Effects of haloperidol on the multitrial partial reinforcement extinction effect (PREE): evidence for neuroleptic drug action on nonreinforcement but not on reinforcement

Two experiments investigated the effects of haloperidol (0.1 mg/kg) on the partial reinforcement extinction effect (PREE). In experiment 1 two groups of rats were trained to run in a straight alley using six trials/day with an intertrial interval (ITI) of 5–8 min. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Haloperidol was administered in a 2 × 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. In experiment 2 two groups of rats were trained to press a lever in an operant chamber using a discrete trial procedure of ten trials/day with an ITI of 60 s. The CRF group was rewarded on each trial and the PRF group was rewarded on a quasi-random 50% schedule. Haloperidol was administered for 22 days prior to the start of the PREE procedure as well as throughout acquisition and extinction. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in both experiments in all drug conditions. In both experiments haloperidol increased the rate of extinction. Experiment 1 revealed that this effect was entirely dur to the administration of the drug in extinction, independently of the drug condition in acquisition. In contrast to previous results in a one trial/day procedure, the administration of haloperidol to CRF animals did not increase resistance to extinction, failing to support the notion that neuroleptics attenuate the rewarding properties of reinforcement.     

Extinction responding by septal and normal rats following acquisition under four schedules of reinforcement

Extinction responding of animals with septal lesions was compared to that of normal animals following acquisition training under either DRL, FI, VI or FR reinforcement schedules (Part 1). During both acquisition and extinction, septals bar pressed more than normals. However, regardless of response levels, a given schedule changed behavior in the same direction for both septals and normals. Thus, if a given schedule led to a decrease in bar pressing by normals, it also led to a decrease by septals, although the absolute level of responding at which this occurred might be different for the two groups. Similarly, if a schedule led to an increase in responding by normals, it also led to an increase by septals. In Part 2 of the experiment operant levels of septals were not found to be different from those of normals, and noncontingent food delivery generated no more nor less bar pressing in septals than in normals. It was proposed that the septal area may be of importance in the initiation of behavior which competes with the required or reinforced response.     

The effects of competition and motor reprogramming on visuomotor selection in unilateral neglect

Patients with unilateral neglect following right hemisphere damage may have difficulty in moving towards contralesional targets. To test the hypothesis that this impairment arises from competing motor programs triggered by irrelevant ipsilesional stimuli, we examined 16 right hemisphere patients, eight with left visual neglect and eight without, in addition to eight healthy control subjects. In experiment 1 subjects performed sequences of movements using their right hand to targets on the contralesional or ipsilesional side of the responding limb. The locations of successive targets in each sequence were either predictable or unpredictable. In separate blocks of trials, targets appeared either alone or with a simultaneous distractor located at the immediately preceding target location. Neglect patients were significantly slower to execute movements to contralesional targets, but only for unpredictable movements and in the presence of a concurrent ipsilesional distractor. In contrast, healthy controls and right hemisphere patients without neglect showed no directional asymmetries of movement execution. In experiment 2 subjects were required to interrupt a predictable, reciprocating sequence of leftward and rightward movements in order to move to an occasional, unpredictable target that occurred either in the direction opposite to that expected, or in the same direction but twice the extent. Neglect patients were significantly slower in reprogramming the direction and extent of movements towards contralesional versus ipsilesional targets, and they also made significantly more errors when executing such movements. Right hemisphere patients without neglect showed a similar bias in reprogramming direction (but not extent) for contralesional targets, whereas healthy controls showed no directional asymmetry in either condition. On the basis of these findings we propose that neglect involves a competitive bias in favour of motor programs for actions directed towards ipsilesional versus contralesional events. We suggest that programming errors and increased latencies for contralesional movements arise because the damaged right hemisphere can no longer effectively inhibit the release of inappropriate motor programs towards ipsilesional events. Received: 1 October 1996 / Accepted: 21 October 1997     

Effects of frustration on behaviour and plasma corticosteroid levels in pigs

Frustration was elicited in pigs by not rewarding the operant response of subjects having learnt to press a panel with their snout to get a food reward. When pigs were exposed singly to this situation, they extinguished their operant responding. Plasma corticosteroid levels increased during frustration and the number of responses emitted was correlated negatively with the initial plasma corticosteroid levels. When two pigs were submitted together to the frustration situation, they developed aggressive behaviour accompanied by increases of plasma corticosteroid levels. These experiments demonstrate that pigs are sensitive to the effects of frustration elicited by the omission of an expected reward.     

Dorsal bundle extinction effect: Motivation or attention?

Male albino Wistar rats were injected bilaterally with 4 micrograms of 6-hydroxydopamine into the dorsal noradrenergic bundle to deplete forebrain noradrenaline to less than 5% of control values. Acquisition learning of a fixed interval schedule or a continuously reinforced schedule was not altered but resistance to extinction was seen after food reinforced training on either schedule but not after water reinforced training. A possible increase in food motivation was tested by the use of preloading with free food prior to a fixed interval session but both control and lesioned rats reacted similarly to this manipulation thus appearing to exclude an increase in food motivation. An attentional explanation is proposed and tested by the demonstration that resistance to extinction does not occur after a partially (variable ratio 4), as opposed to a continuously, reinforced schedule. Further evidence in favour of an attentional mechanism comes from the finding that on both a fixed interval and a continuously reinforced schedule the lesion has to be present during the acquisition phase to result in subsequent resistance to extinction. Intact animals trained on either schedule and subsequently subjected to the lesion failed to show an increased resistance to extinction.     

Temporal aspects of the dependency of a dimorphic rate of extinction on testosterone.

Previous work has shown that rate of extinction of a conditioned taste aversion is affected by concurrent levels of testosterone in adult rats. In the present study, castrated male and female adult rates were given either oil or testosterone during acquisition of the conditioned taste aversion and then either oil or testosterone during extinction. The males and females that received testosterone during the extinction of the aversion showed the slower, masculine rate of extinction regardless of the type of injections they received during acquisition. Conversely, the animals that received oil during extinction showed the faster, feminine rate of extinction regardless of the type of injection during acquisition. In light of these findings, a number of alternative behavioral changes that could account for the effect of testosterone on the rate of extinction were evaluated.     

Hormonal influences on the extinction of conditioned taste aversion

Conditioned taste aversion for a 5% glucose solution (sugar water) was induced in rats by an i.p. injection of LiCl 30 min after the first presentation of sugar water. Extinction of conditioned taste aversion was measured either in the forced-drinking test or in the preference-drinking test. In the forced-drinking test sugar water was the only fluid presented to the animals during extinction sessions. In the preference-drinking test the animals had the choice of tap water or sugar water. The rate of extinction was much slower in the preference test.The ACTH-analogues, ACTH_4–10 and ACTH_{4–10 7D Phe}, and -MSH delayed extinction in the preference test but not extinction in the forced-drinking test. ACTH_11–24 was without any effect. MSH-release inhibiting factor (MIF) facilitated extinction in the forced-drinking test but did not alter extinction in the preference test. The peptides did not affect intake of tap water or preference of sugar water over tap water by control rats.     

Nucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats (N=13) during cocaine self-administration sessions consisting of three phases. In phase one (maintenance), each lever press resulted in an intravenous cocaine infusion (0.33 mg, 6 s) paired with a tone-houselight stimulus (20 s). Of 144 Acb cells recorded during maintenance, 39 neurons (27%) exhibited phasic firing relative to the cocaine-reinforced response [4-8]. Briefly, Acb neurons showed increases in firing rate within seconds preceding the reinforced response and/or changes (increases or decreases) in activity within seconds following response completion. In phase two (extinction), saline was substituted for cocaine in the task. Results indicated that cells displaying exclusively anticipatory discharges during maintenance exhibited similar phasic activity during extinction. However, neurons that displayed post-response activity during the maintenance phase typically showed significant attenuation of phasic firing rates during extinction. After 30 min of no responding, animals were 'primed' with an intravenous infusion of cocaine, and self-administration was reestablished during phase three (reinstatement). Results showed that pre-response discharge patterns remained relatively intact while post-response cells typically exhibited a partial recovery of phasic activity. Similar findings were observed during other extinction experiments in which the stimulus only was removed (CS extinction). These findings support the notion that specific factors operating within the self-administration context differentially control pre- versus post-response discharge patterns of Acb neurons.     

EXTINCTION OF THE SOLEUS H REFLEX INDUCED BY CONDITIONING STIMULUS GIVEN AFTER TEST STIMULUS

Objective. To quantify the extinction of the soleus H reflex induced by a conditioning stimulus above the motor threshold to the post-tibial nerve applied 10 12 ms after a test stimulus (S2 method). Methods. Ten healthy subjects participated. The sizes of extinction induced by a test stimulus above the motor threshold (conventional method) and by the S2 method were measured. Results. The size of the conditioned H reflex decreased as the intensity of the S2 conditioning stimulus increased. The decrease was less than that induced by the conventional method. The difference between the two methods correlated highly with the amount of orthodromically activated recurrent inhibition. When the S2 conditioning stimulus evoked an M wave that was roughly half of the maximum M wave, the decrease in the size of the conditioned H reflex depended on the size of the unconditioned H reflex. Conclusion. The S2 method allows us to observe extinction without changing the intensity of the test stimulus. The amount of the extinction depends partially on the size of the unconditioned H reflex. The difference in the sizes of extinction between the S2 and conventional methods should relate to recurrent inhibition.     

Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice

The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.