Selectively increased trace conditioning under the neurotensin agonist PD 149163 in an aversive procedure in which SR 142948A was without intrinsic effect

There is evidence to suggest that neurotensin (NT) may enhance cognitive function. The present study, therefore, examined the role of NT in associative learning between a conditioned stimulus (CS) and an unconditioned stimulus (UCS). This was tested in a trace procedure using conditioned suppression of drinking with a noise CS and foot shock UCS. We compared the effects of an NT agonist (PD 149163, 0.25 and 1 mg/kg) with those of an NT antagonist (SR 142948A, 0.01 and 0.1 mg/kg). Conditioning after drug treatment was followed by drug-free tests of associative learning. At 0.25 but not 1 mg/kg, PD 149163 selectively increased conditioning over the trace interval: there was no such increased conditioning in the 0s group. This increased conditioning over the trace is an effect that is reliably produced by dopamine (DA) agonists in the same procedure. However, dissimilar to the effects of DA agonists, conditioning to box context, was reduced under PD 149163. Doses of SR 142948A, selected on the basis of their effects in similar aversively motivated tests of latent inhibition, were without intrinsic effect in the present procedure. The dose-related dissociation between trace and contextual conditioning effects under PD 149163 is considered as cognitive enhancement.     

Amphetamine decreases the expression and acquisition of appetitive conditioning but increases the acquisition of anticipatory responding over a trace interval

The effects of amphetamine on selective learning were tested in a trace conditioning procedure, in which the informativeness of the conditioned stimulus (CS) (noise) was manipulated through the introduction of a time interval before the delivery of the unconditioned stimulus (UCS) (food). The results showed that d-amphetamine (0.5 and 1.5 mg/kg) impaired both the expression (Experiment 1b) and acquisition (Experiment 2) of appetitive conditioning. This was true for both trace and contiguously conditioned groups. The effects of the 0.5 mg/kg dose of d-amphetamine were not attributable to general motor (measured pre-CS) or motivational (measured post-UCS) effects of the drug. Moreover, the same pattern of effects (impaired appetitive conditioning, irrespective of the trace interval between CS and UCS) was confirmed in drug-free extinction tests. By contrast to the general depression in the acquisition and expression of associative learning observed under amphetamine, the 0.5 mg/kg dose promoted the acquisition of anticipatory responses made later in the trace interval (in Experiment 2 but, again, not the expression of previous conditioning in Experiment 1b). This suggests a dissociable effect of low-dose d-amphetamine on learning about the temporal relationship between CS and UCS.     

Methylphenidate and nicotine focus responding to an informative discrete CS over successive sessions of appetitive conditioning

Methylphenidate (MP) and nicotine would be expected to improve associative learning, though previous evidence suggests that they should reduce the selectivity with which associations are formed. Here we tested their effects on learning the association between a conditioned stimulus (CS) and food (unconditioned stimulus, UCS) in male Wistar rats. The UCS was delivered immediately (0 s) following CS offset or after a 10 s trace. In addition to the measures of discrete CS conditioning, contextual and trace responding was measured in the inter-trial- and the inter-stimulus-interval, respectively. In all cases, conditioning was measured as nose poking for food. Both MP and nicotine improved the acquisition of discrete cue conditioning. Acquisition was accelerated (compared to saline) under 5 but not 1 mg/kg MP and 0.6, but not 0.4 mg/kg nicotine. In each case, this effect was observed in 0 s but not 10 s conditioned groups. For comparison, some earlier published data obtained following the same procedure with D-amphetamine were re-analysed in the same way. Amphetamine similarly improved conditioning in the 0 s group, in this case at 0.5, but not 1.5 mg/kg. Thus three different dopamine agonists increased the ability to focus responding to CS presentations over successive sessions of appetitive acquisition.     

The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats

Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625-8.0 mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0 mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01-1.0 mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0 mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0 mg/kg dose. The atypical antipsychotic drug clozapine (2.5-10.0 mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0 mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, d-amphetamine (1.0 mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties.     

Sensory and associative effects of LSD on classical appetitive conditioning of the rabbit jaw movement response

Three experiments were conducted to determine the effects of LSD (30 nmol/kg) in classical appetitive conditioning of the rabbit jaw movement response (JMR). In experiment 1, LSD significantly enhanced the acquisition of conditioned responses (CRs). The performance of control groups receiving unpaired presentations of the conditioned stimulus (CS) and unconditioned stimulus (UCS) demonstrated that LSD's enhancing effect on conditioning could not be attributed to an elevation in baseline responding, sensitization, or pseudoconditioning. Accordingly, experiments 2 and 3 were conducted to determine whether LSD's enhancement of conditioning could have arisen from its altering the sensory processing of either the CS or UCS, or botj. In experiment 2, LSD was found to have no significant effect on the functions relating UCS magnitude to the frequency, amplitude, or number of sinusoidal peaks comprising each unconditioned response (UCR). In contrast, experiment 3 revealed that LSD significantly enhanced the frequency of CRs to an extended range of CS intensities and lowered the CS intensity threshold. It was concluded that the enhancing effect of LSD on the acquisition of CRs is attributable, at least in part, to the drug's enhancement of the sensory processing of the CS.     

Effects of a neurotensin analogue (PD149163) and antagonist (SR142948A) on the scopolamine-induced deficits in a novel object discrimination task

Various lines of evidence suggest a role in cognition for the endogenous neuropeptide, neurotensin, involving an interaction with the central nervous system cholinergic pathways. A preliminary study has shown that central administration of neurotensin enhances spatial and nonspatial working memory in the presence of scopolamine, a muscarinic receptor antagonist which induces memory deficits. Utilizing similar methods, the present study employed a two-trial novel object discrimination task to determine the acute effect of a neurotensin peptide analogue with improved metabolic stability, PD149163, on recognition memory in Lister hooded rats. Consistent with previous findings with neurotensin, animals receiving an intracerebroventricular injection of PD149163 (3 microg) significantly discriminated the novel from familiar object during the choice trial. In addition, a similar dose of PD149163 restored the scopolamine-induced deficit in novelty recognition. The restoration effect on scopolamine-induced amnesia produced by PD149163 was blocked by SR142948A, a nonselective neurotensin receptor antagonist, at a dose of 1 mg/kg (intraperitonial) but not at 0.1 mg/kg. In conclusion, the present results confirm a role for neurotensin in mediating memory processes, possibly via central cholinergic mechanisms.     

Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and conditioned reinforcement: contrasts with midazolam

 In a test of conditioned punishment, saline-treated controls showed a moderate bias in responding away from a lever producing a response-contingent auditory conditioned stimulus (CS) that had been paired with mild footshock during training and towards a lever producing a neutral auditory CS. Systemic treatment with the indirect dopamine (DA) agonist amphetamine (0.25–1.0 mg/kg) produced a dose-dependent increase in the punishing effect of the aversive CS, whilst responding on the neutral CS lever was unchanged. Treatment with the dopamine-receptor antagonist α-flupenthixol (0.125, 0.25 mg/kg) decreased the efficacy of the punishing CS, but again left responding on the neutral lever unchanged. The benzodiazepine midazolam (0.1, 0.3 mg/kg) had a similar effect to α-flupenthixol, but treated animals showed a preference for the aversive CS. Parallel results were observed with amphetamine (0.25 mg/kg) and α-flupenthixol (0.125, 0.25 mg/kg) in a matched test of positive conditioned reinforcement, with amphetamine enhancing, and α-flupenthixol reducing, the efficacy of the CS paired with food. Midazolam treatment (0.1–1.0 mg/kg) had no effect on the reinforcing impact of an appetitive CS. Thus dopaminergic agents modulate the behavioural impact of both appetitively and aversively motivated conditioned stimuli on instrumental performance, whilst the benzodiazepine midazolam has a selective impact on aversively-motivated stimuli that is qualitatively distinct from that of the dopaminergic antagonist α-flupenthixol. Received: 27 March 1996 / Final version: 6 August 1996     

Blockade of neurotensin receptors affects differently hypo-locomotion and catalepsy induced by haloperidol in mice

Antipsychotic drug treatment increases neurotensin (NT) neurotransmission, and the exogenous administration of NT produces antipsychotic-like effects in rodents. In order to investigate whether "endogenous" NT may act as a natural occurring antipsychotic or may mediate antipsychotic drug activity, the effects of the selective NT receptor antagonists SR 48692 and SR 142948A were analyzed in different behavioural tests of locomotor activity using vehicle, amphetamine, or haloperidol in mice. SR 48692 (0.1-1 mg/kg, i.p.) and SR 142948A (0.03-0.1 mg/kg, i.p.) failed to affect mouse spontaneous locomotor activity and amphetamine-induced (2.5 mg/kg, i.p.) hyper-locomotion. However, SR 48692 (0.1 and 0.3 mg/kg, i.p.) and SR 142948A (0.03 and 0.05 mg/kg, i.p.) significantly alleviated the reduction of locomotor activity elicited by haloperidol (0.01 and 0.04 mg/kg, s.c.) in vehicle- or amphetamine-treated mice. Finally, SR 48692 (0.3 mg/kg, i.p.) and SR 142948A (0.05 and 0.1 mg/kg, i.p.) increased mouse catalepsy produced by haloperidol (0.3 mg/kg, s.c.). The present results indicate that while endogenous NT is not involved in the modulation of either mouse spontaneous locomotor activity or amphetamine-induced hyper-locomotion, it might act by enhancing the therapeutic effects of haloperidol and by attenuating the extrapyramidal side effects elicited by this antipsychotic.     

The acute and subchronic effects of a brain-penetrating, neurotensin-1 receptor agonist on feeding, body weight and temperature

The neurotensin-1 (NT1) receptor has been implicated in mediating a number of important neurotensin effects. We have found that PD149163, a selective, brain-penetrating, NT1 receptor agonist, produces a number of therapeutic-like preclinical effects after peripheral administration including pro-cognitive, antipsychotic and anxiolytic effects. In this study, we investigated PD149163's effect on food intake and thermal regulation, two physiological processes thought to be mediated by NT1 receptors.Brown Norway rats and leptin-deficient mice (ob/ob) mice were administered subcutaneous PD149163 (0, 0.1, 0.25, or 1 mg/kg) for ten consecutive days. Weight and 24-h food intake were measured in mice and rats and core body temperature was also measured in rats.PD149163 significantly decreased food intake in rats and ob/ob mice and no tolerance was demonstrated to this effect over the course of the study. PD149163-treated animals exhibited weight loss compared to saline-treated animals. PD149163 produced hypothermia as expected but this effect did show tolerance over the course of the study, unlike feeding. The results suggest that NT1 receptor agonists are candidates for treatment of obesity and that somewhat different mechanisms are involved in NT1-induced feeding regulation and temperature regulation.     

Effects of neurotensin receptor antagonism on latent inhibition in Sprague-Dawley rats

RATIONALE: It has been postulated that the tridecapeptide neurotensin (NT) functions as an endogenous antipsychotic peptide. A critical test of this hypothesis would be to determine if NT is involved in the expression of latent inhibition (LI), a psychophysiological and pharmacological model of schizophrenia. OBJECTIVE: This report describes the effects of disrupting NT neurotransmission by systemic administration of the NT receptor antagonists SR48692 and SR142948A on the acquisition of LI in rats. METHODS: The effects of 30-300 microg/kg SR48692 or 0.1-100 microg/kg SR142948A on the expression of LI following 0, 20 or 30 pre-exposures were first investigated. This was followed by the assessment of the effects of 10 microg/kg SR142948 A on the LI effect of increasing stimulus pre-exposures (10-40). Finally, the role of dopamine transmission in the effects of SR142948A on the acquisition of LI (30 pre-exposures) was tested by coadministering 10 microg/kg SR142948A and 100 mg/kg of the dopamine D(2) antagonist sulpiride. RESULTS: The higher tested doses of SR48692 (100-300 microg/kg) and SR142948A (10-100 microg/kg) decreased acquisition of LI following 20, 30 and even 40 pre-exposures to the to-be-conditioned stimulus. Cotreatment with the dopamine D(2) antagonist sulpiride prevented the LI-disrupting effects of SR142948A.CONCLUSIONS: NT neurotransmission appears to be necessary for the acquisition of LI. The main effect of NT receptor antagonism is a disruption of LI, most likely via enhancement of dopamine transmission. This effect is opposite that of antipsychotic drugs, which have been shown to enhance NT release, supporting the hypothesis of NT as an endogenous antipsychotic peptide.     

Sodium pentobarbital: sensory and associative effects in classical conditioning of the rabbit nictitating membrane response

Four experiments were conducted to determine the effects of sodium pentobarbital (0, 3, 9, and 15 mg/kg) on the acquisition of the rabbit's classically conditioned nictitating membrane response (NMR) and to determine the locus of the drug's effects on sensory, motor, associative, and nonassociative processes. In experiment 1, classical conditioning of the NMR was accomplished by pairing tone and light conditioned stimuli (CSs) with paraorbital shock as the unconditioned stimulus (US). The experiment revealed that pentobarbital retarded the acquisition of conditioned responses (CRs) to both tone and light CSs. Experiment 2, employing unpaired CS, UCS presentations, indicated small but significant drug effects on NMR base rate and nonassociative NMRs to the CS. Experiment 3 revealed no significant drug effect on the psychophysical functions relating UCS intensity to UCR frequency or amplitude, nor on the UCS intensity threshold for eliciting UCRs. On the other hand, in experiment 4, the drug significantly impaired CR frequency over an extended range of CS intensities and raised CS intensity threshold. It was concluded that pentobarbital's attenuation of CS intensity also operated to impair CR acquisition.     

Cocaine impairs acquisition of an autoshaped lever-touch response

 The effects of daily peripheral (IP) post-session injection of cocaine on the development of an autoshaped lever-touch response in rats were investigated. Male Sprague-Dawley rats received ten daily pairings of a retractable lever (conditioned stimulus; CS) and food delivery (unconditioned stimulus; UCS). Food delivery occurred if the subjects contacted the extended lever within 10 s, or, if the subjects failed to contact the lever, at the end of the 10-s stimulus interval. These contingencies resulted in increased lever-touch responses over 10 days of conditioning. Cocaine (5.6–19.0 mg/kg) impaired development of the lever-touch response, as compared to saline-treated control subjects. Because the injections were given immediately after each conditioning session, we suggest that cocaine affects the neural processes involved in consolidation. Three additional control experiments support this suggestion. The effect of cocaine on lever-touch acquisition was time-dependent as daily injection of cocaine (5.6 mg/kg) 3 h after each conditioning session did not affect lever-touch acquisition. In addition, the effect of cocaine was dependent upon the explicit pairing of lever extension (CS) and food delivery (UCS) as immediate post-session cocaine (5.6 mg/kg) administration did not alter responding when the presentation of both the CS and the UCS was uncorrelated. Cocaine (5.6 mg/kg) administered to subjects previously trained to a performance criterion did not affect lever-touch responding, indicating that cocaine administration (5.6 mg/kg) impairs the development, but not the maintenance, of autoshaped lever-touch responding. In contrast, the highest dose of cocaine tested, 19.0 mg/kg, did decrease lever-touch responding in well-trained subjects, indicating that post-session administration of higher doses of cocaine can produce aversive effects that may affect both the acquisition and maintenance of appetitively motivated behavior in the rat. The relative contributions of the instrumental and classical associations inherent in the autoshaping procedure were investigated by altering response contingencies. Rats showed no evidence of learning the lever-touch response when lever insertion and food delivery were positively correlated, and no explicit response contingency was present (classical conditioning); further, cocaine-treated subjects did not differ from saline-treated subjects. However, cocaine did impair lever-touch responding in the instrumental version of the task. Taken together, these results show that the post-session administration of cocaine can impair the acquisition of a multi-trial, multi-session appetitively motivated response. Received: 24 February 1996 / Final version: 5 November 1996     

Conditioned suppression with cocaine as the unconditioned stimulus

A conditioned-suppression procedure was used to study drug conditioning using cocaine as the unconditioned stimulus (UCS). Rats were first trained to nose poke for food-reinforcement during daily 60-min sessions. At least 1 week following jugular vein catheterization, a 5-min tone-light compound stimulus was presented 30 min into the food-reinforcement session. Two minutes after the onset of the stimulus, either 0 (saline), 1.0, 3.0 or 5.6 mg/kg cocaine, was administered i.v. to separate groups of rats. For another group, the stimulus was presented, and the 5.6 mg/kg dose of cocaine was injected in an unpaired fashion (i.e., at different times). After 5 days of training a test was given with the tone-light stimulus presented alone. No disruption of responding during the tone-light stimulus was observed in the saline and 1.0 mg/kg cocaine groups or for the unpaired group. When the tone-light stimulus was paired with 5.6 mg/kg cocaine; however, it produced nearly a 50% reduction in responding, which then gradually extinguished when the stimulus was presented alone for 5 days. The 3.0 mg/kg cocaine group produced intermediate suppression. When the tone-light compound stimulus was shortened to 70 s and the interstimulus interval (ISI) was 0, 30, or 60 s in three separate groups of rats, the most robust conditioned suppression was observed at the 60 s ISI. Therefore, the conditioned suppression procedure, using 3.0 or 5.6 mg/kg i.v. cocaine doses as the UCS, produced robust conditioning effects comparable to other drugs and more conventional reinforcers. The conditioned suppression procedure may be a useful model for studying the classically conditioned effects of cocaine.     

Endogenous neurotensin in the ventral tegmental area contributes to amphetamine behavioral sensitization.

Studies showing psychostimulant-like effects of exogenous neurotensin (NT) infused into the ventral tegmental area (VTA) prompted us to examine the role in the VTA of the endogenous NT in behavioral sensitization to amphetamine. Rats were sensitized to amphetamine by means of a subcutaneous amphetamine (1 mg/kg) injection, and the same dose was injected 7 days later to evaluate the expression of sensitization. The highly selective NT-receptor antagonist SR 142948A was injected into the VTA prior to the first and/or second amphetamine administration. SR 142948A (5 pmol/side) given before the first amphetamine exposure prevented the induction of behavioral sensitization, but did not alter the acute response to amphetamine. SR 142948A given with the second amphetamine administration did not affect the expression of behavioral sensitization. In contrast to administration into the VTA, intraperitoneal administration of SR 142948A (0.03, 0.1, or 0.3 mg/kg) had no detectable effect on the induction of amphetamine sensitization. These results suggest that activation of VTA NT receptors by endogenous NT may contribute to the neuroadaptations underlying behavioral sensitization to amphetamine.     

The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food

Rationale The CB1 receptor antagonist SR141716A reduces food intake in rats. This effect is likely to depend on modulation of reward related processes.Objective To investigate the effects of SR141716A on responding for food under a second order instrumental task in which responding and consumption of food can be separated, and on Pavlovian responding for a stimulus predictive of food reward.Methods Instrumental responding and pellet consumption following administration of SR141716A (0–3 mg/kg) were recorded under an FI5 min FR5(5:S) operant schedule that incorporates both a 5 min initial appetitive phase and a 25 min consummatory phase. We compared the drug-induced change in responding to that recorded following a reduction in motivational state induced by pre-feeding. In a second experiment we assessed the effects of SR141716A (0–3 mg/kg) on Pavlovian approach behaviour for a stimulus (lever) associated with food reward (CS+) and a neutral stimulus (lever) not associated with reward (CS–).Results SR141716A reduced pellet consumption and instrumental responding during both the appetitive and consummatory phases of the second order schedule. Pre-feeding had a similar effect on responding during the appetitive phase, suggesting an effect on incentive motivation. SR141716A also blocked an enhancement of responding that occurred during the consummatory phase in pre-fed animals. SR141716A and pre-feeding had no effect on responding in the Pavlovian autoshaping paradigm.Conclusions SR141716A impacts on motivational processes in both the appetitive and consummatory phases of feeding behaviour.     

The neurotensin-1 receptor agonist PD149163 blocks fear-potentiated startle

Preliminary evidence suggests that the neuropeptide, neurotensin (NT) may regulate fear/anxiety circuits. We investigated the effects of PD149163, a NT1 receptor agonist, on fear-potentiated startle (FPS). Sprague Dawley rats were trained to associate a white light with a mild foot shock. In one experiment, animals were treated with either subcutaneous vehicle or PD149163 (0.01, 0.1 or 1.0 mg/kg) 24 h after training. Twenty minutes later their acoustic startle response in the presence or absence of the white light was tested. In a second experiment, saline and 1.0 mg/kg PD149163 were tested using a separate group of rats. In the first experiment, PD149163 produced a non-significant decrease in baseline acoustic startle at all three doses. As expected, saline-treated rats exhibited significant FPS. An ANOVA of percentage FPS revealed no significant effect of treatment group overall but the high dose group did not display FPS strongly suggesting an FPS effect at this dose. This finding was confirmed in the second experiment where the high dose of PD149163 reduced percent FPS relative to saline (P < 0.05). These data suggest that systemically administered NT1 agonists modulate the neural circuitry that regulates fear and anxiety to produce dose-dependent anxiolytic-like effects on FPS.     

Methylphenidate can reduce selectivity in associative learning in an aversive trace conditioning task

There are good grounds to expect that methylphenidate (MP) should enhance cognitive function. However, experimental evidence on this point is scant. The present study therefore examined the effects of MP on learning the association between a conditioned stimulus (CS, in this case, noise) and an unconditioned stimulus (UCS, in this case, footshock) in an aversive variant of a trace conditioning procedure. Learning was measured off-the-baseline as conditioned suppression of drinking (both latencies to drink, expressed as suppression ratios, and the amount drunk, expressed as the number of licks, in the presence of the CS). In addition to the measures of discrete cue conditioning, MP effects on contextual conditioning were measured as suppression to apparatus cues and an experimental background stimulus. MP was administered at 1 or 5 mg/kg prior to conditioning sessions. As attention deficit hyperactivity disorder (ADHD) has been characterized as involving a ;wide attentional window' (e.g. Shalev and Tsal, 2003), it was predicted that MP, as the treatment of choice for ADHD, should increase selectivity (narrowing the attentional window). This outcome would show as reduced levels of conditioning (compared to control rats) to less informative trace and contextual cues present during conditioning. Contrary to prediction, both 1 and 5 mg/kg MP increased learning about all the available stimuli, including the less informative trace CS and the background stimulus. These findings are consistent with reduced rather than increased selectivity in learning (because of increased rather than decreased conditioning to weak cues) under MP.     

Disruption of trace conditioning of the nictitating membrane response in rabbits by central cholinergic blockade

 Central muscarinic cholinergic involvement in classical conditioning of eyeblink responses was determined in trace and delay paradigms. Rabbits were trained on a trace procedure in which a 250-ms tone conditioned stimulus (CS) and a 100-ms air-puff unconditioned stimulus (UCS) were presented with a 500-ms trace interval. Each training session day consisted of ten tone alone, ten air-puff alone and 80 paired CS-UCS trials. Scopolamine hydrochloride at doses of 0.03 and 0.1 mg/0.5 ml per kg, SC dose-dependently disrupted acquisition of conditioned responses. Rabbits that were treated with scopolamine and failed to learn showed a gradual increase in conditioned responses during an additional training period with saline injections and no transfer from earlier training. Scopolamine methyl bromide, which does not appreciably cross the blood-brain barrier, showed no effects in the trace conditioning paradigm at a dose of 0.1 mg/kg, SC, indicating central cholinergic blockade is responsible for the suppressive effect of scopolamine. Scopolamine hydrochloride at a dose of 0.1 mg/kg, SC did not block acquisition in the delay procedure with a 250-ms inter-stimulus interval, although the rate of acquisition was somewhat reduced by the drug. These data are the first to demonstrate that classical conditioning of the eyeblink response in the trace procedure is highly sensitive to central cholinergic deficits. Received: 16 August 1996 / Final version: 14 January 1997     

Physostigmine accelerates the development of associative memory processes in the infant rat

Previous research has shown that 15-day-old rats are quite poor at associating temporally separated events. However, by 17 days of age, this capability has improved substantially (Moye and Rudy 1987a). In the present study, the centrally active anticholinesterase physostigmine was found to enhance the ability of 15-day-olds to associate a tone conditioned stimulus (CS) with a shock unconditioned stimulus (US) when these events were separated by a 10-s trace interval. In effect, the drug produced trace conditioning performance similar to that observed in older animals. We suggest that performance in the trace conditioning task requires the development of associative memory processes that allow the young rat to retain a representation of a CS over time. Furthermore, the enhancement of trace conditioning by physostigmine indicates that central cholinergic maturation is an important factor in the expression of associative memory.     

Effects of MDA on classical conditioning of the rabbit nictitating membrane response

In Experiment 1, classical conditioning of the rabbit's nictitating membrane response (NMR) was accomplished by pairing tone and light conditioned stimuli (CSs) with a shock unconditioned stimulus (UCS). MDA impaired the acquisition of conditioned responses (CR) to a tone-CS, while significantly enhancing CR acquisition to a light-CS. Experiment 2, employing explicitly unpaired CS, UCS training, revealed no reliable effects of MDA upon nonassociative processes. Subsequent efforts determined if MDA's CR acquisition effects resulted from alterations in sensory processing of the CS, UCS, and/or UCR motor functioning. Specifically, it was determined that MDA: (a) increased the tone-CS intensity threshold for eliciting CRs (Experiment 3); (b) attenuated the tone-induced reflex modification of the unconditioned NMR (Experiment 4); and (c) enhanced UCR frequency at varying UCS intensities (Experiment 5). It was concluded that MDA's effect upon CR acquisition reflected the drug's effect upon CS and UCS/UCR processing and thereby altered the ability of these components of conditioning to enter into associative learning.