Reinforcement Task Research Articles

遅延のある選択におけるラットの眼窩前頭皮質の役割

Previous studies have reported that lesions of the orbitofrontal cortex (OFC) in rats induce impulsive choices in delayed reinforcement tasks. However, some studies have suggested that the OFC is not related to impulsivity but instead to compulsivity. In this study, we investigated the effects of OFC lesions on choice in a T-maze. First, 14 rats were trained to discriminate spatially between a high-reward arm with a delay of 15 seconds and a low-reward arm without a delay. The high-reward arm contained 10 food pellets, whereas the low-reward arm contained only one pellet. In the presurgery test, all rats chose the high-reward arm in most trials. In the postsurgery test, both OFC lesioned (n = 7) and control (sham-lesioned and intact; n = 7) rats continued to choose the high-reward arm in most trials. Following the postsurgery test, the high- and low-reward arms were reversed. In the reversal test, OFC lesioned rats made significantly fewer high-reward choices than did control rats. These results indicate that OFC lesions induced compulsive choices rather than impulsive choices.

Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise.

Reinforcement and error-based processes are essential for motor learning, with the cerebellum thought to be required only for the error-based mechanism. Here we examined learning and retention of a reaching skill under both processes. Control subjects learned similarly from reinforcement and error-based feedback, but showed much better retention under reinforcement. To apply reinforcement to cerebellar patients, we developed a closed-loop reinforcement schedule in which task difficulty was controlled based on recent performance. This schedule produced substantial learning in cerebellar patients and controls. Cerebellar patients varied in their learning under reinforcement but fully retained what was learned. In contrast, they showed complete lack of retention in error-based learning. We developed a mechanistic model of the reinforcement task and found that learning depended on a balance between exploration variability and motor noise. While the cerebellar and control groups had similar exploration variability, the patients had greater motor noise and hence learned less. Our results suggest that cerebellar damage indirectly impairs reinforcement learning by increasing motor noise, but does not interfere with the reinforcement mechanism itself. Therefore, reinforcement can be used to learn and retain novel skills, but optimal reinforcement learning requires a balance between exploration variability and motor noise.

Seeking behavior, place conditioning, and resistance to conditioned suppression of feeding in rats intermittently exposed to palatable food.

Binge eating disorder is characterized by excessive consumption of highly palatable food within short periods of time accompanied by loss of control over eating. Extensive evidence provides support for the consideration of binge eating disorder as an addiction-like disorder. In this study, we wanted to determine whether rats undergoing an operant binge-like eating procedure could develop maladaptive forms of conditioned feeding behaviors. For this purpose, we trained male rats to self-administer either a sugary, highly palatable diet ("Palatable" rats) or a chow diet ("Chow" rats) for 1 hour a day. After escalation and stabilization of palatable food intake, we tested Chow and Palatable rats in (a) a conditioned place preference test, (b) a second-order schedule of reinforcement, (c) a cue-induced suppression of feeding test. In the conditioned place preference task, Palatable rats spent significantly more time in the compartment that was previously paired with the palatable food, compared to Chow controls. Furthermore, in the second-order schedule of reinforcement task, Palatable rats exhibited active lever responding 4- to 6-fold higher than Chow control rats. Finally, in the cue-induced suppression of feeding test, although Chow control subjects reduced responding by 32% in the presence of the conditioned punishment, Palatable rats persevered in responding despite the aversive cue. These results further characterize this animal model of binge-like eating and provide additional evidence for the addictive properties of highly palatable food.

Salt marshes to adapt the flood defences along the Dutch Wadden Sea coast

Concern about the effects of climate change have set in motion a search for flood protection measures to adapt coastlines to the foreseen accelerated sea level rise. In this context, the potential role of salt marshes to adapt the Wadden Sea’s flood defences was explored in the Netherlands Wadden Region Delta Programme. This paper provides an overview of the steps taken by the programme in developing a climate change adaptation strategy so that others might learn from its experiences. The second aim is to summarize the knowledge generated by the programme on the potential role of salt marshes as part of a climate change adaption strategy. Explorative modelling results indicate that Wadden Sea salt marshes affect wave heights, even under extreme conditions. Therefore, a salt-marsh zone in front of the Wadden Sea dikes that could keep pace with sea level rise may result in a reduced dike reinforcement task. A salt marsh potential map gives a rough impression of locations that are potentially interesting for salt marsh conservation and development, based on the current situation, on available information about abiotic conditions for salt marsh formation and the habitats present in the coastal zone. Besides elongated stretches were seminatural salt marshes are already present or developing, several stretches along the Dutch Wadden Sea coast have favourable abiotic conditions for salt marsh development. However, the prospects for integrating salt marshes into flood defences depend also on other aspects. Various nature conservation agreements are in effect with their associated obligations. Furthermore, the foreseen value of salt marsh development compared to traditional reinforcements, in terms of both costs and benefits, must be considered.

Food reinforcement and parental obesity predict future weight gain in non-obese adolescents

Background: Food reinforcement, the extent to which people are willing to work to earn a preferred snack food, and parental obesity are risk factors for weight gain, but there is no research comparing the predictive effects of these factors for adolescent weight gain. Methods: 130 non-obese adolescents (M age = 15.2 ± 1.0; M BMI = 20.7 ± 2.0; M zBMI = 0.16 ± 0.64) at differential risk for weight gain based on parental obesity completed baseline food and money reinforcement tasks, and provided zBMI data over a 2-year follow-up. Results: The number of obese (BMI ≥ 30) parents (p = 0.007) and high food reinforcement (p = 0.046) were both significant independent predictors of greater zBMI increases, controlling for age, sex, parent education and minority status. Having no obese parents or being low or average in food reinforcement was associated with reductions in zBMI, but those high in food reinforcement showed larger zBMI increases (0.102) than having one obese parent (0.025) but less than having two obese parents (0.177). Discussion: Food reinforcement and parental obesity independently predict future weight gain among adolescents. It might be fruitful for obesity prevention programs to target both high risk groups.

Genetic deletion of PDE10A selectively impairs incentive salience attribution and decreases medium spiny neuron excitability

The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution.

Extraversion predicts neural sensitivity to reward in large fMRI studies

Although the theory has been widely adopted that Extraversion reflects individual differences in brain systems governing reward sensitivity, the evidence base for this theory is surprisingly thin. A few fMRI studies have correlated brain activity in response to monetary rewards or pleasant emotional stimuli with Extraversion, but their samples sizes have generally been very small ( N N > 90), we show that Extraversion (and no other of the Big Five) is associated with neural sensitivity to monetary reward in a simple reinforcement task (guessing whether a computer-generated number will be high or low) and in a decision making task assessing delay discounting (choosing between smaller, sooner rewards and larger, later rewards). These studies provide strong evidence for the theory that Extraversion reflects reward sensitivity.

Effects of restriction on children’s intake differ by child temperament, food reinforcement, and parent’s chronic use of restriction

Parents’ use of restrictive feeding practices is counterproductive, increasing children’s intake of restricted foods and risk for excessive weight gain. The aims of this research were to replicate Fisher and Birch’s (1999b) original findings that short-term restriction increases preschool children’s (3–5y) selection, intake, and behavioral response to restricted foods, and to identify characteristics of children who were more susceptible to the negative effects of restriction. The experiment used a within-subjects design; 37 children completed the food reinforcement task and heights/weights were measured. Parents reported on their use of restrictive feeding practices and their child’s inhibitory control and approach. Overall, the findings replicated those of Fisher and Birch (1999b) and revealed that the effects of restriction differed by children’s regulatory and appetitive tendencies. Greater increases in intake in response to restriction were observed among children lower in inhibitory control, higher in approach, who found the restricted food highly reinforcing, and who had previous experience with parental use of restriction. Results confirm that the use of restriction does not reduce children’s consumption of these foods, particularly among children with lower regulatory or higher appetitive tendencies.

Selective inhibition of phosphodiesterase 10A impairs appetitive and aversive conditioning and incentive salience attribution

The pharmacological effect of the selective PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline succinic acid (MP-10) on aversively and appetitively motivated behavior in C57BL/6J mice was examined. MP-10 dose-dependently impaired performance on a highly demanding reward schedule during appetitive conditioning. The compound further affected cue-based, but not contextual aversive conditioning. Finally, dose-dependent impaired performance in an instrumentally conditioned reinforcement (ICR) task was found. This suggests that the observed behavioral effects of MP-10 can be at least partially ascribed to impaired incentive salience attribution. MP-10 administration dose-dependently enhanced striatal expression of the immediate early gene Zif268, which suggest that MP-10 affects the studied motivated behaviors by enhancing PDE10A-regulated striatal signaling. Striatal signaling thus appears to be crucial in processes that control reward-motivated behavior in general, and incentive salience attribution in particular. Continued research will prove valuable towards a better understanding of psychopathologies that affect reward-motivated behaviors, such as drug addiction and schizophrenia.

CB1 cannabinoid receptor-mediated aggressive behavior

This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5-hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (ACo), basomedian (BMA) and basolateral (BLA) amygdaloid nuclei. The behavioral effects of the CB1r agonist ACEA (1 and 2 mg/kg) on aggression were also evaluated in isolated OF1 mice. CB1KO mice housed in groups showed higher levels of offensive aggression. Isolation increased aggressive behavior only in WT. In grouped CB1KO mice COMT gene expression was significantly higher in the MnR and DR, while MAO-A gene expression was lower in the MnR. Gene expression of 5HT1Br, COMT and MAO-A was higher in the amygdala of CB1KO mice. CB1r double-immunohistochemistry revealed cytoplasmic-labeled COMT-ir cells in the raphe nuclei and in the ACo, BMA and BLA. CB1r immunolabeling was observed only in ACo, BMA and BLA, where it was localized in axons and buttons. The density of labeled processes increased in BLA. Acute administration of the CB1 agonist ACEA (2 mg/kg) significantly decreased the aggression levels of OF1 mice. These results suggest that CB1r plays an important role in social interaction and aggressive behavior.

Disrupted Reinforcement Learning and Maladaptive Behavior in Women With a History of Childhood Sexual Abuse

Childhood sexual abuse (CSA) has been associated with psychopathology, particularly major depressive disorder (MDD), and high-risk behaviors. Despite the epidemiological data available, the mechanisms underlying these maladaptive outcomes remain poorly understood. We examined whether a history of CSA, particularly in conjunction with a past episode of MDD, is associated with behavioral and neural dysfunction in reinforcement learning, and whether such dysfunction is linked to maladaptive behavior. Participants completed a clinical evaluation and a probabilistic reinforcement task while 128-channel event-related potentials were recorded. Academic setting; participants recruited from the community. Fifteen women with a history of CSA and remitted MDD (CSA + rMDD), 16 women with remitted MDD with no history of CSA (rMDD), and 18 healthy women (controls). Three or more episodes of coerced sexual contact (mean [SD] duration, 3.00 [2.20] years) between the ages of 7 and 12 years by at least 1 male perpetrator. Participants' preference for choosing the most rewarded stimulus and avoiding the most punished stimulus was evaluated. The feedback-related negativity and error-related negativity-hypothesized to reflect activation in the anterior cingulate cortex-were used as electrophysiological indices of reinforcement learning. No group differences emerged in the acquisition of reinforcement contingencies. In trials requiring participants to rely partially or exclusively on previously rewarded information, the CSA + rMDD group showed (1) lower accuracy (relative to both controls and the rMDD group), (2) blunted electrophysiological differentiation between correct and incorrect responses (relative to controls), and (3) increased activation in the subgenual anterior cingulate cortex (relative to the rMDD group). A history of CSA was not associated with impairments in avoiding the most punished stimulus. Self-harm and suicidal behaviors correlated with poorer performance of previously rewarded, but not previously punished, trials. Irrespective of past MDD episodes, women with a history of CSA showed neural and behavioral deficits in utilizing previous reinforcement to optimize decision making in the absence of feedback (blunted "Go learning"). Although our study provides initial evidence for reward-specific deficits associated with CSA, future research is warranted to determine if disrupted positive reinforcement learning predicts high-risk behavior following CSA.

Acute and chronic effects of gum chewing on food reinforcement and energy intake

Although chewing gum has been considered a potential method for reducing energy intake, little empirical data exist to support this idea. The purpose of this study was to test the hypothesis that chewing gum before eating reduces motivation to eat, hunger, and energy intake. In order to test this hypothesis, we conducted two experiments in which participants chewed gum prior to completing a food reinforcement task or before all eating occasions for two of three weeks. In Experiment 1, we found that chewing gum had no influence on the reinforcing value of food, but chewing mint gum reduced liking of and energy intake from fruit. In addition, chewing gum reduced self-reported hunger immediately after gum chewing and after eating compared with the no gum condition. In Experiment 2, gum chewing had no significant effect on total energy intake, but participants consumed fewer meals, consumed more energy per meal, and had a lower nutrient adequacy ratio during the gum chewing weeks. These studies provide no evidence that acute or chronic gum chewing reduces hunger or energy intake. In fact, chewing mint-flavored gum may deter consumption of fruit and reduce diet quality.

Catecholamine receptors differentially mediate impulsive choice in the medial prefrontal and orbitofrontal cortex

Impulsivity is characteristic of several mental health disorders and is largely mediated by the prefrontal cortex subregions: the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Dopamine (DA) and norepinephrine (NE) are known to modulate activity of the prefrontal cortex, however their direct role in impulsive choice is not known. The aim of the present study was to investigate the effect of microinjecting DA or NE compounds in the mPFC or OFC on impulsive choice as measured by a delayed reinforcement (DR) task in male Wistar Kyoto rats. Following training in the DR task, rats were pretreated with DA D(1) and D(2) receptor antagonists (SCH23390 3 μg/side, raclopride 3 or 6 μg/side) or NE α(1) and α(2) receptor agonists (phenylephrine 0.1 or 0.3 μg/side, guanfacine 1 or 3 μg/side, respectively) into the mPFC or OFC and the effect on impulsive behavior was assessed. Pretreatment with raclopride into the mPFC or OFC significantly increased impulsive choice, however only pretreatment with SCH23390 into the mPFC, and not the OFC, significantly increased impulsive choice. Pretreatment with the NE receptor agonists had no effect on impulsive choice. This study suggests that DA receptors, but not NE receptors, differentially mediate impulsive choice in sub-regions of the prefrontal cortex.

Long-term effects of chronic oral Ritalin administration on cognitive and neural development in adolescent wistar kyoto rats.

The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed “normal” (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in “normal” WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls.

Pregabalin‐ and topiramate‐mediated regulation of cognitive and motor impulsivity in DBA/2 mice

Impulsivity is a core symptom in many neuropsychiatric disorders. The main objective of this study was to evaluate the effects of topiramate and pregabalin on the modulation of different impulsivity dimensions in DBA/2 mice. The effects of acute and chronic administration of pregabalin (10, 20 and 40 mg·kg(-1) ) and topiramate (12.5, 25 and 50 mg·kg(-1) ) were evaluated in the light-dark box (LDB), hole board test (HBT) and delayed reinforcement task (DRT). α(2A) -Adrenoceptor, D(2) -receptor and TH gene expression were evaluated by real-time PCR in the prefrontal cortex (PFC), accumbens (ACC) and ventral tegmental area (VTA), respectively. Acute pregabalin administration showed a clear anxiolytic-like effect (LDB) but did not modify novelty-seeking behaviour (HBT). In contrast, topiramate produced an anxiolytic effect only at the highest dose, whereas it reduced novelty seeking at all doses tested. In the DRT, acute pregabalin had no effect, whereas topiramate only reduced motor impulsivity. Chronically, pregabalin significantly increased motor impulsivity and topiramate diminished cognitive impulsivity. Pregabalin decreased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA. These results suggest that the usefulness of pregabalin in impulsivity-related disorders is related to its anxiolytic properties, whereas topiramate modulates impulsivity. These differences could be linked to their opposite effects on α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively.

Cannabinoid CB2 receptor‐mediated regulation of impulsive‐like behaviour in DBA/2 mice

This study evaluated gene expression differences between two mouse strains, characterized by opposite impulsivity-like traits and the involvement of the cannabinoid CB(2) receptor in the modulation of impulsivity. Behavioural tests were conducted to compare motor activity, exploration and novelty seeking, attention and cognitive and motor impulsivity (delayed reinforcement task: session duration 30 min; timeout 30 s) between A/J and DBA/2 mice. Expression of genes for dopamine D(2) receptors, CB(1) and CB(2) receptors were measured in the cingulate cortex (CgCtx), caudate-putamen (CPu), accumbens (Acc), amygdala (Amy) and hippocampus (Hipp). Involvement of CB(2) receptors in impulsivity was evaluated in DBA/2 mice with a CB(2) receptor agonist (JWH133) and an antagonist (AM630). DBA/2 mice presented higher motor and exploratory activity, pre-pulse inhibition impairment and higher cognitive and motor impulsivity level than A/J mice. In addition, DBA/2 mice showed lower (CgCtx, Acc, CPu) D(2) receptor, lower (Amy) and higher (CgCtx, Acc, CPu, Hipp) CB(1) receptor and higher (CgCtx, Acc, Amy) and similar (CPu, Hipp) CB(2) receptor gene expressions. Treatment with JWH133 (0.5, 1, 3 mg·kg(-1), i.p.) reduced cognitive and motor impulsivity level, accompanied by CB(2) receptor down-regulation (CgCtx, Acc, Amy) but did not modify other behaviours. In contrast, AM630 (1, 2, 3 mg·kg(-1), i.p.) improved pre-pulse inhibition and reduced novelty seeking behaviour in DBA/2 mice. CB(2) receptors might play an important role in regulating impulsive behaviours and should be considered a promising therapeutic target in the treatment of impulsivity-related disorders.

Changes in the hippocampal ripples and prefrontal neuronal activity associated with delayed reinforcement task in rats

Changes in the hippocampal ripples and prefrontal neuronal activity associated with delayed reinforcement task in rats

Bilateral striatal lesions disrupt performance in an operant delayed reinforcement task in rats

In order to provide an animal model of the impulsivity observed in Huntington's disease, the effects of bilateral neostriatal lesions in rats were evaluated in an operant delayed reinforcement task. When given a choice between responding to one lever for a small but immediate reward and a second lever for a larger delayed reward, normal rats exhibit a marked preference for responding to the high reward lever when the imposed delay is short, but progressively choose the lever associated with immediate small reward as the delays increase. Following striatal lesions, the animals continue to express similar preferences, but the lesions initially impose a distinct flattening of the delay-preference function, suggesting a relative insensitivity to the increasing delay parameter in making their response choices. However, this deficit declines with extend retraining on the task, such that 1-2 months after lesion the delay-dependent shift of preference from the delayed to the immediate lever as the delays lengthened was comparable in lesion and sham animals. Amphetamine further disinhibited all animals, apparent as a further increase in the number and reduction of the latencies of responses made to the lever associated with immediate reward. Striatal lesions had little influence on the effects of amphetamine on task performance, other than the increase in the numbers of omissions of lever and panel responses induced by the drug was more marked in the lesion than sham animals, and the lesioned animals exhibited less delay-dependency than the controls in their preference for responding to the lever associated with the larger delayed reinforcement at the highest (1.5 mg/kg) dose tested. The present results indicate small but clear effects of dorsal striatal lesions in an operant delayed reinforcement task, suggestive of an initial impairment in response selection and a reduction in their sensitivity to the delay interval itself. This deficit recovered with further training, which may be dependent upon relearning choice response procedures disrupted by the lesion, but might be reinstated by treatment with stimulant drugs. This article is part of a special issue entitled 'Behavioural, Anatomical, and Genetic Characterisation of Mouse and Rat Models of Huntington's Disease.'

Inadequate early social experience increases the incentive salience of reward-related cues in adulthood

The mechanisms by which childhood abuse and/or neglect become risk factors for the development of drug addiction, problem gambling, and other disorders of behavioral inhibition are unknown. The loss of behavioral inhibition is often triggered by reward-related cues that acquire incentive salience. This study examined whether inadequate early-life social experience in rats affects the incentive salience of reward-related cues. Rats were deprived of early-life social experience with the mother and litter through artificial-rearing (AR). A group of AR rats (AR + STM) received additional tactile stimulation that mimicked maternal licking, a critical component of rat maternal care. Control rats were maternally reared (MR). The incentive salience attributed to a food cue was measured in adult rats using a conditioned approach task, where a conditional stimulus (CS; lever) was paired with food delivery, and in a conditional reinforcement task. The dependent measures were approach towards the CS (sign-tracking) versus approach towards the place of food delivery (goal-tracking) and instrumental responding for the CS. AR rats made significantly more sign-tracking responses than MR rats. AR rats also made more instrumental responses when reinforced with the CS. AR + STM rats’ responses were intermediate to MR and AR rats. Thus, inadequate early-life social experience enhanced the incentive salience of a reward-related cue in adulthood. Replacement of maternal licking partially reversed this effect. These results highlight a potential link between early-life social adversity and susceptibility to disorders of behavioral inhibition.

Reward‐seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors

The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information. Because participation of D4Rs in executive learning is largely unknown, we challenged D4R knockout mice (Drd4(-/-)) and their wild-type (WT) littermates, neonatally treated with 6-hydroxydopamine (6-OHDA; icv) or vehicle in two operant learning paradigms. A continuous reinforcement task, in which one food-pellet was delivered after every lever press, showed that 6-OHDA-treated mice (hypodopaminergic) WT mice pressed the reinforcing lever at much lower rates than normodopaminergic WT mice. In contrast, Drd4(-/-) mice displayed increased lever pressing rates, regardless of their dopamine content. In another study, mice were trained to solve an operant two-choice task in which a first showing lever was coupled to the delivery of one food pellet only after a second lever emerged. Interval between presentation of both levers was initially 12 s and progressively shortened to 6, 2, and finally 0.5 s. Normodopaminergic WT mice obtained a pellet reward in more than 75% of the trials at 12, 6, and 2 s, whereas hypodopaminergic WT mice were severely impaired to select the reward-paired lever. Absence of D4Rs was not detrimental in this task. Moreover, hypodopaminergic Drd4(-/-) mice were as efficient as their normodopaminergic Drd4(-/-) siblings in selecting the reward-paired lever. In summary, hypodopaminergic mice exhibit severe impairments to retrieve rewards in two operant positive reinforcement tasks, but these deleterious effects are totally prevented in the absence of functional D4Rs.