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PubMed1992

Pavlovian conditioning of L-dopa induced movement.

Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drug L-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence of L-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as the L-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior and L-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlike L-dopa-induced contralateral rotation, is not affected by D1/D2 receptor blockade. Thus, the conditioned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D1/D2 antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects of L-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.

Animals↗
PubMed1995

Localization of genes influencing ethanol-induced conditioned place preference and locomotor activity in BXD recombinant inbred mice.

Genetic differences in ethanol's ability to induce conditioned place preference were studied in 20 BXD Recombinant Inbred (RI) mouse strains and in the C57BL/6J and DBA/2J progenitor strains. Male mice from each strain were exposed to a Pavlovian conditioning procedure in which a distinctive floor stimulus (CS+) was paired four times with ethanol (2 g/kg). A different floor stimulus (CS-) was paired with saline. Control mice were injected only with saline. Floor preference testing without ethanol revealed significant genetic differences in conditioned place preference, with some strains spending nearly 80% time on the ethanol-paired floor while others spent only 50% (i.e., no preference). Control mice showed genetic differences in unconditioned preference for the floor cues, but unconditioned preference was not genetically correlated with conditioned preference. There were also substantial genetic differences in ethanol-stimulated activity, but contrary to psychomotor stimulant theory, ethanol-induced activity on conditioning trials was not positively correlated with strength of conditioned place preference. However, there was a significant negative genetic correlation (r = -0.42) between test session activity and preference. Quantitative trait loci (QTL) analyses showed strong associations (P < 0.01) between conditioned place preference and marker loci on chromosomes 4, 8, 9, 18 and 19. Weaker associations (0.01 < P < 0.05) were identified on several other chromosomes. Analysis also yielded several significant QTL for unconditioned preference, ethanol-stimulated activity, and sensitization. Overall, these data support the conclusion that genotype influences ethanol-induced conditioned place preference, presumably via genetic differences in sensitivity to ethanol's rewarding effects. Moreover, several chromosomal regions containing candidate genes of potential relevance to ethanol-induced conditioned place preference have been identified.

Animals↗
PubMed1995

Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning.

Dose-dependent effects of 7-OH-DPAT on several behaviors, including place preference, were assessed. Three 2-day conditioning trials were conducted. On 1 day, animals received an injection of one of eight doses of 7-OH-DPAT (0-5 mg/kg) and were placed into a distinct compartment for 40 min. On the other day, animals received an injection of saline and were placed into a different compartment for 40 min. Locomotion, sniffing, and yawning were measured following the first and last injection of 7-OH-DPAT. Place conditioning was assessed on the day following the last trial. 7-OH-DPAT produced a U-shaped dose-dependent change in locomotion and sniffing, and an inverted U-shaped dose-dependent change in yawning. Additionally, repeated administration of 0.1 mg/kg sensitized yawning, whereas 5 mg/kg sensitized locomotion. None of the doses of 7-OH-DPAT produced conditioned place preference, however, there was a trend for conditioned place aversion at 0.03 mg/kg. By contrast, LiCl (127 mg/kg) produced conditioned place aversion and amphetamine (1 mg/kg) produced conditioned place preference using the same conditioning parameters. A subsequent experiment in which the number of animals and conditioning trials were increased demonstrated that the 0.03 mg/kg dose of 7-OH-DPAT produced conditioned place aversion. 7-OH-DPAT has a higher affinity for D3 receptors relative to D2 receptors. Therefore, it is suggested that intermediate doses (0.01-0.1 mg/kg) that increase yawning, and decrease locomotion and sniffing, may preferentially occupy D3 receptors. Furthermore, the results suggest that these putative D3-preferring doses have weak aversive effects.

Amphetamine↗
PubMed1992

Influence of the cerebellar posterior vermis on the acquisition of the classically conditioned bradycardic response in the rabbit.

The magnitude of classically conditioned bradycardia was studied in rabbits in which various cerebellar regions (lobule IX or the posterior vermis or the hemispheres) had been removed surgically. Lesions were shown histologically to be restricted to the cortex and the underlying white matter without any damage to the deep cerebellar nuclei. In the conditioning procedure, tones were employed as conditioned stimuli (CS) and ear shocks as unconditioned stimuli (US). Cerebellar lesions did not affect the characteristics of the bradycardic orienting response, baseline heart rate or the unconditioned tachycardic response to US. The conditioned bradycardia was significantly reduced in magnitude with respect to controls in rabbits submitted to removal of posterior vermis, while it was unaffected in lobule IX and hemispheric lesioned rabbits. The temporal pattern of development and habituation of the bradycardiac response through the conditioning session, as well as its topography, did not differ from controls in any of the lesioned rabbits. After the first conditioning session, some control rabbits were submitted to removal of the posterior vermis and then conditioned again, following an identical procedure. Their pre- and post-lesion conditioned responses did not exhibit any appreciable differences and were similar to the responses exhibited by a group of unoperated controls which were submitted to a reconditioning session. It is concluded that in the rabbit the cerebellar posterior vermis is involved in the initial acquisition of the classically conditioned bradycardia, but it is not the site of its memory trace.

Animals↗
PubMedDate not supplied

Classical conditioning and information processing: different mechanism for prepared and unprepared stimuli?

Although learning without awareness conflicts with recent theories of classical human Pavlovian conditioning, there is at least one type of conditioning in which CS-US contingency is processed without awareness--the so-called prepared conditioning. Therefore, presenting a secondary reaction time probe to measure the amount of information processing capacity required should produce interference with the secondary task in unprepared, but not in prepared conditioning, since in the latter information should be processed in parallel. In a previous study, the authors could not find differences between both types of conditioning, neither in reaction time nor in electrodermal indicators of information processing. The present study was conducted to replicate and extend these findings, using a differential autonomic conditioning paradigm. One half of 42 subjects received spider and snake slides as prepared stimuli, while the other half received flower slides as unprepared stimuli. Both kinds of stimuli were used as CS+ and as CS-. An electric shock served as unconditioned stimulus. During 24 acquisition and 24 extinction trials, electrodermal and heart rate responses, as well as reaction times to probe stimulus were recorded. The results revealed significant conditioning effects in terms of CS-/CS+ differences. However, no differences were found between prepared and unprepared stimuli, neither in autonomic measures nor in reaction time. Again, our results are in favor of serial information processing in both prepared and unprepared stimuli, suggesting that the so-called prepared conditioning may be treated as a subclass of classical autonomic conditioning instead of forming a specific class of learning.

Adult↗
PubMedDate not supplied

Ontogenetic changes in the neural mechanisms of eyeblink conditioning.

The rodent eyeblink conditioning paradigm is an ideal model system for examining the relationship between neural maturation and the ontogeny of associative learning. Elucidation of the neural mechanisms underlying the ontogeny of learning is tractable using eyeblink conditioning because the necessary neural circuitry (cerebellum and interconnected brainstem nuclei) underlying the acquisition and retention of the conditioned response (CR) has been identified in adult organisms. Moreover, the cerebellum exhibits substantial postnatal anatomical and physiological maturation in rats. The eyeblink CR emerges developmentally between postnatal day (PND) 17 and 24 in rats. A series of experiments found that the ontogenetic emergence of eyeblink conditioning is related to the development of associative learning and not related to changes in performance. More recent studies have examined the relationship between the development of eyeblink conditioning and the physiological maturation of the cerebellum, a brain structure that is necessary for eyeblink conditioning in adult organisms. Disrupting cerebellar development with lesions or antimitotic treatments impairs the ontogeny of eyeblink conditioning. Studies of the development of physiological processes within the cerebellum have revealed striking ontogenetic changes in stimulus-elicited and learning-related neuronal activity. Neurons in the interpositus nucleus and Purkinje cells in the cortex exhibit developmental increases in neuronal discharges following the unconditioned stimulus (US) and in neuronal discharges that model the amplitude and time-course of the eyeblink CR. The developmental changes in CR-related neuronal activity in the cerebellum suggest that the ontogeny of eyeblink conditioning depends on the development of mechanisms that establish cerebellar plasticity. Learning and the induction of neural plasticity depend on the magnitude of the US input to the cerebellum. The role of developmental changes in the efficacy of the US pathway has been investigated by monitoring neuronal activity in the inferior olive and with stimulation techniques. The results of these experiments indicate that the development of the conditioned eyeblink response may depend on dynamic interactions between multiple developmental processes within the eyeblink neural circuitry.

Aging↗
PubMedDate not supplied

Heart rate reactivity in HAD and LAD rats during Pavlovian fear conditioning.

Recently, we reported that High-Alcohol-Drinking (HAD) rats exhibited selective deficits in active avoidance learning under alcohol-naive conditions, and that administration of moderate doses of alcohol (0.5 and 1.0 g/kg) facilitated learning in these rats (Blankenship et al., 2000; Rorick et al., 2003b). We hypothesized that the deficits resulted from excessive fear in the aversive learning context and that the anxiolytic properties of alcohol may have contributed to the improved learning that was observed after alcohol administration. This hypothesis was supported by a recent study in which prolonged freezing in HAD rats was seen after a classical fear conditioning procedure (Rorick et al., 2003a). To provide additional evidence that HAD rats indeed exhibit behaviors consistent with the expression of increased fear in aversive learning contexts, we employed a Pavlovian fear conditioning task to measure heart rate in HAD and Low-Alcohol-Drinking (LAD) rats. In this study, HAD (HAD-1 and HAD-2) and LAD (LAD-1 and LAD-2) rats were assigned to one of three pre-exposure conditions: Context Only, Context/Tone, or Sequential (Context Only followed by Context/Tone) Pre-Exposure. Following pre-exposure, fear conditioning acquisition and extinction procedures were identical for all groups. Results indicated that although no baseline differences were observed between HAD and LAD rats, HAD rats receiving Context-Only pre-exposure exhibited excessive heart rate reactivity to the tone conditional stimulus during fear conditioning acquisition, compared to LAD rats receiving the same pre-exposure conditions. These findings support the hypothesis that HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts, as measured by autonomic conditioning.

Acoustic Stimulation↗
PubMed2005

Impaired classical eyeblink conditioning in elderly human subjects: the role of unconditioned response magnitude.

BACKGROUND AND AIMS: Classical conditioning is impaired in elderly subjects, and an experiment investigated the role of unconditioned response magnitude and autonomic arousal in this aging-related impairment. METHODS: Two groups of young (n = 20, mean age 23.8 years) and elderly (n = 21, mean age 73.8 years) healthy subjects participated in the experiment. Single-cue classical eyeblink conditioning was in effect for 72 trials, with a tone as the conditioned stimulus (CS) and an airpuff to the eye as the unconditioned stimulus (US). The CS was presented alone in eight additional trials to allow recordings of skin conductance and heart rate responses. Startle eyeblink reflexes were elicited either alone or in the presence of the CS after the end of the conditioning procedure to investigate startle potentiation. RESULTS: More young (95%) than elderly (76%) subjects identified the CS - US contingency in a post-conditioning questionnaire, whereas only 38% of the elderly and 85% of the young subjects acquired the conditioned response (CR). Unconditioned blink reflex magnitudes were greater in the subjects who had acquired the CR. Heart rate deceleration was seen in both young and elderly subjects who had acquired the conditioned response. Startle reflexes and skin conductance responses were related to conditioning in young but not in elderly subjects. CONCLUSIONS: Unconditioned response magnitude was the best predictor for the acquisition of the CR. Together with the questionnaire data, this indicates that peripheral factors play a significant role in the impairment of classical eyeblink conditioning in elderly people. Autonomic arousal was not related to acquisition of the CR in elderly subjects.

Adolescent↗
PubMed2004

Repeated nicotine exposure enhances responding with conditioned reinforcement.

RATIONALE: Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes. OBJECTIVE: This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion. METHODS: Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 microg per side) prior to the conditioned reinforcement test. RESULTS: Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine. CONCLUSIONS: These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.

Adrenergic Uptake Inhibitors↗
PubMed2005

Influence of the dose and the number of drug-context pairings on the magnitude and the long-lasting retention of cocaine-induced conditioned place preference in C57BL/6J mice.

RATIONALE: The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized. METHODS: The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session. RESULTS: One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups. CONCLUSIONS: The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials.

Animals↗
PubMed2005

The effects of DHBE and MLA on nicotine-induced enhancement of contextual fear conditioning in C57BL/6 mice.

RATIONALE: Previous research indicates that nicotine administration enhances hippocampus-dependent forms of learning, including contextual fear conditioning. This effect is blocked by mecamylamine, a noncompetitive, broad-spectrum nicotinic receptor antagonist. OBJECTIVES: The present study extends previous research by further characterizing the nicotinic acetylcholinergic receptor (nAChR) subtypes through which nicotine acts to enhance contextual fear conditioning. METHODS: C57BL/6J mice were trained with two conditioned stimulus (CS; 30 s, 85-dB white noise)-unconditioned stimulus (US; 2 s, 0.57-mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. The effects of the alpha7 nAChR antagonist methyllycaconitine (MLA; 1.00, 10.00, and 20.00 mg/kg) and the effects of the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (DHBE; 1.00, 3.00, and 6.00 mg/kg) on cued and contextual fear conditioning and on the enhancement of contextual fear conditioning by nicotine (0.25 mg/kg) were examined. RESULTS: We demonstrate that DHBE (all doses) administration attenuates the enhancing effect of nicotine on contextual fear conditioning, and MLA administration has no significant effect on the enhancement of contextual fear conditioning by nicotine. CONCLUSIONS: The data suggest that non-alpha7 nAChRs (most likely alpha4beta2 nAChRs) underlie the enhancement of contextual fear conditioning by nicotine.

Aconitine↗
PubMed2005

NMDA or AMPA/kainate receptor blockade prevents acquisition of conditioned place preference induced by D(2/3) dopamine receptor stimulation in rats.

RATIONALE: Recent experiments from this laboratory demonstrated synergistic effects of AMPA/kainate receptor blockade and D(2/3) dopamine (DA) receptor stimulation on brain stimulation reward and locomotor activity. OBJECTIVES: Using place conditioning, this study explored further the interaction between DA and glutamate (Glu) using the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, the AMPA/kainate receptor antagonist NBQX, and the D(2/3) DA receptor agonist 7-OH-DPAT. METHODS: Effects of these compounds, alone and combined, were measured in male Sprague--Dawley rats using an unbiased two-compartment place conditioning procedure. RESULTS: 7-OH-DPAT (0.03--5.0 mg kg(-1), s.c.) administered immediately prior to conditioning was ineffective; when administered 15 min prior to conditioning, only the highest dose (5.0 mg kg(-1), s.c.) induced conditioned place preference (CPP). Acquisition of 7-OH-DPAT-induced CPP was blocked by MK-801 (0.06 or 0.13 mg kg(-1), i.p.) or NBQX (0.5 microg) microinjected into the nucleus accumbens (NAS) shell subregion. Intra-NAS shell administration of 7-OH-DPAT (5.0 microg) or NBQX (0.5 microg), alone or combined, failed to induce place conditioning, and this lack of effect was not due to state dependency. Administration of MK-801 or 7-OH-DPAT (5.0 mg kg(-1)) during the conditioning phase acutely increased horizontal activity, but neither compound, alone or combined, induced conditioned locomotor effects. CONCLUSIONS: Acquisition of place conditioning induced by systemic administration of 7-OH-DPAT is blocked by systemic NMDA receptor antagonism by MK-801 or by the AMPA/kainate receptor antagonist NBQX microinjected into the NAS shell subregion.

Animals↗
PubMed2006

Drugs, sweat, and fears: a comparison of the effects of diazepam and methylphenidate on fear conditioning.

RATIONALE: Classical conditioning of a fear response involves the formation of an association between a stimulus and an emotional response and can be seen as a basic form of emotional memory. While both benzodiazepines and stimulant drugs may influence the formation of episodic memories for emotional events, their effects on fear conditioning are less clear. OBJECTIVES: This study compared the effects of diazepam with methylphenidate on fear conditioning. MATERIALS AND METHODS: In a single-session between groups design with three conditions [placebo, diazepam (10 mg), and methylphenidate (40 mg)], classical conditioning of a skin conductance response to a visual stimulus previously paired with a 100-db white noise was tested in 45 healthy volunteers. RESULTS: Diazepam blocked fear conditioning, despite responses to the unconditioned aversive stimulus and neutral control stimulus being unimpaired. Conditioning remained intact after methylphenidate. Conditioned responses were not extinguished completely by the end of the experiment, and it was not possible to draw conclusions about the effects of the drugs on extinction. CONCLUSIONS: Although diazepam has well-documented amnesic effects, it has not been found to affect implicit forms of memory like perceptual and conceptual priming. As the present study found impaired fear conditioning after diazepam, it adds weight to recent findings that emotional memories are disproportionately impaired by the benzodiazepines.

Adult↗
PubMed2000

Dynorphin A (2-17) attenuates the unconditioned but not the conditioned effects of opiate withdrawal in the rat.

OBJECTIVES: An unbiased place preference conditioning procedure was used to examine the influence of the non-opioid peptide, dynorphin A 2-17 (DYN 2-17), upon the conditioned and unconditioned effects of opiate withdrawal in the rat. METHODS: Rats were implanted SC with two pellets containing 75 mg morphine or placebo. Single-trial place conditioning sessions with saline and the opioid receptor antagonist naloxone (0.1-1.0 mg/kg; SC) commenced 4 days later. Ten minutes before SC injections, animals received an IV infusion of saline or DYN 2-17 (0.1-5.0 mg/kg). Additional groups of placebo- and morphine-pelleted animals were conditioned with saline and DYN 2-17. During each 30-min conditioning session, somatic signs of withdrawal were quantified. Tests of place conditioning were conducted in pelleted animals 24 h later. RESULTS: Naloxone produced wet-dog shakes, body weight loss, ptosis and diarrhea in morphine-pelleted animals. Morphine-pelleted animals also exhibited significant aversions for an environment previously associated with the administration of naloxone. These effects were not observed in placebo-pelleted animals. DYN 2-17 pretreatment resulted in a dose-related attenuation of somatic withdrawal signs. However, conditioned place aversions were still observed in morphine-pelleted animals that had received DYN 2-17 in combination with naloxone. Furthermore, the magnitude of this effect did not differ from control animals. CONCLUSIONS: These data demonstrate that the administration of DYN 2-17 attenuates the somatic, but not the conditioned aversive effects of antagonist-precipitated withdrawal from morphine in the rat. Differential effects of this peptide in modulating the conditioned and unconditioned effects of opiate withdrawal are suggested.

Animals↗
PubMed2000

Naltrexone effects on ethanol consumption and response to ethanol conditioned cues in C57BL/6 mice.

RATIONALE: The conditions under which naltrexone reduces ethanol consumption and its effect on behavior controlled by ethanol conditioned stimuli remain unclear. OBJECTIVES: The objectives were to determine the effects of naltrexone on ethanol consumption by C57BL/6 (B6) mice when injected subcutaneously (expt 1) or delivered by osmotic minipump (expt 2), and on ethanol conditioned cues (expt 3). METHODS: Naltrexone effects on ethanol consumption and preference were measured in a continuous access two-bottle choice paradigm in groups of mice implanted with osmotic minipumps delivering 0-3.0 mg/kg per day or injected subcutaneously with 0-6.0 mg/kg doses. Naltrexone's (0-3.0 mg/kg) effect on ethanol-conditioned cues was indexed by its effect on the expression of ethanol place conditioning (expt 3). RESULTS: Naltrexone produced a transient reduction in ethanol consumption and a consistent reduction in preference when injected; however, it had no effect on ethanol consumption or preference when delivered continuously by osmotic minipump. Naltrexone attenuated the expression of ethanol place conditioning in a U-shaped dose-response function. CONCLUSIONS: The transient reduction in ethanol consumption produced by injected naltrexone and the absence of an effect when continuously delivered confirms a report that maintaining naltrexone at steady state levels may antagonize its attenuation of ethanol consumption. The reduced expression of ethanol place conditioning in naltrexone-injected mice suggests that the drug can attenuate the reinforcing effects of ethanol conditioned stimuli as was recently reported for lever responding maintained by ethanol conditioned stimuli in rats. These effects were observed at naltrexone doses with no readily apparent adverse side-effects, supporting its usefulness for treating alcoholism.

Animals↗
PubMed1997

Differential effects of ondansetron and alpha-flupenthixol on responding for conditioned reward.

Previous experiments have suggested that 5-HT3 antagonists such as ondansetron may alter reward-related behaviour that is dependent in part upon raised mesolimbic dopamine activity. However, the evidence for this is far from conclusive. One major behavioural role of dopamine is in the control of behaviour elicited by conditioned rewarding stimuli. To date, the effects of 5-HT3 antagonists on this function of mesolimbic dopamine have not been examined. Two experimental procedures were employed to examine the effects of ondansetron (10 and 100 micrograms/kg) on the acquisition of responding for conditioned reward, and on the response potentiating effect of intra-accumbens d-amphetamine (10 micrograms). These effects were compared to those elicited by the dopamine antagonist alpha-flupenthixol (0.1 mg/kg). In the first procedure, rats were trained to associate food pellet delivery with a conditioned stimulus (CS). Rats subsequently allowed to respond on a lever delivering this CS, and on an inactive lever, showed a greater preference for the lever delivering the CS, indicating that this CS functioned as a conditioned reward (CR). Ondansetron administered during the conditioning phase did not alter subsequent responding for the CR, but alpha-flupenthixol induced a small but significant reduction in responding on the CR lever. These results suggest that blockade of dopamine receptors, but not 5-HT3 receptors interfere with the learning of stimulus reward relationships. In the second procedure, d-amphetamine injected into the nucleus accumbens markedly potentiated responding for CR. Ondansetron at 10 micrograms/kg induced a small attenuation of this effect, without altering responding in its own right. However, at a higher dose (100 micrograms/kg) ondansetron plus amphetamine treatment significantly enhanced responding on the inactive lever. At both doses, the net effect of ondansetron was to produce a subtle impairment in the allocation of responses such that the differential responding on the CR versus NCR lever was diminished. In contrast to these effects alpha-flupenthixol significantly attenuated d-amphetamine's selective enhancement of responding for conditioned reward, as well as impairing the ability of the conditioned reward to elicit and maintain behaviour. These results confirm the role of dopamine in responding for conditioned reward, and suggest a possible modulators role for 5-HT3 receptors in this process. However, the effects of ondansetron on the acquisition of, and responding for, conditioned reward are clearly different from those induced by blockade of dopamine receptors.

Animals↗
PubMed1999

Enhanced conditioned inhibition following repeated pretreatment with d-amphetamine.

We have shown that prior repeated exposure to d-amphetamine facilitates appetitive Pavlovian conditioning. However, animals sensitised in this manner also show elevated levels of stimulated activity. To investigate whether enhanced conditioning was dependent upon increased activity, a conditioned inhibition task was employed in the present study. Rats received d-amphetamine (2 mg/kg, i.p.) or vehicle once per day for 7 days. After a 7-day drug-free period, an activity assay confirmed that repeated d-amphetamine treatment markedly elevated the locomotor response to a subsequent challenge with 0.5 mg/kg d-amphetamine. Conditioning began 6 days later. In phase 1, stimulus A+ (light or tone) immediately preceded sucrose availability (excitatory conditioning). In phase 2, sucrose again was presented after A+ alone, but not after presentation of a compound of A+ with a second stimulus (AB-). Sensitisation enhanced the acquisition of conditioned approach behaviour to the excitatory stimulus A+ in phase 1. Furthermore, acquisition of conditioned inhibition to the stimulus compound, AB-, was also facilitated. Thus, sensitised rats showed reduced levels of responding to the stimulus compound far sooner than controls. Finally, a retardation test was carried out in stage 3, in which the inhibitory stimulus B- was paired alone with sucrose reward. Sensitised rats initially showed retarded acquisition of excitatory conditioned responding relative to controls, suggesting that B possessed stronger inhibitory associations in these animals. However, sensitised animals again exhibited higher levels of responding in later sessions, consistent with the enhanced excitatory conditioning shown in phase 1. These findings suggest that prior repeated d-amphetamine enhanced the acquisition of inhibitory and excitatory Pavlovian associations; a propensity not readily attributable to stimulated locomotor hyperactivity.

Amygdala↗
PubMed2005

Trace eyeblink conditioning in human subjects with cerebellar lesions.

Trace eyeblink conditioning was investigated in 31 patients with focal cerebellar lesions and 19 age-matched controls. Twelve patients presented with lesions including the territory of the superior cerebellar artery (SCA). In 19 patients lesions were restricted to the territory of the posterior inferior cerebellar artery (PICA). A 3D magnetic resonance imaging was used to determine the extent of the cortical lesion and possible involvement of cerebellar nuclei. Eyeblink conditioning was performed using a 40 ms tone as conditioned stimulus (CS) followed by a stimulus free trace-interval of 400 ms and a 100 ms air-puff as unconditioned stimulus (US). In SCA patients with lesions including parts of the cerebellar interposed nucleus trace eyeblink conditioning was significantly impaired. Pure cortical lesions of the superior cerebellum were not sufficient to reduce acquisition of trace conditioned eyeblink responses. PICA patients were not impaired in trace eyeblink conditioning. Consistent with animal studies the findings of the present human lesion study suggest that, in addition to forebrain areas, the interposed nucleus is of importance in trace eyeblink conditioning. Although cortical cerebellar areas appear less important in trace compared with delay eyeblink conditioning, the present data strengthen the view that cerebellar structures contribute to different forms of eyeblink conditioning paradigms.

Adult↗