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

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 present 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 5s light stimulus was reduced when this was presented in compound with a 5s 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 the control group previously conditioned to the light alone) was reduced after sertraline (10mg/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 (10mg/kg, i.p.) and fluvoxamine (30mg/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 behavioural 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 10 mg/kg i.p.) on associating a noise conditioned stimulus paired with foot shock (unconditioned stimulus) at a 3 or 30 s 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 10 mg/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 10 mg/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 10 mg/kg Ro 04-6790

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)

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