Effects of fornix transection and pituitary-adrenal modulation on extinction behavior.

We examined whether the absence of a dynamic pituitary-adrenal response contributes to the behavioral deficit seen in hippocampally damaged rats following the transition to extinction of a learned behavior. In the first experiment, total lever presses and detailed behaviors of rats with fornix-transected and replacement ACTH4–20 or ACTH were compared with the behavior of fornix-transected and sham-transection groups during acquisition and extinction of lever pressing. Fornix-transected rats showed increased resistance to extinction and an altered pattern or mode of extinction responding. ACTH4–20 or ACTH acted similarly in reducing extinction lever presses in fornix-transected rats without altering the mode of extinction responding. In the second experiment the extinction behaviors of rats with fornix transection were compared with those of normal, sham-transection adrenalectomized, or dexamethasone-treated rats. Fornix-transected rats again showed increased resistance to extinction and a different mode of responding during extinction. Adrenalectomized rats showed an extinction deficit but differed from fornix-transected rats. The behavior of dexamethasone-treated rats was similar to that of controls. The results are interpreted to mean that ACTH and corticosterone both affect extinction behavior (in opposite ways) but do not account for the extinction deficit seen in hippocampally damaged rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of D-cycloserine on the extinction of appetitive operant learning.

Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1A and 1B tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of nonresponse-contingent deliveries of the reinforcer (that theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, that is, one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Extinction of tolerance to the analgesic effect of morphine: Intracerebroventricular administration and effects of stress.

Previous research demonstrated that tolerance to the analgesic effect of morphine in rats is attenuated by administrations of a placebo in the context of drug-associated cues. Such apparent extinction of tolerance has been interpreted as support for a Pavlovian conditioning model of tolerance. Recently, it has been suggested that these findings are attributable to stress, induced during placebo sessions and augmenting the analgesic effect of morphine (rather than to Pavlovian extinction). Our results indicate that placebo sessions actually attenuate tolerance by extinguishing the association between predrug cues and the systemic effects of the drug. In addition, the results indicate that conditioning contributes to analgesic tolerance when morphine is administered intracerebroventricularly, which suggests that conditional alterations within the central nervous system mediate such tolerance. This contrasts with alternative suggestions that conditional alterations in drug distribution or metabolism mediate the effects of conditioning manipulations on tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanisms of resurgence of an extinguished instrumental behavior.

Four experiments examined “resurgence” of an instrumental behavior after extinction. All experiments involved three phases in which rats were (1) trained to press one lever for food reward, (2) trained to press a second lever while the first leverpress was extinguished, and (3) tested under conditions in which neither leverpress was rewarded. In each experiment, the first leverpress recovered (resurged) in Phase 3, when the second leverpress was extinguished. The results demonstrated that resurgence occurred when the schedules of reinforcement employed in Phases 1 and 2 yielded either an upshift, downshift, or no change in the rate of reward delivery between those phases. They also demonstrated that initial training on the first lever was required to observe a robust increase in pressing at test (resurgence is thus an associative effect). Resurgence was shown to occur over a wide variety of schedules of reinforcement in Phase 2 (including ratio, interval, and leverpress-independent schedules). Finally, the results do not support the view that resurgence occurs because response competition suppresses leverpressing of the first lever during extinction. Overall, they are consistent with the view that resurgence is a renewal effect in which extinction of an instrumental behavior is specific to the context provided by rewarded leverpressing during the extinction phase. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Some conditions of anxiety extinction.

Four procedures for extinguishing anxiety were tested with rats as Ss. The results support the following conclusions: 1. Remaining away from an anxiety-eliciting situation for a short period of time does not bring about extinction of anxiety; 2. The Pavlovian extinction operation does weaken the strength of conditioned anxiety; 3. The anxiety extinction process is accelerated by the pairing, during the extinction operation, of the anxiety-producing stimulus with a positive reinforcer (a cage mate stimulus animal); and tentatively, 4. An additional emotionalizing operation (blocking of escape) that is concurrent with the extinction operation will impede the extinction process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Counterconditioning versus forced exposure in extinction of avoidance responding and conditioned fear in rats.

Conducted 2 experiments using 64 and 32 male Long-Evans hooded rats, respectively. Exp. I investigated the extinction of the conditioned avoidance response (CAR) by response prevention and counterconditioning methods. Response prevention was most effective in extinguishing both the CAR and associated conditioned fear, although counterconditioning produced greater extinction than the regular extinction procedure. Exp. II equated the counterconditioning and response-prevention conditions for duration of CS exposure and demonstrated the superiority of the latter in extinguishing the CAR; both methods were equally effective in decreasing conditioned fear as compared to the regular extinction procedure. Extinction of the CAR was facilitated to the extent to which different procedures eliminated response-contingent feedback by reducing escape-avoidance responses. Conditioned fear was a function of the amount of nonreinforced exposure to the CS during extinction. (24 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cortical, hippocampal, and striatal mediation of schedule-induced behaviors.

The sequential occurrence of licking, locomotor activity, entries into the food magazine (panel pressing), and nonreinforced lever pressing engendered by a periodic schedule of food presentation were measured in each 60-s interreinforcement interval in normal and brain-damaged rats. The development of these responses was measured over 20 days in different groups of food-deprived rats that had received aspirations of the hippocampus, small lesions of the cortex overlying the hippocampus (hippocampal-operated control group), decortication, or 6-hydroxydopamine lesions of the caudate nucleus or nucleus accumbens. All lesions produced distinctive patterns of change in the measured behaviors, and dissociations as well as similarities in their effects were evident. These results are discussed with respect to dissociations in the motor and motivational effects of the various lesions and in terms of contemporary hypotheses of schedule-induced behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of septal area damage and base-line activity levels on conditioned heart-rate response in rats.

Exp. I subjected 7 unrestrained male Long-Evans rats with septal area lesions and 8 nonoperated controls to Pavlovian heart-rate conditioning with footshock as the UCS. Experimental Ss displayed lower degrees of tachycardia to both the CS and UCS than did controls, but there were no significant differences in amount of skeletal movement. In Exp. II, 6 control and 6 septal-damaged Ss received CS-shock pairings while lever pressing for food and while not lever pressing. There was no difference in conditioned suppression, but less conditioned tachycardia was again seen in experimental Ss, indicating dissociation between the 2 measures of conditioning. All Ss exhibited greater tachycardia during the non-lever-pressing condition, illustrating the effect of base-line activity on conditioned heart-rate responses. (24 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Pavlovian conditioned stimulus-unconditioned stimulus pairings during avoidance response-prevention trials in rats.

Response prevention (blocking) has been shown to hasten extinction of an instrumental avoidance response. One interpretation suggests that the facilitation effect is mediated by Pavlovian fear reduction during conditioned stimulus exposure on blocked trials. To test the fear-reduction hypothesis 30 male Holtzman albino rats received either a typical blocking treatment, blocking with shock, or extinction alone. Results indicate that blocking with the UCS was as effective as regular blocking in facilitating extinction of avoidance. An ancillary part of the experiment to assess the effectiveness of response prevention in 30 immature Ss showed that blocking did not facilitate extinction with the weanlings. Findings suggest that facilitated extinction is not solely attributable to Pavlovian fear reduction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.

Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study, the authors investigated the effects of the Type-5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction-training sessions required to meet extinction criteria. Pre- or postextinction-training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self-administration and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Pavlovian aversive context conditioning using carbon dioxide as the unconditional stimulus.

Four experiments were conducted to examine the utility of carbon dioxide (CO?) as an aversive unconditioned stimulus/stimuli (UCS) in a Pavlovian context conditioning paradigm. Exp 1 demonstrated that rats exposed to CO? in a distinctive context showed elevated levels of freezing relative to controls. Exp 2 replicated this basic effect with a modified conditioning procedure and additionally demonstrated conditioned analgesia. Exp 3 demonstrated a positive monotonic relationship between UCS duration and resistance to extinction of freezing behavior as well as conditioned analgesia. Exp 4 demonstrated extinction and an extinction-related phenomenon, renewal. These studies clearly demonstrate the utility of CO? as a Pavlovian UCS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Limitations to the generality of cocaine locomotor sensitization.

Repeated exposure to cocaine often leads to tolerance to effects on operant behavior, whereas sensitization often develops to effects on locomotor activity. The purpose of the present set of experiments was to examine if locomotor sensitization to cocaine would develop in the presence or absence of an operant contingency in rats. In Experiment 1, rats lever pressed on an FR schedule of reinforcement, and were administered chronic cocaine. Tolerance to effects of cocaine on lever pressing developed in most subjects. No subjects developed locomotor sensitization even when the operant contingency was removed. Experiment 2 examined effects of chronic cocaine administration in rats with no exposure to an operant contingency. Tolerance developed to locomotor effects of cocaine in some subjects, but none developed sensitization. In Experiment 3, rats were exposed to a shorter drug regimen, and given time off before a sensitization-test session. Some, but not all subjects showed locomotor sensitization during the test session. The present results, therefore, show that locomotor sensitization to cocaine is not an inevitable consequence of repeated exposure to the drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats.

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADs ≤9 seconds) or low (LoI; MADs ≥13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats.

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Operant and Pavlovian control of visual stimulus orienting and food-related behaviors in rats with lesions of the amygdala central nucleus.

The effects of superimposing operant reward and omission contingencies on 2 Pavlovian conditioned responses evoked by a visual conditioned stimulus paired with food were examined in rats with lesions of the amygdala central nucleus (CN). In sham-lesioned rats, the frequency of an orienting response, rearing, was increased by reward contingencies and decreased by omission contingencies, compared with yoked Pavlovian controls. In contrast, in CN-lesioned rats, rearing was not affected by either operant contingency and occurred at lower levels with Pavlovian procedures alone than in sham-lesioned rats. Nevertheless, CN-lesioned and sham-lesioned rats showed similar increases in the frequency of conditioned food-cup behavior with reward contingencies, similar decreases with omission contingencies, and similar levels of that response with Pavlovian procedures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampus and Pavlovian Fear Conditioning in Rats: Muscimol Infusions Into the Ventral, but Not Dorsal, Hippocampus Impair the Acquisition of Conditional Freezing to an Auditory Conditional Stimulus.

The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Species generality of within-subjects reward magnitude effects.

12 female pigtail, stumptail, and squirrel monkeys and 4 female Holtzman albino rats were given acquisition, extinction, and reacquisition training in a discrete-trials 2-lever spatial discrimination situation. In acquisition the left and right levers were associated with 5- and 1-pellet rewards, respectively, and in reacquisition, response to either lever produced 5-pellet reward. The 4 species showed similar patterns of preference for the 5-pellet lever on 2-lever choice trials and differential responding on 1-lever forced trials in acquisition, and similar within-Ss extinction effects which were at variance with the typical crossover of large- and small-reward extinction curves in between-groups reward magnitude studies with rats. Species differences appeared in over-all relative rate of extinction, with the macaques showing the fastest extinction, and in the degree to which historical effects of acquisition conditions appeared and persisted in reacquisition. (French summary) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Normal conditioning inhibition and extinction of freezing and fear-potentiated startle following electrolytic lesions of medial prefrontal cortex in rats.

The authors investigated the role of medial prefrontal cortex (mPFC) in the inhibition of conditioned fear in rats using both Pavlovian extinction and conditioned inhibition paradigms. In Experiment 1, lesions of ventral mPFC did not interfere with conditioned inhibition of the fear-potentiated startle response. In Experiment 2, lesions made after acquisition of fear conditioning did not retard extinction of fear to a visual conditioned stimulus (CS) and did not impair "reinstatement" of fear after unsignaled presentations of the unconditioned stimulus. In Experiment 3, lesions made before fear conditioning did not retard extinction of fear-potentiated startle or freezing to an auditory CS. In both Experiments 2 and 3, extinction of fear to contextual cues was also unaffected by the lesions. These results indicate that ventral mPFC is not essential for the inhibition of fear under a variety of circumstances. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrical stimulation of the prefrontal cortex increases cholecystokinin, glutamate, and dopamine release in the nucleus accumbens: an in vivo microdialysis study in freely moving rats

In vivo microdialysis, radioimmunoassay, and HPLC with electrochemical or fluorometric detection were used to investigate the release of cholecystokinin (CCK), glutamate (Glu), and dopamine (DA) in nucleus accumbens septi (NAS) as a function of ipsilateral electrical stimulation of medial prefrontal cortex (mPFC). CCK was progressively elevated by mPFC stimulation at 50-200 Hz. Stimulation-induced CCK release was intensity-dependent at 250-700 microA. NAS Glu and DA levels were each elevated by stimulation at 25-400 Hz; the dopamine metabolites DOPAC and homovanillic acid were increased by stimulation at 100-400 Hz. When rats were trained to lever press for mPFC stimulation, the stimulation induced similar elevations of each of the three transmitters to those seen with experimenter-administered stimulation. Perfusion of 1 mM kynurenic acid (Kyn) into either the ventral tegmental area (VTA) or NAS blocked lever pressing for mPFC stimulation. VTA, but not NAS, perfusion of Kyn significantly attenuated the increases in NAS DA levels induced by mPFC stimulation. Kyn did not affect NAS CCK or Glu levels when perfused into either the VTA or NAS. The present results are consistent with histochemical evidence and provide the first in vivo evidence for the existence of a releasable pool of CCK in the NAS originating from the mPFC. Although dopamine is the transmitter most closely linked to reward function, it was CCK that showed frequency-dependent differences in release corresponding most closely to rewarding efficacy of the stimulation. Although not essential for the reward signal itself, coreleased CCK may modulate the impact of the glutamatergic action in this behavior.     

A developmental dissociation of context and GABA effects on extinguished fear in rats.

Although extinction has attracted considerable attention in recent years, there has been very little empirical work on extinction during development. Using Pavlovian fear conditioning, the authors provide evidence for developmental differences in extinction. Specifically, Postnatal Day (PND) 23 rats exhibited recovery of an extinguished freezing response to an auditory conditioned stimulus when tested in a context different from that in which extinction occurred (i.e., renewal) or when injected with the gamma-amino butyric acid (GABA) inverse agonist FG7142 prior to test. In contrast, PND 16 rats failed to exhibit either of these effects, although a subsequent experiment demonstrated that FG7142 alleviated spontaneous forgetting in PND 16 rats. Taken together, it appears that there are fundamental differences in the processes involved in extinction across development. (PsycINFO Database Record (c) 2010 APA, all rights reserved)