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Hippocampal multiple unit activity was recorded in rabbits during each of four preacquisition treatments and during subsequent classical conditioning of the nictitating membrane response. Three preexposure conditions were employed: CS alone presentations, presentations of the CS paired with a second, neutral stimulus, or unpaired presentations of the CS and second stimulus. It was predicted that (a) CS alone preexposures would produce a decrease in hippocampal activity and a retarded rate of subsequent conditioned response (CR) acquisition and (b) the magnitude of both effects would be attenuated by preexposures of the CS paired with a second stimulus. The results partially supported both predictions. Hippocampal activity was inhibited during CS alone preexposures and that inhibition was attenuated by pairing the CS with a second, neutral stimulus. Behaviorally, all of the preexposure groups showed equivalent, retarded rates of acquisition compared to a nonpreexposed control group. Hippocampal activity throughout acquisition was significantly greater in the nonpreexposed group compared to the group preexposed to the CS alone. Hippocampal activity of the other two groups was intermediate between the nonpreexposed and the CS alone groups. It is suggested that alterations in the magnitude of hippocampal activity may provide a reliable, neuronal correlate of CS associability changes.

The 5-HT(2A/2C) receptor antagonist, ritanserin, was reported to retard the acquisition of conditioned responses (CRs) during classical conditioning of the rabbit's nictitating membrane (NM) response. The present study compared the effects of ritanserin on acquisition of CRs to a tone conditioned stimulus (CS) with that of the 5-HT(2A/2C) receptor antagonist, LY-53,857 and the 5-HT2A selective antagonist, MDL-11,939. All three drugs were injected at equimolar doses of 0.067, 0.67 and 6.7 micromol/kg, SC, 1 h before behavioral testing. Ritanserin and MDL-11,939 retarded CR acquisition to a tone CS, while LY-53,857 had no effect. Control experiments demonstrated that ritanserin (1 micromol/kg), MDL-11,939 (1 micromol/kg) and LY-53,857 (2 micromol/kg) had no effect on baseline responding or non-associative responding to the CS. However, both ritanserin and MDL-11,939 impaired the performance of the unconditioned NM reflex, as measured by a decrease in UR amplitudes on US alone trials, while LY-53,857 had no effect. In previously trained animals, ritanserin robustly impaired the performance of CRs, as measured by a reduced ability of the CS to elicit CRs, while the effects of LY-53,857 and MDL-11,939 were marginal. The retardation of associative learning produced by ritanserin and MDL-11,939 may have been due, at least in part, to their impairment of the NM reflex arc. Since MDL-11,939 is a highly selective 5-HT2A antagonist, the retardation of learning and impairment of UR amplitudes produced by MDL-11,939 and ritanserin may have been due to blockade of the 5-HT2A receptor. The ability of ritanserin and MDL-11,939 to produce effects on learning and performance that were opposite to that of 5-HT(2A/2C) agonists suggests that they may be acting as inverse agonists at that receptor. These results stress the importance of the serotonergic system for optimal associative learning and motor function.

d-Lysergic acid diethylamide (LSD), an agonist at the 5-HT(2A/2C) and 5-HT1A receptors, has previously been demonstrated to enhance associative learning as measured by accelerated acquisition of the rabbit's classically conditioned nictitating membrane (NM) response. The present study examined further the role of these receptors in the action of LSD. LSD (30 nmol/kg, I.V.) significantly enhanced conditioned response (CR) acquisition to both tone and light conditioned stimuli (CSs), while the 5-HT1A receptor agonists 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT; 50 and 200 nmol/kg) and lisuride (0.3-30 nmol/kg) had no effect. Ritanserin (6.7-6700 nmol/kg, S.C.), a selective 5-HT(2A/2C) receptor antagonist, retarded acquisition of CRs to both tone and light CSs in a dose-dependent manner. Ritanserin (6.7-670 nmol/kg, S.C.) also dose dependently antagonized the enhancement of CR conditioning produced by LSD (30 nmol/kg, I.V.) to both tone and light CSs. We conclude that the enhancement of CR acquisition by LSD was due to an action at the 5-HT(2A/2C) receptor. These results suggest that the 5-HT(2A/2C) receptor plays an important role in learning.

Previous studies had demonstrated that in utero exposure to cocaine produces structural changes in the development of the rabbit's anterior cingulate cortex. Because the anterior cingulate cortex has been proposed to subserve a variety of cognitive processes including associative learning, we investigated the effects of intrauterine exposure to cocaine on the acquisition of the rabbit's classically conditioned nictitating membrane response. Adult, sexually mature rabbits born of dams that had received intravenous injections of either saline or cocaine (4 mg/kg, twice a day) from day 8 to day 29 of gestation were classically conditioned by pairing tone and light CSs with an airpuff US. Rabbits that had been exposed to cocaine in utero demonstrated a more rapid acquisition of CRs to a tone CS but not to a light CS as compared with saline controls. Control experiments indicated that the accelerated learning to the tone CS was not due to sensitization, pseudoconditioning, altered baseline rate of responding, an increased responsiveness to the airpuff US, or to a change in the intensity threshold of the tone CS for elicitation of CRs. We conclude that in utero exposure to cocaine alters the processing of auditory stimuli and this leads to an abnormally rapid acquisition of CRs. It is suggested that this functional consequence of prenatal exposure to cocaine is due to structural abnormalities in anterior cingulate cortex.

Pavlovian conditioning of the rabbit's nictitating membrane response was used to determine whether the retardation of learning produced by enkephalin derivatives was mediated through an action on mu- or delta-opioid receptors. Intraventricular injection of the highly selective mu-agonist, [D-Ala2, MePhe4, Gly-ol5] enkephalin (DAMGO) significantly retarded (2 nmol) or completely blocked (20 nmol) the acquisition of conditioned responses. The retarded or blocked acquisition of conditioned responses produced by DAMGO could still be detected when the rabbits were tested two days after cessation of drug injections, suggesting that DAMGO had affected learning and not simply performance of conditioned responses. Intraventricular injection of a comparable dose (20 nmol) of the highly selective delta-agonist, [D-Pen2,5] enkephalin (DPDPE) did not retard learning. A higher dose of DPDPE (200 nmol), which would be expected to act at both mu- and delta-receptors, did produce a retardation of acquisition that was comparable to the effects of a 2-nmol dose of DAMGO. However, unlike DAMGO, the retardation of learning produced by this dose of DPDPE appeared to be due, at least in part, to a reduction in the aversive properties of the unconditioned stimulus. The retardation of learning produced by 2 nmol of DAMGO and 200 nmol of DPDPE was due to an action on an opioid receptor because this effect was blocked by a subcutaneous injection of naloxone (2.5 mumol/kg), a specific opioid antagonist. The stereoselective effects of the mu-opioid agonist levorphanol further confirmed that the retarded learning was mediated through actions at the mu-opioid receptor. Autoradiographic studies indicated that a 2-nmol, intraventricular dose of DAMGO achieved contents greater than 1 pmol/mg in tissue lying within 2 mm of the lateral ventricle, third ventricle and cerebral aqueduct. These data suggest that enkephalins produce a retardation of learning through an effect on the mu-type of opioid receptor and that at least one locus of their actions is produced at periventricular sites lying within 2 mm of the ventricles.(ABSTRACT TRUNCATED AT 250 WORDS)

This study reexamined the effects of unilateral damage to cerebellar hemispheral lobule VI on the rabbit's conditioned nictitating membrane (NM) response. Extensive unilateral removal of hemispheral lobule VI in 11 rabbits impaired ipsilateral conditioned responses as reflected by reductions of 52% in mean frequency and 53% in mean amplitude during test trials on the first postoperative session. The decreases in the amplitude and frequency of conditioned responses were highly correlated (r = 0.82). The frequency of conditioned responses recovered to control levels but their amplitudes remained reduced such that the correlation between these two measures of responding was no longer significant by the 12th postoperative conditioning session. The decrease in the amplitude of conditioned responses was not accompanied by changes in onset latency or rise time. There was no significant impairment of conditioned responses in surgical controls and animals with only partial damage to hemispheral lobule VI. It was concluded that hemispheral lobule VI plays an important role in the regulation of motor centers in the brainstem so as to facilitate the initiation and optimum execution of the conditioned NM reflex. This cortical regulation of the conditioned NM response may contain learned elements; however, these cannot be resolved with lesion methods, nor has their existence been proven in this or other lesion studies. Nevertheless, the results of this study do demonstrate that the cerebellar cortex cannot be considered as the single locus necessary for NM conditioning.

The effects of dorsal hippocampal lesions on retention of classical trace conditioned responses were examined using the rabbit nictitating membrane preparation. Animals were trained to criteria and then lesioned either in the cortex or in the hippocampus and the cortex. Hippocampal damage had no effect on the retention of responses but produced significantly longer onset latencies. A control group of hippocampal animals acquired conditioned responses (CRs) at least as quickly as the prelesion subjects, and they also exhibited longer response onset latency. A second experiment evaluated the performance of hippocampal lesioned animals in classical trace conditioning with either a low-intensity periorbital shock or corneal air puff as the unconditioned stimulus (UCS). Hippocampal animals successfully acquired CRs under both conditions but exhibited an alteration of response onset which was dependent on the form of the UCS. Hippocampal animals displayed shorter response onset in the air-puff condition and longer response onset in the shock condition. Cortical animals timed responses consistently regardless of the UCS. These findings strongly suggest that the hippocampus modulates temporal characteristics of learned behavior.

These experiments were conducted to examine extinction and retention of a classically conditioned response in acute spinal cats. Conditioning was obtained by pairing a mild electrical stimulus to the superficial peroneal sensory nerve (CS) with a stronger electrical stimulus to the ankle skin (US) of the same leg. Subsequent extinction was produced by presenting CS-alone trials. In the first experiment, animals given massed extinction trials showed response decrements to base levels. Response decrements were not found in animals that received distributed extinction trials. In the second experiment, .5-, 1-, 2-, 3-, or 4-hr intervals between acquisition and extinction produced no significant differences in the extinction data. In the third experiment, animals received extinction trials immediately or 30 min after acquisition trials, followed by 20 additional extinction trials 30 min later. Analyses of these data indicated significant acquisition and extinction in the 10- and 20- acquisition trial groups. As in Experiment 2, varying the interval between acquisition and extinction did not produce any group differences in the extinction data. The results of these experiments demonstrate that response increases produced by paired trials in the spinal preparation do not decay spontaneously over time and are not caused by sensitization effects.