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PubMed2005

Extinction of cocaine self-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens.

While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and post-response dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Pre-response transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, post-response dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic--differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.

Analysis of Variance↗
PubMed2006

Cycloheximide impairs acquisition but not extinction of cocaine self-administration.

The aim of the present study was to assess the role of de novo protein synthesis in the acquisition and extinction of cocaine self-administration. In a first experiment, rats were trained to respond for intravenous cocaine infusions (0.3 mg/kg) and a protein synthesis inhibitor, cycloheximide (CHX; 3 mg/kg, s.c.) was injected immediately after each self-administration session. In a second experiment, rats were allowed to acquire cocaine self-administration and CHX was injected immediately after subsequent extinction sessions. CHX impaired the acquisition, but not extinction, of cocaine self-administration. In control experiments, CHX (3 mg/kg) blocked c-Fos protein expression after foot-shock stress and impaired the acquisition of conditioned freezing but did not inhibit spontaneous locomotor activity and sucrose drinking. Our results suggest that: i) the acquisition and extinction of cocaine-reinforced behaviour have a different molecular basis; and ii) only the former process requires de novo protein synthesis.

Animals↗
PubMed2004

Auditory extinction: the effect of stimulus similarity and task requirements.

Auditory extinction was examined in six patients with right hemisphere lesions, using an auditory double simultaneous stimulation task using letters spoken in male and female voices. Patients had to detect where the stimuli were located, and identify either the letter or the voice (the task-relevant dimension). Auditory extinction was greatest when the two stimuli were the same on the task-relevant dimension, paralleling previous studies of visual extinction. Furthermore, we found that errors of omission were much less frequent in the contralesional field if the patients were not required to report both identity and the location of stimuli. These results are consistent with the notion that auditory extinction may be due in part to a failure to bind together identity and location.

Acoustic Stimulation↗
PubMed2005

A psychophysical study of visual extinction: ipsilesional distractor interference with contralesional orientation thresholds in visual hemineglect patients.

Visual extinction was investigated in left (n=15) and right (n=25) brain-damaged patients with or without visual neglect, and in normal control subjects (n=14), using a psychophysical paradigm. Orientation discrimination thresholds were determined for both left and right hemifield gratings presented either in isolation or simultaneously with a contralateral distractor grating. To minimize the influence of possible sensory-perceptual deficits, the luminances of both target and distractor gratings were chosen to be 20 times the luminances necessary to discriminate between horizontal and vertical grating orientations. The location of the target grating was always cued, making the distractor grating task irrelevant. Even after equalizing the visibility of left and right hemifield stimuli, neglect patients still displayed an increased interference effect from an ipsilesional distractor (and no interference from a contralesional distractor). Left or right brain-damaged controls did not show this asymmetric interference of irrelevant distractors, even the patients who demonstrated extinction on standard extinction testing. This suggests that visual extinction is a critical component of the visual neglect syndrome and that it involves an attentional deficit.

Adult↗
PubMed2004

Extinction deficit and fear reinstatement after electrical stimulation of the amygdala: implications for kindling-associated fear and anxiety.

Generalized seizures produced by electrical kindling of the amygdala in laboratory rats are a widely used animal model of temporal lobe epilepsy. In addition to seizure evolution amygdala kindling enhances emotionality. The relative roles of electrical stimulation and seizure induction in fear responding are unclear. Here we investigate this issue using extinction and reinstatement of fear-potentiated startle. After classical conditioning (light+footshock pairings) laboratory rats were fear extinguished with each light presentation followed by nonepileptogenic amygdala stimulation. In contrast to the normal extinction learning of control subjects, amygdala stimulated animals exhibited conditioned fear after 120 presentations of the nonreinforced conditioned stimulus (CS). In a second experiment electrical stimulation of the amygdala restored extinguished fear responding and the fear reinstatement was specific to extinction context. The reinstatement effect did not involve sensitized fear to the CS produced by amygdala stimulation. The possibility that electrical activation of the amygdala produces unconditioned fear was considered. Animals uniformly failed to demonstrate fear-potentiated startle using electrical stimulation of the amygdala as the unconditioned stimulus. This was the case with a subthreshold afterdischarge stimulus and a stimulation schedule that produced kindled seizures. The extinction deficit and fear reinstatement results were interpreted to suggest that amygdala stimulation activates acquired excitatory stimulus-affect neural connections formed during Pavlovian fear conditioning. Our data supports a model in which excitation of an amygdala-based memory-retrieval system reinforces the expression of learned fear behaviors.

Acoustic Stimulation↗
PubMed2006

On the participation of hippocampal p38 mitogen-activated protein kinase in extinction and reacquisition of inhibitory avoidance memory.

Inhibitory avoidance (IA) learning relies on the formation of an association between stepping down from a platform present in a certain context (conditioned stimulus; CS) with an aversive unconditioned stimulus (US; i.e. a footshock). A single CS-US pairing establishes a robust long-term memory expressed as an increase in step-down latency at testing. However, repeated retrieval of the avoidance response in the absence of the US induces extinction of IA memory. That is, recurring presentation of the CS alone results in a new learning indicating that the CS no longer predicts the US. Although the signaling pathways involved in the consolidation of IA and other fear-motivated memories have been profusely studied, little is known about the molecular requirements of fear memory extinction. Here we report that, as happens with its consolidation, extinction of IA long-term memory requires activity of the p38 subfamily of mitogen-activated protein kinases (MAPK) in the CA1 region of the dorsal hippocampus. Moreover, we found that inhibition of hippocampal p38MAPK blocked memory reacquisition after extinction without affecting either the increase in IA memory retention induced by a second training session or animal's locomotor/exploratory activity and anxiety state.

Animals↗
PubMed2006

Learning deficits expressed as delayed extinction of a conditioned running response following perinatal exposure to vinclozolin.

Vinclozolin (Vz) is one member of a group of fungicides whose metabolites are androgen receptor antagonists. These fungicides have been shown to block androgen-driven development and compromise reproductive function. The current study sought to determine if Vz also affects learning following exposure to low doses during the perinatal period. To test this, an androgen-dependent behavior was examined, the extinction of a previously reinforced running response. Pregnant Long-Evans rats were administered a daily oral dose of 0, 1.5, 3, 6 or 12 mg/kg Vz from the 14th day of gestation through postnatal day 3. After reaching adulthood, male and female offspring were trained to run through a short alleyway for food reinforcement. Acquisition of the response was not affected by Vz exposure. However, males required more trials than females for response extinction once food was no longer available in the apparatus. Males exposed to 6 or 12 mg/kg Vz failed to show any extinction by the end of the procedure, while the lowest dose of Vz appeared to facilitate extinction in both male and female offspring. These results demonstrate that endocrine disrupting antiandrogens can alter nervous system development in addition to the reproductive system.

Androgen Antagonists↗
PubMed1999

Neglect without extinction.

A patient, AB, is reported who showed clear signs of neglect but no extinction (N+ E-). Several hypotheses proposed to account for this dissociation were put to the test. The postulated association between motor neglect and extinction did not hold good, nor did the possibility that the N+ E- dissociation may be traced back to the difference in test requirements and therefore observed only in patients with object-centred neglect. Likewise, manipulating the physical features of the stimuli (relative size, exposure time, presentation synchrony) did not elicit extinction. However, when the task demands were modified by asking the patient to perform a further spatial analysis of the stimuli, rather than simply detect them, extinction emerged. Since AB performed well on several neglect tasks requiring parallel processing, while failing all tasks calling for serial processing, the hypothesis is put forward that AB's N+ E- dissociation could be interpreted within the parallel/serial distinction framework.

Aged↗
PubMed2000

Sensory and response interference by ipsilesional stimuli in tactile extinction.

Extinction is thought to be due to a pathologically limited attentional capacity in which multiple stimuli cannot be processed simultaneously to conscious awareness. Patients with tactile extinction are aware of being touched on a contralesional limb, but seem unaware of similar contralesional touch if touched simultaneously on their ipsilesional limb. The ipsilesional stimulus interferes and competes with the processing of the contralesional stimulus. Most theorists assume that the ipsilesional stimulus affects the sensory processing of the contralesional stimulus, although the precise functional level at which this interference occurs is not clear. We report a series of experiments using signal detection analyses to investigate tactile extinction in one patient (DC). These analyses revealed that ipsilesional stimuli, in addition to interfering with processing of contralateral sensations, also interfere with verbal reports of those sensations. This influence on responses suggests that interference in tactile extinction can occur at a post-perceptual level, further 'downstream' than previously thought.

Aged↗
PubMed2001

Reaching with a tool extends visual-tactile interactions into far space: evidence from cross-modal extinction.

Several recent studies have shown cross-modal visual-tactile extinction in patients with right hemisphere lesions. In the present case, patient BV, a visual stimulus close to the right hand extinguished awareness of a touch on the left hand that would otherwise have been felt. Such extinction was reduced if the right visual stimulus was placed more distant from the patient's hand in the radial plane. However, when the patient held sticks in both hands, so that a far right visual stimulus was now at the end of the "tool" in his right hand, cross-modal extinction from this far stimulus increased. This effect depended on the patient holding a stick that reached to the position of the far visual stimulus; a similar large stick, but not connected with the patient's hand and laying passively on the right, had no effect. Wielding the stick induced a re-mapping of space, so that the far light became treated as near (and reachable by) the hand, thus modifying the spatial nature of cross-modal extinction. This may relate to the properties of multimodal neurons as found in the monkey intraparietal sulcus.

Aged↗
PubMed2002

Visual extinction with double simultaneous stimulation: what is simultaneous?

Patients with unilateral lesions to the parietal lobe leading to extinction were tested with stimuli presented in both hemifields. In addition to simultaneous presentation of two stimuli, trials were given with the contralesional or ipsilesional side having an onset slightly before the other. In the first experiment, subjects were asked to identify the stimuli. In agreement with di Pellegrino et al. [Neuropsychologia 35(1997)1215], all patients showed maximal extinction when the stimuli were physically simultaneous. In the second experiment, the same patients were requested to report whether the left or right item had been presented first. In accordance with Rorden et al. [Neuropsychologia 35(1997)421], all three patients required the contralesional item to have a significant lead in order to in order to be judged as occurring first. Taken together, these findings appear to present a paradoxical picture of extinction: the first task implies that items compete maximally when they are physically simultaneous, while the second study suggests that the physical simultaneity is not phenomenally special to the patients. Attempts to reconcile these findings with popular models of extinction are discussed.

Aged↗
PubMed2000

Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction.

To explore the way in which drugs act to reinstate drug-seeking behavior, we studied drug-induced reinstatement of a cocaine-induced conditioned place preference (CPP). In a series of experiments, we studied the establishment, maintenance, extinction and reinstatement of a cocaine-induced CPP in a three-chamber 'unbiased' apparatus. Groups of rats were given four 20-min pairings of one chamber with cocaine (10.0 mg/kg, i.p.) and four of the other with saline on alternate days. In 15-min tests for CPP, drug-free rats were placed in the center choice chamber with access to the entire apparatus. Experiments were designed to study the expression of the CPP, the maintenance of the CPP in tests given at 2, 4, and 6 weeks after training, and the reinstatement of the CPP by cocaine (5.0 mg/kg) after extinction by 12 repeated tests in the non-drugged state, and after extinction by pairing each chamber, on alternate days, with saline on four occasions. Robust CPPs were obtained that endured for 4 weeks and were maintained for up to 6 weeks when tests were given at 2-week intervals. Both extinction procedures led to the loss of the CPP that was in turn reinstated by priming injections of cocaine. These results indicate that a cocaine-induced CPP, once developed, endures for several weeks, and is maintained by occasional testing even in the absence of additional drug experience. The fact that the CPP is easily reinstated when testing is preceded by a priming injection of cocaine suggests that drugs may induce relapse by renewing the incentive value of drug-associated cues.

Animals↗
PubMed2001

Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug-seeking behavior by rats.

The present experiment employed chronoamperometry with stearate-graphite paste electrodes to monitor dopamine efflux in the nucleus accumbens during extinction and subsequent reinstatement of bar-pressing for a conditioned stimulus (CS) following presentation of a CS or following a systemic injection of d-amphetamine. Rats self-administered d-amphetamine (0.25 mg/kg per infusion) for 3 h a day on 6 consecutive days. Each infusion was paired with a flashing light CS. On the 7th day, rats self-administered d-amphetamine for 1 h, followed by 10 h of extinction. Presentation of the CS 2 days following extinction induced small and transient increases in responding for the CS, with no significant associated increases in DA efflux. Lower rates of responding were observed in rats that had received random presentations of the CS during d-amphetamine self-administration, and in an experimentally-naïve control group. A subsequent systemic injection of d-amphetamine increased dopamine efflux in the nucleus accumbens in all groups and was most effective in reinstating bar-pressing in the CS-d-amphetamine paired group. This is consistent with the hypothesis that exposure to psychostimulant drugs, and a drug-paired CS, can reinstate drug-seeking behavior. Together, these findings suggest that enhanced DA efflux may contribute to the reinstatement of drug-seeking behavior induced by the single administration of a psychostimulant drug, but not transient reinstatement induced by presentation of a drug-paired CS alone following extinction.

Animals↗
PubMed2002

Delayed impairment of response extinction after single seizures induced by picrotoxin.

Male Wistar rats were trained with a food rewarded task and treated with single convulsive dose of picrotoxin. Behavioural test for response extinction by non-reinforcement procedure, which was considered as inhibitory learning, was performed 1, 2, 5, or 7 days after the treatment. The results obtained showed that 5 days after seizures, the animals persisted in performing the task, and extinction procedure was hampered. The resistance to response extinction is evidence of delayed influence on inhibitory processes caused by the single seizures. On the contrary, the response extinction was not deteriorated 1, 2 or 7 days after picrotoxin treatment. It is assumed that delayed disturbances of inhibitory learning could result from the deterioration of hippocampal functioning.

Animals↗
PubMed2003

Effects of light deprivation on recovery from neglect and extinction induced by unilateral lesions of the medial agranular cortex and dorsocentral striatum.

A number of previous studies have indicated that an environmental manipulation, 48 h of light deprivation (LD), produces virtually complete and permanent behavioral recovery of function from neglect induced by medial agranular cortex (AGm) lesions. LD-induced behavioral recovery from neglect is correlated with physiological changes in the dorsolateral striatum, an area that contains the projection zone of AGm efferents in the dorsocentral striatum (DCS). In this study, the behavioral effects of 48 h of LD on subjects with either unilateral DCS, AGm, or combined AGm/DCS lesions were investigated to examine whether the integrity of the DCS is crucial for behavioral recovery from neglect and whether LD will have a therapeutic effect on extinction deficits. Subjects were tested for extinction to bilateral simultaneous stimulation of the forepaws, and visual, auditory and tactile neglect. Forty-eight hours of LD failed to produce behavioral recovery from neglect in rats with DCS lesions, or a therapeutic affect on extinction deficits in any of the groups. The results of this study further support the crucial role of the DCS in recovery from neglect induced by AGm lesions and suggests that the DCS may be the crucial site for the mechanisms leading to LD-induced recovery. Further, the ineffectiveness of LD on extinction suggests that components of the neglect syndrome are dissociable and may require different therapeutic interventions.

Animals↗
PubMed2003

Frontal lesions do not alter the differential extinction of taste aversion conditioning in rats, when using two methods of sucrose delivery.

The frontal cortex is involved in the planning of behavioural responses and in the processing of their outcomes. Thus it contributes to several learning mechanisms, including those of conditioned taste aversion (CTA). A solution of sucrose drunk freely by a rat from a drinking tube-self-drinking protocol (SD)-was used as a conditioned stimulus in CTA. The intake of this solution was followed by gastric malaise. It produced an aversion to sucrose that withstood extinction over a week of repetitive tests. But, when the sucrose was perfused intra-orally (IO), i.e. not depending on any specific action by the rat, the extinction of aversion was much faster. Several factors may explain this differential extinction including the contribution of contextual factors linked to the achievement of an action and/or the enhancement of the attention towards the outcome of the action (the taste). The processing of such factors is usually believed to require the prefrontal cortex or the cingulate cortex (CgC). In our first experiment, the frontal cortex was totally transected. In the second experiment, the CgC was removed by aspiration. None of these lesions elicited any change in CTA, either in IO or in SD conditions, meaning that the differential extinction remained. The surprising absence of a frontal lesion effect was thought to indicate the low attentional demand required in both CTA protocols.

Animals↗
PubMed2001

Measuring ethanol-seeking behavior: the effect of using repeated extinction trials.

The development of a reliable measure of the level of ethanol-seeking behavior in an animal model is important to understanding the concept of craving. However, most existing models do not allow for the separation of the behavior associated with obtaining ethanol from that involved in consumption of ethanol. In this study, we determined the ability of repeated, single-session extinction tests in an appetitive and consummatory procedure of ethanol self-administration to assess the level of seeking behavior. The findings indicated that there were no major effects of previous extinction trials on later trials, when there were at least four reinforced sessions between tests. During reinforced sessions, the rats were consuming an average of 0.80 g of ethanol per kilogram of body weight in less than 20 min from a sipper tube. In addition, the amount of extinction responding was found to be similar to a previous measure of the appetitive strength of ethanol by using a breakpoint procedure. This method of repeated extinction tests seems to be valuable for examining the effects of pharmacological treatments that might alter ethanol seeking.

Alcohol Drinking↗
PubMedDate not supplied

EtOH self-administration on shuttle box avoidance learning and extinction in rats.

The effects of ethanol on the acquisition and extinction of the two-way active avoidance response were examined in adult, male Wistar rats from two treatment groups, oral self-administration of alcohol solution (10% v/v ethanol and 3% w/v glucose in distilled water) and oral self-administration of control solution (3% w/v glucose in distilled water). Alcohol or control solutions were available 1 h per day during 15 days simultaneously with food, with free water for the rest of the day. Blood was drawn in the last day of this phase to evaluate blood ethanol levels (BEL). After this period, rats were tested in a two-bottle paradigm for 1 h per day and placed in a shuttle box immediately afterwards. This phase went lasted for 10 days. Subjects were trained to avoid an electric foot shock in the first 5 days (15 trials per day). Following this, half of the subjects were tested in an "easy extinction with punishment" (EEP) and the other half in a "difficult extinction with punishment" (DEP) of the avoidance response for the last 5 days. Alcohol accelerates the avoidance responding acquisition, and no significant effects of alcohol were seen in the extinction phase. Data are discussed in terms of the specificity of the effects of alcohol on learning.

Animals↗