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PubMed2002

An examination of nucleus accumbens cell firing during extinction and reinstatement of water reinforcement behavior in rats.

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats (n = 13) during water reinforcement sessions consisting of three phases. During phase one (maintenance), a lever press resulted in water reinforcement (fixed ratio 1; 0.05 ml/press) paired with an auditory stimulus (0.5 s). Of 128 Acb neurons recorded during maintenance, 40 cells (31%) exhibited one of three types of neuronal firing patterns described previously [J. Neurosci. 14 (12) (1994) 7735-7746; J. Neurosci. 20 (11) (2000) 4255-4266]. Briefly, Acb neurons exhibited increases in firing rate within seconds preceding the reinforced response (type PR) or increases (type RFe) or decreases (type RFi) in activity seconds following response completion. In phase two (extinction), subsequent lever pressing had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, animals were given water reinforcement/auditory stimulus 'primes' to reestablish lever pressing behavior during the third phase (reinstatement). Results indicated that all types of phasic neurons (PR, RFe and RFi) exhibited an attenuated firing rate during extinction, and in some cases recovery of patterned discharges were observed during reinstatement. No significant changes in cell firing were observed for any cell type during presentation of the stimulus prime used to reestablish operant responding following extinction. These findings are discussed in terms of how Acb neurons process information related to 'natural' reinforcers versus drugs of abuse.

Acoustic Stimulation↗
PubMed2000

Acquisition, extinction, and reinstatement of Pavlovian fear conditioning: the roles of the NMDA receptor and nitric oxide.

The acquisition and extinction of Pavlovian conditioned fear have been shown to be mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor. This study found that the NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801) blocked the reinstatement of Pavlovian conditioned fear in rats. The role of nitric oxide (NO) in the acquisition and extinction of Pavlovian fear conditioning was also examined. L-NAME, an NO synthase inhibitor, failed to block the acquisition or extinction of Pavlovian fear conditioning. The results are discussed in the context of hierarchical associations and the array of NMDA and calcium mediated mechanisms of synaptic strengthening.

Animals↗
PubMed2006

Temporal and spatio-temporal attention to tactile stimuli in extinction patients.

The temporal deployment of attention to tactile stimuli delivered to the same or to a symmetrical position of the body was assessed in 6 Right-Brain Damaged (RBD) patients with left tactile extinction and 6 healthy controls. Two different tasks called Temporal (T) and Spatio-Temporal (ST) extinction were used. In the T task single or double electro tactile stimuli were delivered to the same point to the left or, in separate blocks, to the right index finger. Double stimuli were separated by different Stimulus Onset Asynchronies (SOAs). In the ST task, stimuli could be single (left or right) or double (left and right). Double stimuli were delivered to the index finger of both hands simultaneously or sequentially. In both tasks subjects were asked to report the number of the stimuli they perceived. In the ST task, subjects were also requested to report the stimuli location. Results show that in both tasks RBD patients' detection of left sided stimuli was significantly lower than of right sided stimuli detection, mainly at shortest SOAs. Moreover, detection of left sided stimuli was higher when two stimuli were delivered in sequence and in symmetrical body areas and in different sides of the space than when stimuli were delivered in sequence in the same body area. Results suggest that the interaction between spatial and temporal variables enhances the ability of tactile extinction patients to detect left sided stimuli.

Aged↗
PubMed2001

Effects of CP-154,526 on responding during extinction from cocaine self-administration in rats.

Conditioned cues associated with cocaine induce craving and relapse. Although the role of corticotropin releasing hormone (CRH) in stress- and cocaine-induced relapse has been reported, its involvement in cue-induced behavior has not been established. Using responding during extinction as a model of cue-induced craving, we tested the effects of a selective CRH1 receptor antagonist, CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine). Rats were trained to respond on a multiple schedule of cocaine self-administration and food reinforcement. On extinction test days, saline was substituted for cocaine. Pretreatment with CP-154,526 (20 mg/kg, i.p.) decreased responding on the cocaine-associated lever during extinction, suggesting an involvement of CRH1 receptors in cue-induced craving.

Animals↗
PubMed1998

Piracetam inhibits Pavlovian extinction and reversal learning in a spatial task for rats.

Young male rats, trained in a spatial three-choice test, showed improved task acquisition after chronic treatment with piracetam (250 mg kg(-1)). After reaching a learning criterion, one group of animals was observed during Pavlovian extinction of the task skill and another group was assigned to reversal learning. The rate of extinction was slowed down in piracetam treated specimens compared to control animals. During reversal training, a new choice had to be learned while the previously acquired choice was no longer reinforced. Acquisition of the new skill was significantly impeded by piracetam in contrast to acquisition of the first skill, which was facilitated. Also during reversal learning, the piracetam treated group persevered longer than the control group in repeating the first acquired choice at the expense of learning the new choice. It is therefore suggested, that the impediment of reversal learning was caused by inhibition of extinction. In an open-field test, the time spent exploring in motion was increased by piracetam while the velocity of locomotion was unaffected by the drug. In a novelty test, piracetam increased the rate of loss of interactions with the novel object.

Animals↗
PubMed2002

Impaired perception of temporal order in auditory extinction.

It has been proposed that patients with extinction show a chronic bias of spatial attention towards the ipsilesional side. In this case, the law of 'prior entry' predicts that ipsilesional events should be perceived earlier than physically synchronous contralesional stimuli. In line with this prediction, previous studies have revealed substantial delays of awareness for contralesional visual and tactile events in patients with visual and with tactile extinction. The present study provides evidence that a 'prior entry' bias also occurs in the auditory modality. Patients with auditory extinction perceived two acoustic events (one presented to the left ear, the other to the right ear) as being 'simultaneous' when the contralesional sound was leading by 270 ms. The magnitude of this asynchrony was quite similar to that measured previously in the visual modality. Thus, the pathological delay of awareness for contralesional events may be independent of the sensory modality of the stimuli.

Acoustic Stimulation↗
PubMed1997

Extinction of a conditioned taste aversion in rats: I. Behavioral effects.

The literature is divided over whether a conditioned taste aversion (CTA) can be fully extinguished. In Experiment 1, we created a powerful aversion in 54 rats by pairing the taste of 0.0025 M NaSaccharin (CS) with intraperitoneal injections of 127 mg/kg LiCl (US) on 3 occasions. We then offered 23-h deprived rats NaSaccharin for 10 min/day to observe the course of recovery. Extinction occurred in three phases: static, dynamic, and asymptotic. During the static phase (mean = 9.6 days), rats consumed the CS at < 10% of their preconditioned rate. With dynamic recovery (6.0 days), they increased acceptance to > 80% of preconditioning levels. Finally, they achieved asymptote (3.1 days) at 100% acceptance. In Experiment 2, we used 8 additional conditioned rats and 8 unconditioned controls. We followed the same 1-bottle extinction procedure and, again, obtained 100% acceptance. Then we offered both NaSaccharin and water for 8 days at 23 h/day and monitored lick patterns every 6 s to determine taste preferences. The conditioned animals consumed less NaSaccharin than controls on Day 1, and less NaSaccharin as a percentage of total fluid as late as Day 3. For the last 5 days of 2-bottle preference testing, there were no significant differences between the groups with regard to 1. volume of NaSaccharin or water consumed, 2. percentage of total fluid taken as NaSaccharin, 3. consumption of each fluid associated with a meal or taken spontaneously, 4. intake during the light or dark periods, or 5. the characteristics of ingestion, including number of drinking bouts, duration of bouts, number of licks/bout, and rate of licking. Therefore, a robust CTA is subject to complete behavioral extinction.

Animals↗
PubMed1999

Effects of aging on the acquisition and extinction of excitatory conditioning in Drosophila melanogaster.

Young (7-day-old), middle-aged (28-day-old), and old (49-day-old) Drosophila melanogaster were compared for acquisition, then extinction, of excitatory conditioning of the Proboscis Extension Response. The contribution of nonassociative processes (sucrose-induced Central Excitatory State, Pseudoconditioning) in the elicitation of conditioned responses was simultaneously assessed. Old flies displayed a faster and stronger acquisition than middle-aged ones, whereas no significant acquisition was stated in young flies. The influence of nonassociative processes on the acquisition was of minor importance, even though Central Excitatory State increased with age. Old flies proved also to be the slowest to extinguish. Because nonassociative contamination was not involved during extinction, one may wonder whether extinction was delayed in old flies mainly due to a higher level of acquisition or to a behavioral rigidity.

Aging↗
PubMed1988

Response variation in instrumental extinction in rats with fornix transections.

The present experiment examined spatial and response variation interpretations of the large difference in magnitude between operant and instrumental extinction deficits seen in hipocampally damaged animals. Latency measures and detailed behaviors of rats with fornix transections were compared to those of control rats during acquisition and extinction in an enriched spatial runway. Control rats, in comparison to rats with fornix transections, exhibited larger increases in start box, runway, and goal box latencies, but no spatial gradients were found. Control rats also exhibited less goal persistence and more response variation following the transition to extinction. The results suggest no fundamental difference between operant and instrumental deficits following hippocampal damage, but an interaction between strategies employed and traditional response measures.

Animals↗
PubMed2003

Subhypnotic doses of propofol accelerate extinction of conditioned taste aversion.

Subhypnotic doses of propofol accelerate extinction of conditioned taste aversion. Some intravenous anesthetic agents including propofol is known to induce anterograde and retrograde amnesia. We evaluated whether propofol affect the long-term memory formed by the conditioned taste aversion (CTA) paradigm. Rats were allowed a 4h access to water through the experiments. After preconditioning water intake, the rats were offered 0.1% sodium saccharin (Sac) as conditioned stimulus (CS) for 20 min. An intraperitoneal (i.p.) injection of several concentrations (0.5-100 mg/kg) of propofol 10 min after Sac exposure was followed by an i.p. injection of 0.15M LiCl (2% of body weight) as unconditioned stimulus (US) 30 min after CS-exposure. The volumes of intake of Sac for 20 min were measured on the successive 4 days. The rats, which acquired CTA by every CS-US paradigm, strongly avoided Sac on the first test day after conditioning and maintained the avoidance for 3 days. However, when subhypnotic dose of propofol was injected before LiCl-injection, Sac intake abruptly increased on the second test day and the almost complete extinction occurred on the third test day after conditioning. The extinction process of CTA was barely affected by hypnotic dose of propofol. These results suggest that propofol affects the retention mechanism of the CTA memory in a dose-dependent manner. Subhypnotic dose of propofol may affect the sub-cellular process of the memory consolidation in CTA.

Anesthetics, Intravenous↗
PubMedDate not supplied

An empirical analysis of two forms of extinction to treat aggression.

We compared the effectiveness of two extinction interventions, extinction by omission and noncontingent delivery of reinforcement, to treat aggressive behavior with a 10-year-old boy. Before the intervention, a functional analysis revealed that aggression was maintained by positive reinforcement in the form of attention. The extinction by omission intervention consisted of ignoring aggressive behavior. Noncontingent reinforcement involved delivering attention to the boy on a fixed-time schedule. Both treatments were compared using a multielement research design. Noncontingent reinforcement produced a more rapid elimination of aggression. Additionally, the schedule of noncontingent reinforcement was gradually thinned during the intervention. Finally, both parents successfully implemented the noncontingent schedule of reinforcement independently for up to 5 weeks after treatment.

Aggression↗
PubMed2001

Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues.

The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous cocaine (S(+)) vs. the availability of non-rewarding (S(-)) saline solution, and then placed on extinction conditions during which intravenous solutions and S(D) were withheld. The rats were then presented with the S(+) or S(-) alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S(+), a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S(+) selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period. In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D(1) antagonist SCH 39166 (10 microg/kg), the D(2/3) antagonist nafadotride (1 mg/kg), and the D(2/3) agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D(1) agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S(+) to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.

Amygdala↗
PubMed1996

Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior.

Both cocaine and cocaine-associated stimuli can reinstate extinguished self-administration behavior in animals. It has been suggested that reinstatement of drug-seeking behavior may be mediated by enhanced dopamine (DA) neurotransmission. To examine this hypothesis, DA overflow was measured in the nucleus accumbens (NAc) of rats during both extinction and cocaine-induced reinstatement of self-administration behavior. Rats were either allowed to self-administer cocaine for 3 hours daily for 14 days, or they received yoked administration of saline. A stimulus light above the lever was illuminated during drug delivery. Baseline DA overflow was measured in the NAc, using in vivo microdialysis 7 to 8 days after the last self-administration session. The rats were then placed into the operant chambers and allowed to respond in extinction for 90 minutes, during which responses resulted in presentation of the stimulus light. The rats then received a cocaine injection that reinstated self-administration behavior. Contrary to our hypothesis, cocaine-experienced animals exhibited less DA overflow in the NAc relative to controls during both extinction and reinstatement.

Animals↗
PubMed1999

Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat.

Clinical observations suggest that stimuli associated with the availability or consumption of ethanol can evoke subjective feelings of craving and trigger episodes of relapse in abstinent alcoholics. To study the motivational significance of alcohol-related environmental cues experimentally, the effects of discriminative stimuli previously predictive of alcohol availability on the reinstatement of ethanol-seeking behavior were examined. Wistar rats were trained to lever-press for 10% (w/v) ethanol or water in the presence of distinct auditory cues. The rats were then subjected to an extinction phase where lever presses had no scheduled consequences. After extinction, the animals were exposed to the respective auditory cues without the availability of ethanol or water. Neither the ethanol (SA+) nor water-associated (SA-) auditory cue increased responding over extinction levels. In contrast, subsequent presentation of an olfactory cue associated with ethanol (SO+), but not a water-associated (SO-) cue significantly reinstated lever pressing behavior in the absence of the primary reinforcer. Moreover, responding elicited by the concurrent presentation of the SO+ and SA+ was selectively attenuated by the opiate antagonist naltrexone (0.25 mg/kg; s.c.). The results suggest that ethanol-associated cues can reinstate extinguished ethanol-seeking behavior in rats, but that the efficacy of these stimuli may be modality-specific. In addition, the present procedures may be useful for studying neurobiological mechanisms of alcohol-seeking behavior and relapse.

Acoustic Stimulation↗
PubMed2002

Behavioral and neural analysis of extinction.

The neural mechanisms by which fear is inhibited are poorly understood at the present time. Behaviorally, a conditioned fear response may be reduced in intensity through a number of means. Among the simplest of these is extinction, a form of learning characterized by a decrease in the amplitude and frequency of a conditioned response when the conditioned stimulus that elicits it is repeatedly nonreinforced. Because clinical interventions for patients suffering from fear dysregulation seek to inhibit abnormal, presumably learned fear responses, an understanding of fear extinction is likely to inform and increase the efficacy of these forms of treatment. This review considers the behavioral, cellular, and molecular literatures on extinction and presents the most recent advances in our understanding while identifying issues that require considerable further research.

Animals↗
PubMed2003

Effects of same- and different-modality cues in a Posner task: extinction-type, spatial, and non-spatial deficits after right-hemispheric stroke.

The response delay to left target stimuli preceded by right-side cues, first described by Posner et al. [J. Neurosci. 4 (1984) 1863-1874] appears to be a stable marker of right-parietal injury. However, only few studies compared patients' performance to age-matched controls. Furthermore, only few studies compared visual and auditory stimuli in this task. Therefore, two groups of right-hemisphere stroke patients, with and without left visual hemineglect, and a healthy control group were studied in three versions of Posner's paradigm. Visual or auditory target stimuli were presented to the subject's left or right, following a visual or auditory cue by 150 ms. The classical 'extinction-type' effect, an increase in missing responses for right visual cue/left visual target, was specifically observed in neglect patients. In the same condition, an 'extinction-type' response delay was present in patients with neglect and in those without neglect. No such delay occurred in any group when cues were auditory. Specifically in neglect patients, response times were generally longer for left than for right visual targets, regardless of cue side and of cue modality. Response times were generally prolonged in neglect patients regardless of target modality. This suggests that three components impair neglect patients' performance in this paradigm: a non-spatial, supramodal deficit, a global, neglect-type deficit of the contralesional hemi-field, and the extinction-type impairment. The latter two deficits appear to be most marked within the visual domain.

Acoustic Stimulation↗
PubMed1997

Visual extinction and cortical connectivity in human vision.

Visual extinction is a common, poorly understood, consequence of unilateral cerebral damage, where a patient fails to detect one of two simultaneously presented stimuli (the one more contralateral to the lesion), despite the fact that each stimulus is correctly detected when presented in isolation. The phenomenon implies a failure of shifting attention from an attended object to an unattended one. We show here that pair detection is improved in conditions where the two stimuli presented to the two halves of the visual field are proximal, co-oriented and co-axial. It is further shown that stimulus properties producing reduced extinction correlate with the selectivity pattern of spatial lateral interactions observed in the primary visual cortex. We suggest that neuronal activity in early stages of cortical visual processing encodes, using long-range lateral interactions, an image description in which visual objects are already segmented and marked. Segmentation seems to function properly even in the presence of significant destruction of the parietal cortex leading to extinction.

Cerebral Cortex↗
PubMed2003

Memory extinction requires gene expression in rat hippocampus.

Rats with cannulae in the dorsal CA1 region of the hippocampus were trained in one-trial step-down inhibitory avoidance, and submitted to four consecutive daily test sessions without the footshock. This produced extinction of the conditioned response in control animals. The bilateral infusion into the CA1 region of the dorsal hippocampus of two different inhibitors of gene transcription, DRB (80 microg/side) or alpha-amanitin (25 pg/side), or of the protein synthesis inhibitor, anisomycin (80 microg/side) blocked extinction of the CR. The treatments were effective when given 15 min before, but not 1 or 3h after the first test session. Retrieval itself was not affected by the drugs. The treatments did not affect general activity in an open field or anxiety levels measured in an elevated plus maze. The data indicate that gene transcription and protein synthesis are necessary at the time of the first test session in order to generate extinction. These requirements are to be expected from learning that involves new synaptic associations.

Amanitins↗