From safety to frustration: The neural substrates of inhibitory learning in aversive and appetitive conditioning procedures.

Inhibitory associative learning counters the effects of excitatory learning, whether appetitively or aversively motivated. Moreover, the affective responses accompanying the inhibitory associations are of opponent valence to the excitatory conditioned responses. Inhibitors for negative aversive outcomes (e.g. shock) signal safety, while inhibitors for appetitive outcomes (e.g. food reward) elicit frustration and/or disappointment. This raises the question as to whether studies using appetitive and aversive conditioning procedures should demonstrate the same neural substrates for inhibitory learning. We review the neural substrates of appetitive and aversive inhibitory learning as measured in different procedural variants and in the context of the underpinning excitatory conditioning on which it depends. The mesocorticolimbic dopamine pathways, retrosplenial cortex and hippocampus are consistently implicated in inhibitory learning. Further neural substrates identified in some procedural variants may be related to the specific motivation of the learning task and modalities of the learning cues. Finally, we consider the translational implications of our understanding of the neural substrates of inhibitory learning, for obesity and addictions as well as for anxiety disorders.

Strain comparisons in inhibitory discrimination learning and novel object recognition procedures.

Strain differences in visual abilities and exploratory tendencies can confound rats' performance in cognitive tests of learning and memory. In the present study we compared the performance of albino Wistar and pigmented Lister Hooded rats in appetitive conditioning and recognition memory procedures, specifically within-subjects inhibitory learning (A+ /AX-) and novel object recognition (NOR) variants. The inhibition task included an excitatory training stage and summation and retardation tests. Difference scores were used to help control for individual variation in baseline nosepoke responding. NOR was tested after a 10 min delay, following 24hr delay and using a recency variant. Discrimination ratios were used to control for individual variation in exploratory activity. In the inhibitory learning procedure, Lister Hooded showed more magazine activity prior to stimulus presentations than Wistar rats but this was a transient effect restricted to day 1 of excitatory training. There was no strain difference in associative learning at the excitatory training stage. The Wistars went on to show some performance advantage at the inhibitory discrimination stage and marginally stronger retardation test performance. In the NOR tasks, there was no significant effect of strain on cognitive performance, but the Wistars showed some advantage in the 10 min delay variant, whereas in the 24hr delay and relative recency NOR variants, the Lister Hooded rats showed some advantage. Overall the results of the present study confirm the suitability of Wistar rats for use in associative learning and basic NOR procedures.

Data showing regional differences in rat brain monoaminergic function.

Chemical neurotransmitters (such as dopamine) modulate cognitive function via ascending projections to various cortical and sub-cortical brain regions. This report describes and links to a relatively large dataset (up to N = 112) compiled from control (untreated) brain samples taken during a series of experimental in vivo studies. The dataset is freely available, to explore the normal interrelationships between levels of neurotransmitter (e.g., dopamine, serotonin), across brain regions implicated in both normal reward and drug addiction, as well as in disorders such as schizophrenia (e.g., nucleus accumbens, prefrontal cortex). Most experimental studies run with a relatively small control group, so there is a lack of baseline data on the expected levels of neurotransmitters and their metabolites in different brain regions. Accordingly, the available dataset has been compiled from a number of studies run in the same laboratory, and using closely similar behavioural procedures, sampling selected brain regions of a priori interest. These collated data can be used to explore differences in the distribution of the monoamines and their metabolites, patterns of neurotransmitter intercorrelations, both between and within different brain structures and including some consideration of laterality effects.

Intraperitoneal 8-OH-DPAT reduces competition from contextual but not discrete conditioning cues.

The effects of the serotonergic (5-hydroxytryptamine, 5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.2 and 0.4 mg/kg i.p.) were examined in trace conditioning (Experiment 1) and overshadowing (Experiment 2) procedures. Both experiments used a fear conditioning procedure conducted off-the-baseline in water deprived male Wistar rats. 8-OH-DPAT was administered during conditioning and its effects were examined drug free as the suppression of an established licking response, both upon re-exposure to the cues provided by the conditioning chambers and upon presentation of experimental stimuli. There were no statistically significant effects of 8-OH-DPAT on conditioning to the discrete cue provided by a 5 s conditioned stimulus (CS), irrespective of the length of the trace interval used in Experiment 1, and irrespective of whether the CS took the form of a light alone, or a noise plus light compound in the Experiment 2 overshadowing procedure. The successful demonstration of overshadowing required the use of a second conditioning session which allowed further evaluation of the effects of 8-OH-DPAT in that neither a weak nor a strong overshadowing effect was modulated by either drug dose. Nonetheless conditioning to contextual cues was attenuated by treatment with 8-OH-DPAT at the 30 s trace interval. We therefore conclude that 8-OH-DPAT reduces competition from contextual but not discrete conditioning cues. This pattern of results lends further support to the view that contextual cue conditioning and discrete cue conditioning are modulated by different neuropharmacological mechanisms.

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials.

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

Potentiation rather than distraction in a trace fear conditioning procedure.

Trace conditioning procedures are defined by the introduction of a trace interval between conditioned stimulus (CS, e.g. noise or light) offset and unconditioned stimulus (US, e.g. footshock). The introduction of an additional stimulus as a distractor has been suggested to increase the attentional demands of the task and to extend the usefulness of the behavioural model. In Experiment 1, the CS was noise and the distractor was provided by an intermittent light. In Experiment 2, the CS was light and the distractor was provided by an intermittent noise. In both experiments, the introduction of a 10s trace interval weakened associative learning compared with that seen in a 0s delay conditioned group. However, there was no consistent evidence of distraction. On the contrary, in Experiment 1, associative learning was stronger (in both trace and delay conditioned groups) for rats conditioned also in the presence of the intermittent light. In Experiment 2, there was no such effect when the roles of the stimuli were reversed. The results of Experiment 2 did however confirm the particular salience of the noise stimulus. The finding of increased associative learning dependent on salience is consistent with arousal-mediated effects on associative learning.

Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure.

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05µg/side) or D1 antagonist SCH23390 (0.5µg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning.

Dopaminergic modulation of appetitive trace conditioning: the role of D1 receptors in medial prefrontal cortex.

RATIONALE: Trace conditioning may provide a behavioural model suitable to examine the maintenance of 'on line' information and its underlying neural substrates. OBJECTIVES: Experiment la was run to establish trace conditioning in a shortened procedure which would be suitable to test the effects of dopamine (DA) D1 receptor agents administered by microinjection directly into the brain. Experiment lb examined the effects of the DA D1 agonist SKF81297 and the DA D1 antagonist SCH23390 following systemic administration in pre-trained animals. Experiment 2 went on to test the effects of systemically administered SKF81297 on the acquisition of trace conditioning. In experiment 3, SKF81297 was administered directly in prelimbic (PL) and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) to compare the role of different mPFC sub-regions. RESULTS: Whilst treatment with SCH23390 impaired motor responding and/or motivation, SKF81297 had relatively little effect in the pre-trained animals tested in experiment 1b. However, systemic SKF81297 depressed the acquisition function at the 2-s trace interval in experiment 2. Similarly, in experiment 3, SKF81297 (0.1 µg in 1.0 µl) microinjected into either PL or IL mPFC impaired appetitive conditioning at the 2-s trace interval. CONCLUSIONS: Impaired trace conditioning under SKF81297 is likely to be mediated in part (but not exclusively) within the IL and PL mPFC sub-regions. The finding that trace conditioning was impaired rather than enhanced under SKF81297 provides further evidence for the inverse U-function which has been suggested to be characteristic of mPFC DA function.

Quantitative analysis of performance on a progressive-ratio schedule: effects of reinforcer type, food deprivation and acute treatment with Δ9-tetrahydrocannabinol (THC).

Rats' performance on a progressive-ratio schedule maintained by sucrose (0.6M, 50 µl) and corn oil (100%, 25 µl) reinforcers was assessed using a model derived from Killeen's (1994) theory of schedule-controlled behaviour, 'Mathematical Principles of Reinforcement'. When the rats were maintained at 80% of their free-feeding body weights, the parameter expressing incentive value, a, was greater for the corn oil than for the sucrose reinforcer; the response-time parameter, δ, did not differ between the reinforcer types, but a parameter derived from the linear waiting principle (T0), indicated that the minimum post-reinforcement pause was longer for corn oil than for sucrose. When the rats were maintained under free-feeding conditions, a was reduced, indicating a reduction of incentive value, but δ was unaltered. Under the food-deprived condition, the CB1 cannabinoid receptor agonist Δ(9)-tetrahydrocannabinol (THC: 0.3, 1 and 3 mg kg(-1)) increased the value of a for sucrose but not for corn oil, suggesting a selective enhancement of the incentive value of sucrose; none of the other parameters was affected by THC. The results provide new information about the sensitivity of the model's parameters to deprivation and reinforcer quality, and suggest that THC selectively enhances the incentive value of sucrose.

Intraperitoneal sertraline and fluvoxamine increase contextual fear conditioning but are without effect on overshadowing between cues.

Treatment with selective serotonin reuptake inhibitors (SSRIs) can reduce contextual conditioning. Since contexts comprise a variety of potentially competing cues, impaired overshadowing may provide an account of such effects. The present study therefore compared the effects of two SSRIs on overshadowing and contextual conditioning, testing suppression of an ongoing behavioral response (licking) by cues previously paired with foot shock. Conditioning to a 5 s light stimulus was reduced when it was presented in compound with a 5 s noise, thus overshadowing was demonstrated. In two experiments, this overshadowing was unaffected by treatment with either sertraline or fluvoxamine. However, unconditioned suppression to the noise (tested in a control group previously conditioned to the light alone) was reduced after sertraline (10 mg/kg, i.p.). The successful demonstration of overshadowing required the use of a second conditioning session or an additional conditioning trial within the same conditioning session. Neither weak nor strong overshadowing (of the light by the tone) was affected by any drug treatment. Moreover, counter to prediction, conditioning to contextual cues was increased rather than impaired by treatment with sertraline (10 mg/kg, i.p.) and fluvoxamine (30 mg/kg, i.p.).

Ro 04-6790-induced cognitive enhancement: no effect in trace conditioning and novel object recognition procedures in adult male Wistar rats.

The evidence for cognitively enhancing effects of 5-hydroxytryptamine6 (5-HT6) receptor antagonists such as Ro 04-6790 is inconsistent and seems to depend on the behavioral test variant in use. Trace conditioning holds promise as a behavioral assay for hippocampus-dependent working memory function. Accordingly, Experiment 1 assessed the effect of Ro 04-6790 (5 and 10mg/kg i.p.) on associating a noise conditioned stimulus paired with foot shock (unconditioned stimulus) at a 3 or 30s trace interval in adult male Wistar rats. Contextual conditioning was measured as suppression to the contextual cues provided by the experimental chambers and as suppression to a temporally extended light background stimulus which provided an experimental context. Experiment 2 assessed the effect of Ro 04-6790 (5 and 10mg/kg i.p.) on recognition memory as tested by the exploration of novel relative to familiar objects in an open arena. In Experiment 1, Ro 04-6790 (5 and 10mg/kg) was without effect on trace and contextual conditioning. In Experiment 2, there was no indication of the expected improvement under Ro 04-6790 at the same doses previously found to enhance recognition memory as measured in tests of novel object exploration. Thus, there was no evidence that treatment with the 5-HT6 receptor antagonist Ro 04-6790 acted as a cognitive enhancer in either trace conditioning or object recognition procedures. We cannot exclude the possibility that the experimental procedures used in the present study would have been sensitive to the cognitive enhancing effects of Ro 04-6790 in a different dose range, behavioral test variant, or in a different strain of rat. Nonetheless the drug treatment was not ineffective in that object exploration was reduced under 10mg/kg Ro 04-6790.

Effects of SKF-83566 and haloperidol on performance on progressive ratio schedules maintained by sucrose and corn oil reinforcement: quantitative analysis using a new model derived from the Mathematical Principles of Reinforcement (MPR).

RATIONALE: Mathematical models can assist the interpretation of the effects of interventions on schedule-controlled behaviour and help to differentiate between processes that may be confounded in traditional performance measures such as response rate and the breakpoint in progressive ratio (PR) schedules. OBJECTIVE: The effects of a D1-like dopamine receptor antagonist, 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide (SKF-83566), and a D2-like receptor antagonist, haloperidol, on rats' performance on PR schedules maintained by sucrose and corn oil reinforcers were assessed using a new model derived from Killeen's (Behav Brain Sci 17:105-172, 1994) Mathematical Principles of Reinforcement. METHOD: Separate groups of rats were trained under a PR schedule using sucrose or corn oil reinforcers. SKF-83566 (0.015 and 0.03 mg kg(-1)) and haloperidol (0.05 and 0.1 mg kg(-1)) were administered intraperitoneally (five administrations of each treatment). Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model's parameters were compared between treatments. RESULTS: Haloperidol reduced a (the parameter expressing incentive value) in the case of both reinforcers, but did not affect the parameters related to response time and post-reinforcement pausing. SKF-83566 reduced a and k (the parameter expressing sensitivity of post-reinforcement pausing to the prior inter-reinforcement interval) in the case of sucrose, but did not affect any of the parameters in the case of corn oil. CONCLUSIONS: The results are consistent with the hypothesis that blockade of both D1-like and D2-like receptors reduces the incentive value of sucrose, whereas the incentive value of corn oil is more sensitive to blockade of D2-like than D1-like receptors.

Paradoxical effects of low dose MDMA on latent inhibition in the rat.

The cognitive effects of MDMA ('Ecstasy') are controversial, particularly in the case of acute administration of low doses. Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received non-reinforced pre-exposure, an effect typically abolished by amphetamines and enhanced by antipsychotics. LI enhancement has also been shown using the 5-HT reuptake blocker sertraline. In the present study, the effects of MDMA (6 mg/kg, known to increase 5-HT release) were tested using 10 and 40 pre-exposures to produce weak and strong LI in controls, respectively. MDMA (injected twice, prior to pre-exposure and conditioning) significantly enhanced LI in that the effect was clearly demonstrated after only 10 pre-exposures, when it was absent in the saline controls. On its own such a profile of action would be consistent with a procognitive effect of MDMA mediated by increased availability of 5-HT. However, paradoxically the same MDMA treatment reduced LI in the 40 pre-exposures condition. This component of action is likely attributable to MDMA's actions on catecholaminergic systems and is consistent with other evidence of its adverse effects. Moreover, there were small but significant reductions in 5-HT in medial prefrontal cortex (mPFC) and amygdala assayed 7 days post MDMA administration (2 × 6 mg/kg, 24 h apart).

Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule.

It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes.

A clozapine-like effect of cyproheptadine on progressive ratio schedule performance.

The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT2) and histamine (H1) receptor antagonist effects, are shared by the non-selective 5-HT receptor antagonist cyproheptadine. Atypical antipsychotics have a characteristic profile of action on operant behaviour maintained by progressive ratio schedules, as revealed by Killeen's (1994) mathematical model of schedule controlled behaviour. These drugs increase the values of a parameter that expresses the 'incentive value' of the reinforcer (a) and a parameter that is inversely related to the 'motor capacity' of the organism (δ). This experiment examined the effects of acute treatment with cyproheptadine and clozapine on performance on a progressive ratio schedule of food reinforcement in rats; the effects of a conventional antipsychotic, haloperidol, and two drugs with food intake-enhancing effects, chlordiazepoxide and Δ9-tetrahydrocannabinol (THC), were also examined. Cyproheptadine (1, 5 mg kg⁻¹) and clozapine (3.75, 7.5 mg kg⁻¹) increased a and δ. Haloperidol (0.05, 0.1 mg kg⁻¹) reduced a and increased δ. Chlordiazepoxide (3, 10 mg kg⁻¹) increased a but reduced δ. THC (1, 3 mg kg⁻¹) had no effect. Interpretation based on Killeen's (1994) model suggests that cyproheptadine and clozapine enhanced the incentive value of the reinforcer and impaired motor performance. Motor impairment may be due to sedation (possibly reflecting H1 receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H1 and 5-HT2 receptors, which has been proposed as the mechanism underlying the food intake-enhancing effect of cyproheptadine. In agreement with previous findings, haloperidol impaired motor performance and reduced the incentive value of the reinforcer. Chlordiazepoxide's effect on a is consistent with its food intake-enhancing effect.

Catecholaminergic depletion in nucleus accumbens enhances trace conditioning.

PURPOSE: To examine the effect of dopamine depletion in nucleus accumbens on trace conditioning; to distinguish the role of core and shell sub-regions, as far as possible. MATERIAL/METHODS: 6-hydroxydopamine was used to lesion dopamine terminals within the core and shell accumbens. Experiment 1 assessed conditioning to a tone conditioned stimulus that had previously been paired with footshock (unconditioned stimulus) at a 30s trace interval. Experiment 2 subsequently assessed contiguous conditioning (at 0s trace) using a light conditioned stimulus directly followed by the unconditioned stimulus. RESULTS: Both sham and shell-lesioned animals showed the normal trace effect of reduced conditioning to the trace conditioned stimulus but 6-hydroxydopamine injections targeted on the core subregion of the nucleus accumbens abolished this effect and enhanced conditioning to the trace conditioned stimulus. However, the depletion produced by this lesion placement extended to the shell. In Experiment 2 (at 0s trace), there was no effect of either lesion placement as all animals showed comparable levels of conditioning to the light conditioned stimulus. Neurochemical analysis across core, shell and comparison regions showed some effects on noradrenalin as well as dopamine. CONCLUSIONS: The pattern of changes in noradrenalin did not systematically relate to the observed behavioural changes after core injections. The pattern of changes in dopamine suggested that depletion in core mediated the increased conditioning to the trace conditioned stimulus seen in the present study. However, the comparison depletion restricted to the shell subregion was less substantial, and a role for secondarily affected brain regions cannot be excluded.

Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing.

Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to-be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0 mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0 µg/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates.

Reduced dopamine function within the medial shell of the nucleus accumbens enhances latent inhibition.

Latent inhibition (LI) manifests as poorer conditioning to a CS that has previously been presented without consequence. There is some evidence that LI can be potentiated by reduced mesoaccumbal dopamine (DA) function but the locus within the nucleus accumbens of this effect is as yet not firmly established. Experiment 1 tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of DA terminals within the core and medial shell subregions of the nucleus accumbens (NAc) would enhance LI under conditions that normally disrupt LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures (to a noise CS) and 2 conditioning trials. The vehicle-injected and core-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the medial shell, however, produced potentiation of LI, demonstrated across two extinction tests. In a subsequent experiment, haloperidol microinjected into the medial shell prior to conditioning similarly enhanced LI. These results underscore the dissociable roles of core and shell subregions of the NAc in mediating the expression of LI and indicate that reduced DA function within the medial shell leads to enhanced LI.

Catecholaminergic depletion within the prelimbic medial prefrontal cortex enhances latent inhibition.

Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received repeated non-reinforced pre-exposure. Investigations into the neural substrates of LI have focused on the nucleus accumbens (NAc) and its inputs from the hippocampal formation and adjacent cortical areas. Previous work has suggested that lesions to the medial prefrontal cortex (mPFC), another major source of input to the NAc, do not disrupt LI. However, a failure to observe disrupted LI does not preclude the possibility that a particular brain region is involved in the expression of LI. Moreover, the mPFC is a heterogeneous structure and there has been no investigation of a possible role of different regions within the mPFC in regulating LI under conditions that prevent LI in controls. Here, we tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of dopamine (DA) terminals within the prelimbic (PL) and infralimbic (IL) mPFC would lead to the emergence of LI under conditions that do produce LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures to a noise conditioned stimulus (CS) and two conditioning trials. Sham-operated and IL-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the PL, however, produced potentiation of LI. These results provide the first demonstration that the PL mPFC is a component of the neural circuitry underpinning LI.

A neurotensin agonist and antagonist decrease and increase activity, respectively, but do not preclude discrete cue conditioning.

There is evidence to suggest that neurotensin (NT) may enhance cognitive function. For example, in aversive trace conditioning, the NT agonist PD149163 selectively increased trace conditioning (Grimond-Billa, et al., 2008). The present study, therefore, examined the role of NT in associative learning, tested using an appetitive trace conditioning procedure (0-s or 10-s inter-stimulus-interval [ISI]) with a mixed frequency noise as a conditioned stimulus (CS) and food delivery as the unconditioned stimulus (UCS). The effects of an NT agonist (PD149163, 0.125 and 0.25 mg/kg, Experiment 1) and an NT antagonist (SR142948A, 0.01 and 0.1 mg/kg, Experiment 2) were compared. To take nonspecific effects of these compounds into account, conditioning to the CS was measured as a percentage of total responding, during UCS deliveries and in the inter-trial-interval (ITI). In both experiments, associative learning to the contiguously (0-s) presented CS was demonstrated, although there was a relative reduction in this learning under 0.125 mg/kg PD149163. Counter to prediction, the only effect on trace conditioning was some overall reduction in responding to the CS in the 10-s group conditioned under 0.25 mg/kg PD149163. The NT antagonist was without any effect on appetitive conditioning. However, these NT compounds were not ineffective: decreases and increases in responding in the ITI, ISI and during UCS deliveries seen under PD149163 and SR142948A were dissociable from effects on discrete cue conditioning.