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Serotonin 5-HT(2) antagonists that significantly retard the acquisition of classically conditioned responses (CRs) also impair the performance of the unconditioned response (UR). Effects on the UR appear to be due to an inverse agonist action at the 5-HT(2) receptor. These findings raised the possibility that the learning deficits were either secondary to a performance deficit and/or that the retardation of learning was not due to actions at the serotonin 5-HT(2) receptor. In this study, we examined the effects of the 5-HT(2)-receptor antagonists, namely mianserin and D-2-bromolysergic acid diethylamide hydrogen tartrate (BOL), on CR acquisition. We also determined whether the retarded acquisition of CRs produced by mianserin (a) was due to an action at the 5-HT(2) receptor and (b) was secondary to a performance deficit. Effects of drugs on CR acquisition, maintenance, and retention were determined during trace-conditioning of the rabbit's nictitating membrane (NM) response. BOL (0.058 to 5.8 micromol/kg) had no effect on CR acquisition, whereas mianserin (0.1 to 10 micromol/kg) produced a significant and dose-dependent retardation of CR acquisition. The retarded CR acquisition produced by mianserin (10 micromol/kg) was due to its actions at the 5-HT(2) receptor, because this effect was completely blocked by a dose of BOL (5.8 micromol/kg) that had no effect when given alone. Neither maintenance nor retention of learning was affected by mianserin treatment during acquisition. We conclude that mianserin acts as an inverse agonist at the serotonin 5-HT(2) receptor to produce both a retardation of CR acquisition and an impairment of the UR. However, the learning and performance effects of mianserin are separable.

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.

The nictitating membrane (NM) reflex was assessed in adult Dutch-belted rabbits exposed to cocaine in utero. The intensity threshold for eliciting the reflex was increased in cocaine progeny and the amplitude of the reflex was decreased at the lower stimulus intensities. However, cocaine and saline progeny showed equivalent rates of habituation of the NM reflex when tested with a suprathreshold eliciting stimulus. Reliable modification of the NM reflex was obtained when the reflex-eliciting stimulus was preceded by an auditory stimulus at intervals of 100-800 ms. Cocaine and saline progeny exhibited an increase in the peak amplitude of the reflex, a shortening of the latency of the reflex, and a shortening of the latency to achieve peak amplitude of the reflex as a function of increases in the interstimulus interval. Furthermore, cocaine progeny showed significantly longer response latencies than saline progeny across all interstimulus intervals, although neither the peak amplitude nor the latency to achieve peak amplitude was affected. Thus, prenatal exposure to cocaine affected elicitation of the defensive NM reflex to an aversive stimulus but did not affect the sensorimotor integration necessary for modification of the reflex by antecedent stimulation.

Previous studies had shown that intrauterine exposure to cocaine produces an increase in the number of immunoreactive GABA neurons and abnormal dendritic structure of pyramidal cells in the anterior cingulate cortex, a brain region known to be involved in attentional processes and discrimination learning. Because structural abnormalities might be expected to produce related functional deficits, we examined whether intrauterine exposure to cocaine would affect discrimination learning in adult rabbits. We previously reported that cocaine progeny undergoing concurrent acquisition to visual and auditory CSs show a normal rate of learning to a light CS and an accelerated rate of learning to a tone. Here, we report that adult, Dutch-belted rabbits exposed to cocaine in utero showed impaired discrimination learning when responding to a positive visual cue but not when responding to a positive auditory cue. The nature of the deficit consisted of an impaired ability to acquire learned responses to the visual CS+ rather than in an impaired ability to withhold responses to the auditory CS-. Given that auditory stimuli tend to be more salient than visual stimuli in the normal rabbit, the preceding pattern of results suggests that intrauterine cocaine exposure affected the ability to preferentially attend to less salient but relevant stimuli and to ignore more salient, irrelevant stimuli. More importantly, these results indicate that prenatal exposure to cocaine produces neurobehavioral abnormalities which persist into adult life.

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.

This study examined the effects of the hallucinogen, MDA, on brain content of monoamines and their metabolites in the rabbit. A single 1.8 mg/kg dose of MDA produced 30 to 64% increases in the 5-HT content of frontal cortex from 30 to 120 min after injection and a decrease in 5-HT turnover from 30 min to 8 h, but had no effect in hippocampus, caudate nucleus, or hypothalamus. A single 3.6 mg/kg dose of MDA also reduced the turnover of 5-HT in frontal cortex, but this was accompanied by a decrease in 5-HIAA with no increase in 5-HT. The 1.8 and 3.6 mg/kg doses of MDA had no significant or consistent effects on the contents of DA, DOPAC, HVA, and NE in any brain area examined. Chronic administration of MDA (3.6 mg/kg/day for 4 days) failed to produce any evidence of a neurotoxic action on 5-HT neurons. Higher doses could not be employed because the LD50 of MDA was approximately 5 mg/kg. This study has demonstrated that behaviorally effective and nonneurotoxic doses of MDA produce increases in the content and decreases in turnover of 5-HT in frontal cortex that resemble those of other hallucinogens such as LSD and DOM.

The rate of associative learning was assessed in the presence of saline versus methylenedioxymethamphetamine (MDMA) at doses of 0.95, 1.9, and 3.8 mg/kg. The conditioned stimuli (CSs) were lights and tones and the unconditioned stimulus (US) was a corneal air puff. Learning was enhanced by all but the highest dose of drug tested, and the enhancement was most pronounced when light was used as the conditioned stimulus. Nonassociative responding was assessed using unpaired presentations of the lights, tones, and air puffs. MDMA (1.9 mg/kg) produced a slight increase in the percentage of baseline responses but failed to produce an increase in the frequency of nonassociative responding in the presence of the lights or tones. MDMA produced a significant increase in the amplitude of the unconditioned response to the corneal air puff across the 10 sessions. This increase was taken as evidence for sensitization of the unconditioned response, a nonassociative learning phenomenon. In summary, MDMA, like the parent compound methylenedioxyamphetamine (MDA), enhances both conditioned and unconditioned responding. Because this dual effect has not been seen with related psychedelic compounds, the effect appears to be unique to this class of phenylethylamine drugs.

The behavioral effects of a single, acute dose of methylenedioxyamphetamine (MDA) were assessed using the rabbit nictitating membrane (NM) preparation. Acquisition of the classically conditioned NM response was carried out in a single session under MDA at doses of 10 and 20 mumol/kg (1.79 and 3.58 mg/kg, respectively) and retention was assessed during a drug-free state 48 h later. In agreement with previous reports, MDA at a dose of 10 mumol/kg enhanced acquisition of the conditioned NM response and learning was retained in the nondrug state. However, MDA at a dose of 20 mumol/kg failed to affect either acquisition or retention. In further agreement with previous reports, MDA at 10 mumol/kg facilitated the amplitude of the unconditioned response during unpaired stimulus presentations. It is suggested that this enhanced motor response may be due to enhanced neural transmission in the afferent limb of the unconditioned reflex arc.