Ethanol impairs behavioral strategy use in naive rats but does not prevent spatial learning in the water maze in pretrained rats

Abstract Rationale . Ethanol impairs performance in the water maze in rats. A detailed behavioral analysis is required to fully evaluate the nature of the impairment. Objectives. A detailed behavioral analysis was carried out to evaluate the effect of ethanol on performance in the water maze task in male hooded rats given 2.0 or 6.0 g/kg ethanol by gavage. Multiple measures of water maze strategies learning and spatial learning were studied. Methods . Water maze trials were recorded on videotape and digitized for offline analysis. Some rats were naive at the start of spatial training, whereas other rats received water maze strategies pretraining prior to spatial training to familiarize them with the general behavioral strategies required in the task. Results . Naive ethanol-treated rats exhibited both spatial learning and water maze behavioral strategies impairments. There was no evidence of a spatial learning impairment that was independent of an associated behavioral strategies impairment. Further, ethanol impaired the ability of naive rats to swim to a stable visible platform. Pretrained ethanol-treated rats performed significantly better than naive ethanol-treated rats on almost all measures, and were indistinguishable from controls on most measures. Conclusions . These results suggest that ethanol may impair water maze performance in naive rats by interfering with their ability to acquire and use required water maze behavioral strategies and generate adaptive swim paths. Ethanol does not prevent robust spatial learning in rats that are familiar with required water maze behavioral strategies. Electronic Publication     

The effect of subchronic administration of vigabatrin on learning and memory in nonepileptic rats

The present experiments investigated whether subchronic administration of vigabatrin, a GABA-mimetic drug, affects the performance of normal rats in the behavioural tasks assessing learning and memory. The effects of vigabatrin [50-200 mg/kg (IP)/day] administration on the acquisition and retention of water maze and passive avoidance task were studied. According to the results of three experiments, vigabatrin treatment did not markedly impair the acquisition or retention of water maze task. Furthermore, vigabatrin-treated rats were not inferior to saline-treated rats in reversal learning of water maze task. On the other hand, vigabatrin treatment slightly increased the speed of swimming in rats. The administration of vigabatrin did not affect the performance (training latency, number of training trials, testing latency) of rats in the passive avoidance task. According to these results, the effects of vigabatrin, a new antiepileptic drug, on the performance of nonepileptic rats were modest in behavioural tasks used to assess learning and memory.     

Possible role of brain dopaminergic systems in the memory effects of central stimulants

In experiments on male Wistar rats trained and tested for memory retention on an active avoidance task in a maze, it was found that haloperidol at doses of 0.2 and 2 mg/kg injected intraperitoneally one hour prior to or immediately after training impaired learning and/or memory. The central stimulants caffeine (20 mg/kg), strychinine (1 mg/kg) and amphetamine (1 mg/kg) injected intraperitoneally immediately after training improved long-term retention; the central stimulants administered at the same doses but in combination with haloperidol (2 mg/kg) after training did not manifest their retention-facilitating effect. It is assumed that dopaminergic mechanisms underlie learning and memory processes in active avoidance conditioning and that an optimum activity of these mechanisms is necessary for the memory-facilitating effect of the central stimulants to appear.     

Effect of the acetylcholinesterase inhibitor galanthamine on learning and memory in prolonged alcohol intake rat model of acetylcholine deficit.

Different cholinomimetics are used in conditions of CNS acetylcholine (ACh) deficit. In this study, we examined the effect of the acetylcholinesterase inhibitor galanthamine in a prolonged alcohol intake model of ACh deficit in male Wistar rats. After 16 weeks of alcohol intake and a 2-week pause, rats administered galanthamine (2.5 mg/kg/day i.p.) showed an improved speed of learning and short-term memory in the shuttle box test as compared to the saline-injected alcoholic group (p < 0.05). Four weeks later, significant improvement in the passive avoidance memory of alcoholic galanthamine-treated rats was noted in the eight-arm radial maze (14 day test duration) as compared to the saline-injected alcoholic group (p < 0.05). During the first week in the shuttle box test, the nonalcoholic galanthamine-treated animals exhibited significantly impaired performance as compared to the untreated nonalcoholic control, while four weeks later, in the eight-arm radial maze, both groups did not differ. Our results show that galanthamine improves the speed of learning, short-term memory and spatial orientation of rats in conditions of prolonged alcohol intake.     

Castration in rats impairs performance during acquisition of a working memory task and exacerbates deficits in working memory produced by scopolamine and mecamylamine

Rationale Although much research has focused on the effects of ovarian hormones on learning and memory in females, less information is available regarding the effects of testicular hormones on learning and memory in males. Additionally, despite evidence of an interaction of testicular hormones and the cholinergic system in areas of the brain implicated in learning and memory, no information is available regarding the behavioral consequences of that interaction.Objectives We assessed the effect of castration in male rats on working memory during acquisition of a radial maze. We also assessed the interactive effects of castration and scopolamine, a muscarinic receptor antagonist, as well as mecamylamine, a nicotinic receptor antagonist, on behavior.Methods Young adult male rats were castrated or underwent sham surgeries. Beginning 10 days after surgeries, performance on a task of working memory was assessed across 24 days of acquisition in an eight-arm radial maze. Following acquisition, scopolamine and mecamylamine dose–effect curves were established.Results Castration of male rats significantly decreased arm-choice accuracy during acquisition. Castration significantly exacerbated impairments in arm-choice accuracy produced by scopolamine as well as mecamylamine, without altering the disruptive effects of the drugs on the rate at which rats entered the arms of the maze.Conclusions These results indicate that castration in male rats impairs working memory during acquisition of a spatial maze task. Additionally, these results suggest that the absence of testicular hormones increases the sensitivity of male rats to the impairing effects of scopolamine as well as mecamylamine on working memory.     

Correlations between the effects of CNS stimulants on memory processes and open field behavior of rats: the importance of brain cholinergic activity

Wistar rats were tested in open field immediately after training on a discriminative-motor task in a maze or after retention tests given 24 hr later. The animals were treated with CNS stimulants: caffeine, strychnine and amphetamine applied alone or in combination with atropine before or immediately after the training session. The CNS stimulants improved learning and retention of rats, increased their emotionality after acquisition and facilitated their habituation in the new environment in the period of retention. Atropine abolished both the memory and behavioral effects of the CNS stimulants. The results favor the view about common mechanisms in the memory effects of CNS stimulants.     

Neurobehavioral changes in mice treated with methylmercury at two different stages of fetal development.

Pregnant C57BL/6 mice were orally given daily doses of 4 or 6 mg/kg of methylmercury chloride (MeHg) or vehicle during either gestational days 7-9 (GD7-9) or days 12-14 (GD12-14). Their female offspring were tested between 6 and 16 weeks of age on a variety of behavioral tasks. Motor coordination on the rotarod and visual discrimination learning in the Y maze were not affected by administration of MeHg either at GD7-9 or at GD12-14. In the open field, the total number of square crossings was lower in mice treated with 4 and 6 mg/kg of MeHg at GD12-14 than in control mice whether the environment was new or familiar, but prenatal administration of MeHg at GD7-9 had no effect on this measure. Administration of MeHg either at GD7-9 or at GD12-14 had no effect on the percentage of central square crossings or on the frequency of rearings in the open field. On spatial alternation training in the T maze, both treated groups in Condition GD7-9 and the group treated with 6 mg/kg at GD12-14 required more sessions to reach the learning criterion than their respective vehicle groups. When spatial alternation was tested with delays, treated groups did not differ from their respective control groups. In the radial arm maze, the performance of mice treated at GD7-9 was normal, but reference memory and working memory were impaired by administration of MeHg at GD12-14. In mice treated with 4 mg/kg of MeHg, reference memory was impaired only on the first block of trials, whereas in mice treated with 6 mg/kg, the deficit persisted on all blocks of trials. Overall, these results indicate that prenatal administration of MeHg at GD12-14 had more detrimental effects on behavioral performance than administration at GD7-9. It reduced locomotor activity and impaired reference memory for egocentric and allocentric spatial information as well as working memory for places.     

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.     

Chronic administration of the L-type calcium channel blocker nimodipine can facilitate the acquisition of sequence learning in a radial-arm maze

Nimodipine, a dihydropyridine L-type voltage-gated calcium-channel blocker, was examined for its potential effect on the acquisition of a complex-arm sequence task in an automated radial maze. Young (60-day-old) male Wistar rats were injected with saline or nimodipine (5 mg/kg) 15 min prior to radial maze training, or immediately following the radial maze testing. The results of the learning task (over 7 days of testing) showed that rats injected with nimodipine each training session acquired the task more quickly and more efficiently compared to saline-treated animals. There were no significant differences for rats that were pre-/post-treated with nimodipine during the maze-learning task. The number of incorrect arm entries and number of additional lever presses in the same arm were found to be significantly lower in rats treated with nimodipine compared to saline-injected controls. The beneficial effect of nimodipine treatment occurred only in rats that were acquiring the task, and not in rats that had already learned the arm sequence paradigm. There were no potential non-specific influences on locomotor activity or appetite caused by chronic nimodipine treatments. These results strongly suggest that nimodipine can facilitate the acquisition of a complex learning task.     

Tacrolimus (FK506) reduces hippocampal damage but fails to prevent learning and memory deficits after transient, global cerebral ischemia in rats

Transient, global cerebral ischemia (TGCI) leads to hippocampal damage and disruption of spatial learning and memory. The immunosuppressant, tacrolimus (FK506), prevents TGCI-induced hippocampal neurodegeneration, but its effectiveness in promoting the recovery of learning and memory performance after TGCI has been little investigated. Here, we use a confined version of the aversive, non-food rewarded radial maze to evaluate further the effects of FK506 on TGCI-induced learning and memory deficits. In the first experiment, rats were rendered ischemic (15 min 4-VO) and 20 days later were tested for acquisition of the radial maze task over 15 consecutive days (post-operative training). In the second experiment, naive rats were trained for 10 days and subjected to TGCI (pre-operative training); retention of task performance was assessed on days 31, 35 and 39 post-ischemia. Acquisition and retention performances were expressed as a) latency to find a goal box, b) number of reference memory errors, and c) number of working memory errors. Data are presented both across daily training sessions (15 days, 3-day blocks) and as a total value (summed over the 15 days). Histological examination was performed on the day after behavioral testing. In both experiments, FK506 (1.0 mg/kg) was given i.v. at the beginning of reperfusion, followed by doses applied intraperitoneally (i.p.) 6, 24, 48 and 72 h post-ischemia. TGCI markedly disrupted both acquisition and retention performance (p<0.0001-0.05). Treatment with FK506 did not prevent the TGCI-induced acquisition and retention deficits, independently of whether performances were quantified 'daily' or as a 'total' value. In contrast, FK506 reduced hippocampal damage significantly compared to the vehicle alone (p<0.001-0.05). We conclude that the present study did not confirm our earlier behavioral data, and suggest that FK506 is not effective in treating the behavioral outcomes of TGCI, despite its efficacy in reducing CA1, hippocampal damage. However, further studies including other behavioral tasks and more extensive neurohistological analysis, are needed to better elucidate the effectiveness of FK506 in promoting functional recovery in models of transient, global cerebral ischemia.     

Learning and memory in agmatine-treated rats

Agmatine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, was examined for its role in water maze place learning, contextual and auditory-cued (discrete) fear learning and conditioned taste aversion learning, when administered systemically. Male Wistar rats were given saline or 1, 5, 10 or 50 mg/kg agmatine ip 20 min prior to or 30 min following daily training sessions in a hidden-platform (place learning) water maze task. Agmatine did not affect latencies to find the hidden platform or preference for the training quadrant during probe trials. When administered 20 min prior to contextual or auditory-cued fear-conditioning sessions, these doses of agmatine evoked a linear dose-dependent impairment in the magnitude of learned fear to the contextual stimuli when assessed during extinction trials 24 h later, but had no effect on the magnitude of learned fear to the auditory stimulus. Inferences of baseline motor activity and ability to respond to the presentation of footshock stimuli were not affected by the treatment. Injections of 50 mg/kg agmatine concurrently with a malaise-evoking agent following presentations to a novel sucrose solution abolished learned taste aversions; this agent did not evoke conditioned taste aversions alone. These studies indicate that systemically administered agmatine selectively impairs behavioral inferences of specific types of learning and memory.     

Cocaine self-administration improves performance in a highly demanding water maze task

Rationale Long-term potentiation (LTP) is considered to be a cellular substrate of learning and memory. Indeed, the involvement of LTP-like mechanisms in spatial learning has consistently been demonstrated in the Morris water maze test. We have previously shown that hippocampal LTP in Lewis rats was modulated by cocaine self-administration, although the performance of cocaine-self-administered rats in the Morris water maze was not altered. Objective Given that the ease of the task previously used could have masked any possible effects of the cocaine-induced LTP enhancement on spatial learning, a new and more difficult water maze task was devised to address this issue. Materials and methods Animals self-administered cocaine (1 mg/kg) or saline under a fixed ratio 1 schedule of reinforcement for 22 days. Spatial learning was assessed in a difficult water maze task (four sessions, two trials per session with a 90-min intertrial interval), and spatial memory was also evaluated 48 h after training (a 90-s test). Additionally, reversal learning and perseverance were also studied. Results There was a reduced latency in finding the hidden platform during training, as well as improved memory of the platform location in cocaine-self-administered rats with respect to animals that self-administered saline. No differences were observed in reversal learning or perseverance between groups. Conclusions Our data suggest that cocaine self-administration facilitates learning and memory in the water maze test only when animals are submitted to highly demanding tasks, involving working memory or consolidation-like processes during the intertrial interval. Del Olmo and Higuera-Matas contributed equally to this work.     

Chronic alcohol consumption impairs visuo-spatial associative memory in periadolescent rhesus monkeys

Alcohol abuse in the adult is often preceded by high alcohol consumption during adolescence. Profound changes in brain structure and function occur during this developmental period, therefore alcohol may impact essential cognitive skill development during the formal educational years. The objective of this study was to determine if chronic oral alcohol intake slows acquisition and performance of cognitive tasks in male adolescent rhesus monkeys. Treatment groups (Alcohol, N = 4; Control, N = 3) were evaluated on bimanual dexterity and tests of visuo-spatial memory and learning adapted from the Cambridge Neuropsychological Test Automated Battery. Animals were trained daily in 30 min sessions and had subsequent access to alcohol/Tang^® solutions (Alcohol group) or Tang^® only (Control group) Monday through Friday for 11 months. Recordings of brainstem auditory evoked potentials (BSAEP) were conducted periodically before and during the chronic drinking. Results: Chronic alcohol drinking (ave of 1.78 g/kg alcohol per session) impaired behavioral performance assessed ∼22 h after the prior drinking session. The Alcohol group required more trials than the Control group to reach criterion on the visuo-spatial memory task and showed increased sensitivity to trial difficulty and retention interval. Alcohol animals also had slowed initial acquisition of the bimanual task. The latency of P4 and P5 BSAEP peaks were also delayed in the Alcohol group. Chronic alcohol consumption impaired the acquisition and performance of a spatial memory task and disrupted brainstem auditory processing, thus these results show that repeated alcohol exposure in adolescence interferes with a range of brain functions including complex visuo-spatial mnemonic processing.     

Co-dergocrine, cerebral glucose utilization and maze performance in middle-aged rats

The objective of this study was to determine the effect of co-dergocrine in rats on local cerebral glucose utilization and performance in a complex T-maze. Middle-aged (12-16 months) male Fischer-344 rats were given injections of co-dergocrine (3 or 10 mg/kg, IP) 35 min before behavioral testing or the administration of 2-deoxy-D-[1-14C]glucose ([14C]DG), a radiotracer for local cerebral glucose utilization (LCGU). Both doses stimulated LCGU in the locus ceruleus and median raphe nucleus and in subcortical structures associated with learning and memory (hippocampus and subiculum). The higher dose also stimulated LCGU in motor areas (caudate-putamen, globus pallidus, internal capsule). In contrast, co-dergocrine decreased LCGU in the frontal cortex. Poorer performance in a complex maze (increased shocks, errors and run time) was observed in middle-aged as compared with younger animals (3 months). Acute co-dergocrine treatment did not improve performance of middle-aged rats in this task. Thus, in the present experimental paradigm employing single dose administration, co-dergocrine's stimulation of LCGU was not associated with an alteration of maze performance in age-matched animals.     

Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats

Prenatal alcohol exposure can disrupt brain development and lead to a myriad of behavioral alterations, including motor coordination deficits, hyperactivity, and learning deficits. There remains a need, however, to identify treatments and interventions for reducing the severity of alcohol-related neurodevelopmental disorders. Some of the alcohol-induced deficits in learning may be related to alterations in cholinergic functioning. Interestingly, there is a growing literature demonstrating that pre- and/or early postnatal choline supplementation can lead to long-term enhancement in learning and memory and cholinergic activity in rats. The present study examined whether such early choline supplementation might counter the effects of prenatal alcohol treatment on a visuospatial discrimination task. Pregnant Sprague-Dawley rats were randomly assigned to one of three prenatal treatment groups. One group received a liquid diet containing 35% ethanol-derived calories (EDC) from gestational day (GD) 6-20. A second group served as a pair-fed (PF) control group and the third group served as an ad lib lab chow (LC) control. On postnatal day (PD) 2, pups were assigned within-litter to one of three postnatal treatments: choline, saline vehicle, or no treatment. Choline and vehicle pups were intubated with a choline chloride solution or vehicle daily from PD 2 to 21, whereas the non-treated pups were handled daily but not intubated. On PD 45, subjects were tested on a visuospatial discrimination task. Ethanol-exposed subjects who were not treated neonatally with choline committed a significantly greater number of errors both during acquisition and during delayed discrimination training compared to both PF and LC controls. Neonatal choline treatment significantly improved performance on the discrimination task in all groups; however, the beneficial effects of choline were significantly larger in ethanol-exposed subjects. Indeed, the performance of ethanol-exposed pups treated with neonatal choline did not differ from any of the PF or LC groups on any measure. Thus, early postnatal choline supplementation significantly attenuated the effects of prenatal alcohol on this learning task. Importantly, these effects were not due to the acute effects of choline, but rather to long-term changes in brain and behavioral development. These data suggest that early dietary interventions may reduce the severity of fetal alcohol effects.     

Paternal alcohol consumption in the rat impairs spatial learning performance in male offspring

Pubescent (30 day old) male rats were maintained on an alcohol liquid diet containing 35% ethanol-derived calories (ALC) for 39 days or were pairfed an isocaloric control diet (PF). The concentration of alcohol in the diet was gradually increased to permit adaptation, then stabilized and then gradually tapered to prevent an alcohol withdrawal syndrome. Following a drug-free period (2 weeks), the males were mated with nontreated females. Offspring were evaluated on several developmental indices and on various learning/memory tasks to assess functional deficits in adulthood. Offspring sired by ALC-treated males did not differ from the offspring of PF males on several developmental parameters including body weights, when developmental landmarks appeared, or on tests of sensorimotor development. As adults, male offspring groups did not differ on tests of activity or on an object exploration/recognition task. However, male offspring of ALC-treated males demonstrated impaired acquisition performance (days and errors to criterion) on a win-shift spatial discrimination in an eight-arm radial maze and on a win-stay discrimination (days to criterion) conducted in a T-maze at a later age. The radial maze results were replicated in a subsequent experiment using different groups of rats.     

15-deoxy-delta 12, 14-Prostaglandin J2 prevents reactive oxygen species generation and mitochondrial membrane depolarization induced by oxidative stress

Background

Administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine during the perinatal period can produce a variety of behavioral and neuroanatomical changes. Our laboratory has reported reliable changes in learning and memory following a single dose of ketamine administered late in gestation. However, the nature of the drug-induced changes depends on the point during embryonic development when ketamine is administered. Embryonic day 18 (E18) rat fetuses pre-treated with ketamine (100 mg/kg, i.p. through the maternal circulation) and taught a conditioned taste aversion (CTA) learn and remember the CTA, whereas E19 fetuses do not. The current study sought to determine if long-term behavioral effects could be detected in animals that received ketamine or a saline control injection on either E18 or E19. Rat behavior was evaluated on two different measures: spontaneous locomotion and water maze learning. Measurements were collected during 2 periods: Juvenile test period [pre-pubertal locomotor test: Postnatal Day 11 (P11); pre-pubertal water maze test: P18] or Young-adult test period [post-pubertal locomotor test: P60; post-pubertal water maze test: P81].

Results

Water maze performance of ketamine-treated rats was similar to that of controls when tested on P18. Likewise, the age of the animal at the time of ketamine/saline treatment did not influence learning of the maze. However, the young-adult water maze test (P81) revealed reliable benefits of prenatal ketamine exposure – especially during the initial re-training trial. On the first trial of the young adult test, rats treated with ketamine on E18 reached the hidden platform faster than any other group – including rats treated with ketamine on E19. Swim speeds of experimental and control rats were not significantly different. Spontaneous horizontal locomotion measured during juvenile testing indicated that ketamine-treated rats were less active than controls. However, later in development, rats treated with ketamine on E18 were more active than rats that received the drug on E19.

Conclusion

These data suggest that both the day in fetal development when ketamine is administered and the timing of post-natal behavioral testing interact to influence behavioral outcomes. The data also indicate that the paradoxical age-dependent effects of early ketamine treatment on learning, previously described in fetuses and neonates, may also be detected later in young adult rats.     

Learning and memory in rats gestationally and lactationally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Recently we reported that in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or coplanar polychlorinated biphenyls (PCBs) resulted in a reduction of errors on a radial arm maze (RAM) working memory task. The effect was more pronounced in males than in females. In this study, we further investigated the effects of in utero and lactational exposure to TCDD on learning and memory by testing male and female TCDD-exposed rats on three different spatial learning and memory tasks: the RAM, the Morris water maze (MWM), and spatial discrimination-reversal learning (RL), as well as on a nonspatial learning task, visual RL. Time-mated Sprague-Dawley rats were gavaged with either TCDD (0.1 microg/kg/day) or corn oil vehicle on gestation days 10-16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on the same RAM working memory task used in the previous study. Again, the TCDD-exposed male rats displayed a pronounced decrease in errors relative to control males. Following the RAM testing, the same animals were tested on the MWM, but no differences between the exposed and control rats were observed. Another male and female from each litter were tested on spatial RL on a T-maze. There were no differences between the exposed and control rats on this task. Following spatial RL, the same rats were tested on visual RL on the same maze. The exposed animals did not differ from controls on original learning, but took more trials to reach criterion on the first and second reversals. These results demonstrate a reliable, but task-specific, facilitation of spatial learning and memory in male rats exposed to TCDD during gestation and lactation. In contrast, both male and female TCDD-exposed rats showed a deficit in learning on the visual RL task. This pattern is consistent with that seen in earlier monkey studies. Perinatally TCDD-exposed monkeys were facilitated on certain spatial tasks, but impaired on visual RL tasks.     

Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning.

A number of studies have shown that systemic 5-HT(6) receptor antagonists can improve learning and memory, but the mechanism for these observations is not known. As striatum normally expresses 5-HT(6) receptors abundantly and is important in consolidating stimulus-response learning, we used targeted gene delivery to further increase the expression of 5-HT(6) receptors in rat striatum and then examined learning. Increased 5-HT(6) expression had no effect on performance in the Morris water maze, a hippocampal-dependent learning paradigm, and did not alter the latency to approach or consume sucrose tablets. However, rats with increased 5-HT(6) expression failed to acquire a reward-based instrumental learning task, a striatum-dependent learning model, during 3 days of successive sessions as compared to sham surgery or GFP-expressing control rats. This behavioral deficit was observed in rats overexpressing 5-HT(6) receptors in the dorsomedial striatum, but not in rats with increased dorsocentral striatal expression. The 5-HT(6) receptor-associated deficit was reversed by administration of a 5-HT(6) antagonist, SB-258585, before each training session. When animals learned the instrumental learning task before gene transfer, increased 5-HT(6) receptor expression had no effect on long-term recall or performance of the task or on extinction of operant responding. Thus, 5-HT(6) receptor activity in rat striatum disrupts acquisition of new instrumental learning but does not impair memory or performance of reward-motivated behavior once established.