrane response conditioning in rabbit.

Effects of amygdala lesions on reflex facilitation and conditioned response acquisition during nictitating membrane response conditioning in rabbit.

Effects of amygdala lesions on reflex facilitation and conditioned response acquisition during nictitating membrane response conditioning in rabbit.

The present study demonstrated that large lesions of the amygdala disrupt the maintenance of reflex facilitation of the unconditioned nictitating membrane (NM) response and slow the acquisition of conditioned NM responses in rabbit. Before behavioral training, the central nucleus of the amygdala and adjacent areas were lesioned electrolytically. In the 1st experiment, the lesioned animals exhibited no reflex facilitation of the unconditioned NM response at conditioned stimulus (CS)-unconditioned stimulus (US) intervals of 125-8,000 ms. In the 2nd and 3rd experiments in which one CS-US interval (500 ms) was used, the lesions disrupted the maintenance of reflex facilitation but did not alter the facilitation exhibited in the 1st block of training. The lesions retarded the acquisition of conditioned NM responses when the 1000-Hz tone CS intensity was 65 dB but not when the intensity was 85 dB.

Effects of cocaine on conditioning of the rabbit nictitating membrane response

Two experiments were conducted to determine cocaine's (0, 1, 3, and 6 mg/kg) effects on associative, nonassociative, and motor processes in classical conditioning of the rabbit's nictitating membrane response (NMR). In experiment 1, acquisition training consisted of tone- and light-conditioned stimuli (CSs) each paired on separate trials with a shock unconditioned stimulus (UCS). Cocaine injected prior to each session significantly impaired acquisition of conditioned responses (CRs). In Experiment 2, rabbits received cocaine injections prior to each training session involving explicitly unpaired CS-alone presentations. Cocaine had no significant effects upon: base rate of NMRs; frequency of NMRs during presentations of the CSs; and frequency, amplitude, and latency of the UCRs. Consequently, cocaine's impairment of CR acquisition could not be attributed to its effects upon the nonassociative processes of base rate, sensitization, and pseudoconditioning, nor upon the sensory processing of the UCS and/or motor functioning of the UCR. Rather, cocaine's effects upon CR acquisition were mediated by the drug's effect upon associative processes. It appears likely that the drug affected the ability of the CS to enter into the associative conditioning process.

Muscarinic receptor binding increases in anterior thalamus and cingulate cortex during discriminative avoidance learning

Training-induced neuronal activity develops in the mammalian limbic system during discriminative avoidance conditioning. This study explores behaviorally relevant changes in muscarinic ACh receptor binding in 52 rabbits that were trained to one of five stages of conditioned response acquisition. Sixteen naive and 10 animals yoked to criterion performance served as control cases. Upon reaching a particular stage of training, the brains were removed and autoradiographically assayed for 3H-oxotremorine-M binding with 50 nM pirenzepine (OXO-M/PZ) or for 3H-pirenzepine binding in nine limbic thalamic nuclei and cingulate cortex. Specific OXO-M/PZ binding increased in the parvocellular division of the anterodorsal nucleus early in training when the animals were first exposed to pairing of the conditional and unconditional stimuli. Elevated binding in this nucleus was maintained throughout subsequent training. In the parvocellular division of the anteroventral nucleus (AVp), OXO-M/PZ binding progressively increased throughout training, reached a peak at the criterion stage of performance, and returned to control values during extinction sessions. Peak OXO-M/PZ binding in AVp was significantly elevated over that for cases yoked to criterion performance. In the magnocellular division of the anteroventral nucleus (AVm), OXO-M/PZ binding was elevated only during criterion performance of the task, and it was unaltered in any other limbic thalamic nuclei. Specific OXO-M/PZ binding was also elevated in most layers in rostral area 29c when subjects first performed a significant behavioral discrimination. Training-induced alterations in OXO-M/PZ binding in AVp and layer Ia of area 29c were similar and highly correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of MDA on classical conditioning of the rabbit nictitating membrane response

In Experiment 1, classical conditioning of the rabbit's nictitating membrane response (NMR) was accomplished by pairing tone and light conditioned stimuli (CSs) with a shock unconditioned stimulus (UCS). MDA impaired the acquisition of conditioned responses (CR) to a tone-CS, while significantly enhancing CR acquisition to a light-CS. Experiment 2, employing explicitly unpaired CS, UCS training, revealed no reliable effects of MDA upon nonassociative processes. Subsequent efforts determined if MDA's CR acquisition effects resulted from alterations in sensory processing of the CS, UCS, and/or UCR motor functioning. Specifically, it was determined that MDA: (a) increased the tone-CS intensity threshold for eliciting CRs (Experiment 3); (b) attenuated the tone-induced reflex modification of the unconditioned NMR (Experiment 4); and (c) enhanced UCR frequency at varying UCS intensities (Experiment 5). It was concluded that MDA's effect upon CR acquisition reflected the drug's effects upon CS and UCS/UCR processing and thereby altered the ability of these components of conditioning to enter into associative learning.