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associative learning, or the ability to ascribe deterministic relationships between environmental stimuli that signal the probability of receiving a primary reinforcer (e.g. food), has been divided into 3 components or stages [1]. The first, unlearned stage is the organism's experience with a primary reinforcer that elicits some unlearned/innate physiological response (e.g. palatability of a food or satiety). The second phase involves the attachment of salience to external stimuli (discriminative stimuli) that signal whether the delivery of a primary reinforcer will or will not occur based on some emitted behavior (e.g. a rodent lever presses for food pellets only when a stimulus light is illuminated in an operant chamber). Finally, there is the maintenance of associative learning relationships over time (a stimulus light always signifies a food pellet is available subsequent to a lever press) [see refs. [1,2] for review]. Berridge and Robinson [1] have proposed that dopamine plays a pivotal role in the second phase of reinforcement-mediated associative learning by molding the \"incentive salience\" or learned motivational properties of conditioned stimuli. In support of this view are several studies demonstrating that the disruption of dopamine signaling via acute blockade of dopamine receptors with dopamine receptor antagonists [3-9] or 6-OHDA lesions [1,10,11] do not disrupt phase 1, the palatability or primary reinforcing characteristics of a natural reinforcer (e.g. palatability) but disrupt phase 2, the formation of incentive salience.\nDopamine signaling is mediated at the cellular level by two major subclasses of G-protein coupled receptors that are referred to as D-1 like (D1aR, D1b/5R) or D-2 like (D2R, D3R, D4R) [12,13]. Although individual genes code for each dopamine receptor subtype, there is considerable pharmacological overlap between D1-like and D2-like receptors. Several studies have used pharmacological manipulations to investigate the contribution of dopamine receptor subtypes in various stages of associative learning [1,2,14]. Currently it is held that excitatory dopamine D1Rs mediate the acquisition and expression of several conditioned behaviors involving food reinforcers [e.g. [6,7]] as well as responding for conditioned cues predictive of cocaine delivery [9] – consistent with the interpretation that D1R mediated signaling might modulate the maintenance of stimulus-response outcomes. Despite a growing literature demonstrating disrupted associative learning following acute manipulations of dopamine D1R signaling during acquisition of associative learning tasks with food [e.g. [6,7]], the actual contribution of D2R-mediated signaling on acquisition and maintenance of associative learning in rodents is unresolved.\nWhile D2R antagonists have been used in the context of rodent associative learning paradigms, their lack of receptor subtype specificity [13] and motor-disrupting effects [6,8] have prevented a rigorous examination of the actual role this dopamine receptor subtype plays in associative and reversal learning in the context of an operant behavior. Past experiments seeking to explore the possible involvement of dopamine D2Rs in associative learning have utilized low to moderate doses of drugs [2,5,6] and site-specific administration [7,9] in order to avoid the confounding effect that locomotor disruption associated with acute D2R blockade can have on learning performance in rodents. Besides their lack of receptor subtype specificity, an acute exposure to commercially available D2 receptor antagonists fails to completely block signaling mediated solely by D2Rs. Moreover, acute dosing does not recapitulate the marked learning deficits produced in rodents [15,16] by chronic exposure to dopamine D2R antagonists [6,7].\nThe influence of dopamine D2R-mediated signaling on reversal learning is also poorly understood. Reversal learning can be conceptualized as the ability to recognize an unexpected consequence to a previously established associative learning rule and then alter response strategies accordingly [17,18]. Reversal learning in rodents can serve as an index of learning adaptability and alertness that correlates with human attentional-shift paradigms [17,18]. Additionally, a previous report demonstrated that excitotoxic lesions of terminal field targets of mesocortical dopamine have been shown to disrupt reversal learning [19]. Administration of the D2R/D3R antagonist, sulpiride, impairs spatial reversal leaning in mice [20] and has also been shown to impair attention and the cognitive performances of healthy human volunteers [21]. Moreover an inverse relationship between lower dopamine D2R levels and compulsive behavior in human subjects has been reported [22]. Taken together these findings suggest that D2R-mediated signaling could play a critical role in reversal learning but are insufficient to prove it.\nIn an effort to establish the contribution of dopamine D2 receptor-mediated signaling to associative and non-spatial reversal learning in adult mice, we compared mice [23] that had developed in the complete absence of all functional dopamine D2 receptors (D2R-/-) to wild-type littermates (D2R+/+) in a go/no-go operant learning procedure that measures primary reinforcement, sensory processing, and reversal learning [17-19]. Here we report that dopamine D2R-mediated signaling must be intact if a mouse is to efficiently learn to associate a food reinforcer with a specific odor and then adaptively disengage inappropriate behavioral strategies following the reversal of reinforcement contingencies."}

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associative learning, or the ability to ascribe deterministic relationships between environmental stimuli that signal the probability of receiving a primary reinforcer (e.g. food), has been divided into 3 components or stages [1]. The first, unlearned stage is the organism's experience with a primary reinforcer that elicits some unlearned/innate physiological response (e.g. palatability of a food or satiety). The second phase involves the attachment of salience to external stimuli (discriminative stimuli) that signal whether the delivery of a primary reinforcer will or will not occur based on some emitted behavior (e.g. a rodent lever presses for food pellets only when a stimulus light is illuminated in an operant chamber). Finally, there is the maintenance of associative learning relationships over time (a stimulus light always signifies a food pellet is available subsequent to a lever press) [see refs. [1,2] for review]. Berridge and Robinson [1] have proposed that dopamine plays a pivotal role in the second phase of reinforcement-mediated associative learning by molding the \"incentive salience\" or learned motivational properties of conditioned stimuli. In support of this view are several studies demonstrating that the disruption of dopamine signaling via acute blockade of dopamine receptors with dopamine receptor antagonists [3-9] or 6-OHDA lesions [1,10,11] do not disrupt phase 1, the palatability or primary reinforcing characteristics of a natural reinforcer (e.g. palatability) but disrupt phase 2, the formation of incentive salience.\nDopamine signaling is mediated at the cellular level by two major subclasses of G-protein coupled receptors that are referred to as D-1 like (D1aR, D1b/5R) or D-2 like (D2R, D3R, D4R) [12,13]. Although individual genes code for each dopamine receptor subtype, there is considerable pharmacological overlap between D1-like and D2-like receptors. Several studies have used pharmacological manipulations to investigate the contribution of dopamine receptor subtypes in various stages of associative learning [1,2,14]. Currently it is held that excitatory dopamine D1Rs mediate the acquisition and expression of several conditioned behaviors involving food reinforcers [e.g. [6,7]] as well as responding for conditioned cues predictive of cocaine delivery [9] – consistent with the interpretation that D1R mediated signaling might modulate the maintenance of stimulus-response outcomes. Despite a growing literature demonstrating disrupted associative learning following acute manipulations of dopamine D1R signaling during acquisition of associative learning tasks with food [e.g. [6,7]], the actual contribution of D2R-mediated signaling on acquisition and maintenance of associative learning in rodents is unresolved.\nWhile D2R antagonists have been used in the context of rodent associative learning paradigms, their lack of receptor subtype specificity [13] and motor-disrupting effects [6,8] have prevented a rigorous examination of the actual role this dopamine receptor subtype plays in associative and reversal learning in the context of an operant behavior. Past experiments seeking to explore the possible involvement of dopamine D2Rs in associative learning have utilized low to moderate doses of drugs [2,5,6] and site-specific administration [7,9] in order to avoid the confounding effect that locomotor disruption associated with acute D2R blockade can have on learning performance in rodents. Besides their lack of receptor subtype specificity, an acute exposure to commercially available D2 receptor antagonists fails to completely block signaling mediated solely by D2Rs. Moreover, acute dosing does not recapitulate the marked learning deficits produced in rodents [15,16] by chronic exposure to dopamine D2R antagonists [6,7].\nThe influence of dopamine D2R-mediated signaling on reversal learning is also poorly understood. Reversal learning can be conceptualized as the ability to recognize an unexpected consequence to a previously established associative learning rule and then alter response strategies accordingly [17,18]. Reversal learning in rodents can serve as an index of learning adaptability and alertness that correlates with human attentional-shift paradigms [17,18]. Additionally, a previous report demonstrated that excitotoxic lesions of terminal field targets of mesocortical dopamine have been shown to disrupt reversal learning [19]. Administration of the D2R/D3R antagonist, sulpiride, impairs spatial reversal leaning in mice [20] and has also been shown to impair attention and the cognitive performances of healthy human volunteers [21]. Moreover an inverse relationship between lower dopamine D2R levels and compulsive behavior in human subjects has been reported [22]. Taken together these findings suggest that D2R-mediated signaling could play a critical role in reversal learning but are insufficient to prove it.\nIn an effort to establish the contribution of dopamine D2 receptor-mediated signaling to associative and non-spatial reversal learning in adult mice, we compared mice [23] that had developed in the complete absence of all functional dopamine D2 receptors (D2R-/-) to wild-type littermates (D2R+/+) in a go/no-go operant learning procedure that measures primary reinforcement, sensory processing, and reversal learning [17-19]. Here we report that dopamine D2R-mediated signaling must be intact if a mouse is to efficiently learn to associate a food reinforcer with a specific odor and then adaptively disengage inappropriate behavioral strategies following the reversal of reinforcement contingencies."}

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"span":{"begin":3860,"end":3868},"obj":"CHEBI:18243"},{"id":"T909","span":{"begin":3860,"end":3872},"obj":"PR:000001177"},{"id":"T910","span":{"begin":3904,"end":3912},"obj":"GO:0007612"},{"id":"T911","span":{"begin":3949,"end":3957},"obj":"GO:0007612"},{"id":"T912","span":{"begin":4062,"end":4082},"obj":"GO:0008306"},{"id":"T913","span":{"begin":4153,"end":4161},"obj":"GO:0007612"},{"id":"T914","span":{"begin":4165,"end":4172},"obj":"NCBITaxon:9989"},{"id":"T915","span":{"begin":4198,"end":4206},"obj":"GO:0007612"},{"id":"T916","span":{"begin":4255,"end":4260},"obj":"NCBITaxon:9606"},{"id":"T917","span":{"begin":4410,"end":4418},"obj":"CHEBI:18243"},{"id":"T918","span":{"begin":4455,"end":4463},"obj":"GO:0007612"},{"id":"T919","span":{"begin":4492,"end":4495},"obj":"PR:000001177"},{"id":"T920","span":{"begin":4496,"end":4499},"obj":"PR:000001178"},{"id":"T921","span":{"begin":4512,"end":4521},"obj":"CHEBI:32168"},{"id":"T922","span":{"begin":4548,"end":4555},"obj":"GO:0007612"},{"id":"T923","span":{"begin":4559,"end":4563},"obj":"NCBITaxon:10088"},{"id":"T924","span":{"begin":4621,"end":4630},"obj":"GO:0050890"},{"id":"T925","span":{"begin":4655,"end":4660},"obj":"NCBITaxon:9606"},{"id":"T926","span":{"begin":4725,"end":4733},"obj":"CHEBI:18243"},{"id":"T927","span":{"begin":4725,"end":4737},"obj":"PR:000001177"},{"id":"T928","span":{"begin":4772,"end":4777},"obj":"NCBITaxon:9606"},{"id":"T929","span":{"begin":4854,"end":4857},"obj":"PR:000001177"},{"id":"T930","span":{"begin":4916,"end":4924},"obj":"GO:0007612"},{"id":"T931","span":{"begin":5005,"end":5013},"obj":"CHEBI:18243"},{"id":"T932","span":{"begin":5005,"end":5025},"obj":"PR:000001177"},{"id":"T933","span":{"begin":5048,"end":5059},"obj":"_FRAGMENT"},{"id":"T934","span":{"begin":5085,"end":5093},"obj":"GO:0008306"},{"id":"T935","span":{"begin":5103,"end":5107},"obj":"NCBITaxon:10088"},{"id":"T936","span":{"begin":5121,"end":5125},"obj":"NCBITaxon:10088"},{"id":"T937","span":{"begin":5192,"end":5200},"obj":"CHEBI:18243"},{"id":"T938","span":{"begin":5192,"end":5213},"obj":"PR:000001177"},{"id":"T939","span":{"begin":5215,"end":5218},"obj":"PR:000001177"},{"id":"T940","span":{"begin":5249,"end":5252},"obj":"PR:000001177"},{"id":"T941","span":{"begin":5279,"end":5287},"obj":"GO:0007612"},{"id":"T942","span":{"begin":5335,"end":5353},"obj":"GO:0050893"},{"id":"T943","span":{"begin":5368,"end":5376},"obj":"GO:0007612"},{"id":"T944","span":{"begin":5406,"end":5414},"obj":"CHEBI:18243"},{"id":"T945","span":{"begin":5406,"end":5418},"obj":"PR:000001177"},{"id":"T946","span":{"begin":5458,"end":5463},"obj":"NCBITaxon:10088"},{"id":"T947","span":{"begin":5482,"end":5487},"obj":"GO:0007612"},{"id":"T948","span":{"begin":5503,"end":5507},"obj":"CHEBI:33290"},{"id":"T949","span":{"begin":5549,"end":5559},"obj":"GO:0051866"}],"relations":[{"id":"R393","pred":"_lexicallyChainedTo","subj":"T857","obj":"T856"},{"id":"R394","pred":"_lexicallyChainedTo","subj":"T859","obj":"T858"},{"id":"R395","pred":"_lexicallyChainedTo","subj":"T868","obj":"T867"},{"id":"R396","pred":"_lexicallyChainedTo","subj":"T892","obj":"T891"},{"id":"R397","pred":"_lexicallyChainedTo","subj":"T907","obj":"T906"},{"id":"R398","pred":"_lexicallyChainedTo","subj":"T934","obj":"T933"}],"text":"Background\nReinforcement-mediated associative learning, or the ability to ascribe deterministic relationships between environmental stimuli that signal the probability of receiving a primary reinforcer (e.g. food), has been divided into 3 components or stages [1]. The first, unlearned stage is the organism's experience with a primary reinforcer that elicits some unlearned/innate physiological response (e.g. palatability of a food or satiety). The second phase involves the attachment of salience to external stimuli (discriminative stimuli) that signal whether the delivery of a primary reinforcer will or will not occur based on some emitted behavior (e.g. a rodent lever presses for food pellets only when a stimulus light is illuminated in an operant chamber). Finally, there is the maintenance of associative learning relationships over time (a stimulus light always signifies a food pellet is available subsequent to a lever press) [see refs. [1,2] for review]. Berridge and Robinson [1] have proposed that dopamine plays a pivotal role in the second phase of reinforcement-mediated associative learning by molding the \"incentive salience\" or learned motivational properties of conditioned stimuli. In support of this view are several studies demonstrating that the disruption of dopamine signaling via acute blockade of dopamine receptors with dopamine receptor antagonists [3-9] or 6-OHDA lesions [1,10,11] do not disrupt phase 1, the palatability or primary reinforcing characteristics of a natural reinforcer (e.g. palatability) but disrupt phase 2, the formation of incentive salience.\nDopamine signaling is mediated at the cellular level by two major subclasses of G-protein coupled receptors that are referred to as D-1 like (D1aR, D1b/5R) or D-2 like (D2R, D3R, D4R) [12,13]. Although individual genes code for each dopamine receptor subtype, there is considerable pharmacological overlap between D1-like and D2-like receptors. Several studies have used pharmacological manipulations to investigate the contribution of dopamine receptor subtypes in various stages of associative learning [1,2,14]. Currently it is held that excitatory dopamine D1Rs mediate the acquisition and expression of several conditioned behaviors involving food reinforcers [e.g. [6,7]] as well as responding for conditioned cues predictive of cocaine delivery [9] – consistent with the interpretation that D1R mediated signaling might modulate the maintenance of stimulus-response outcomes. Despite a growing literature demonstrating disrupted associative learning following acute manipulations of dopamine D1R signaling during acquisition of associative learning tasks with food [e.g. [6,7]], the actual contribution of D2R-mediated signaling on acquisition and maintenance of associative learning in rodents is unresolved.\nWhile D2R antagonists have been used in the context of rodent associative learning paradigms, their lack of receptor subtype specificity [13] and motor-disrupting effects [6,8] have prevented a rigorous examination of the actual role this dopamine receptor subtype plays in associative and reversal learning in the context of an operant behavior. Past experiments seeking to explore the possible involvement of dopamine D2Rs in associative learning have utilized low to moderate doses of drugs [2,5,6] and site-specific administration [7,9] in order to avoid the confounding effect that locomotor disruption associated with acute D2R blockade can have on learning performance in rodents. Besides their lack of receptor subtype specificity, an acute exposure to commercially available D2 receptor antagonists fails to completely block signaling mediated solely by D2Rs. Moreover, acute dosing does not recapitulate the marked learning deficits produced in rodents [15,16] by chronic exposure to dopamine D2R antagonists [6,7].\nThe influence of dopamine D2R-mediated signaling on reversal learning is also poorly understood. Reversal learning can be conceptualized as the ability to recognize an unexpected consequence to a previously established associative learning rule and then alter response strategies accordingly [17,18]. Reversal learning in rodents can serve as an index of learning adaptability and alertness that correlates with human attentional-shift paradigms [17,18]. Additionally, a previous report demonstrated that excitotoxic lesions of terminal field targets of mesocortical dopamine have been shown to disrupt reversal learning [19]. Administration of the D2R/D3R antagonist, sulpiride, impairs spatial reversal leaning in mice [20] and has also been shown to impair attention and the cognitive performances of healthy human volunteers [21]. Moreover an inverse relationship between lower dopamine D2R levels and compulsive behavior in human subjects has been reported [22]. Taken together these findings suggest that D2R-mediated signaling could play a critical role in reversal learning but are insufficient to prove it.\nIn an effort to establish the contribution of dopamine D2 receptor-mediated signaling to associative and non-spatial reversal learning in adult mice, we compared mice [23] that had developed in the complete absence of all functional dopamine D2 receptors (D2R-/-) to wild-type littermates (D2R+/+) in a go/no-go operant learning procedure that measures primary reinforcement, sensory processing, and reversal learning [17-19]. Here we report that dopamine D2R-mediated signaling must be intact if a mouse is to efficiently learn to associate a food reinforcer with a specific odor and then adaptively disengage inappropriate behavioral strategies following the reversal of reinforcement contingencies."}

{"project":"2_test","denotations":[{"id":"15061865-9858756-12857691","span":{"begin":261,"end":262},"obj":"9858756"},{"id":"15061865-9858756-12857692","span":{"begin":953,"end":954},"obj":"9858756"},{"id":"15061865-12445713-12857693","span":{"begin":955,"end":956},"obj":"12445713"},{"id":"15061865-9858756-12857694","span":{"begin":994,"end":995},"obj":"9858756"},{"id":"15061865-9329075-12857695","span":{"begin":1385,"end":1386},"obj":"9329075"},{"id":"15061865-11509194-12857695","span":{"begin":1385,"end":1386},"obj":"11509194"},{"id":"15061865-11919664-12857695","span":{"begin":1385,"end":1386},"obj":"11919664"},{"id":"15061865-12629161-12857695","span":{"begin":1385,"end":1386},"obj":"12629161"},{"id":"15061865-11027236-12857695","span":{"begin":1385,"end":1386},"obj":"11027236"},{"id":"15061865-12445722-12857695","span":{"begin":1385,"end":1386},"obj":"12445722"},{"id":"15061865-11351937-12857695","span":{"begin":1385,"end":1386},"obj":"11351937"},{"id":"15061865-9858756-12857696","span":{"begin":1409,"end":1410},"obj":"9858756"},{"id":"15061865-12073171-12857697","span":{"begin":1411,"end":1413},"obj":"12073171"},{"id":"15061865-11530224-12857698","span":{"begin":1414,"end":1416},"obj":"11530224"},{"id":"15061865-8494342-12857699","span":{"begin":1785,"end":1787},"obj":"8494342"},{"id":"15061865-9858756-12857700","span":{"begin":2106,"end":2107},"obj":"9858756"},{"id":"15061865-12445713-12857701","span":{"begin":2108,"end":2109},"obj":"12445713"},{"id":"15061865-11257908-12857702","span":{"begin":2110,"end":2112},"obj":"11257908"},{"id":"15061865-12629161-12857703","span":{"begin":2272,"end":2273},"obj":"12629161"},{"id":"15061865-11027236-12857704","span":{"begin":2274,"end":2275},"obj":"11027236"},{"id":"15061865-11351937-12857705","span":{"begin":2353,"end":2354},"obj":"11351937"},{"id":"15061865-12629161-12857706","span":{"begin":2679,"end":2680},"obj":"12629161"},{"id":"15061865-11027236-12857707","span":{"begin":2681,"end":2682},"obj":"11027236"},{"id":"15061865-12629161-12857708","span":{"begin":2989,"end":2990},"obj":"12629161"},{"id":"15061865-12445722-12857709","span":{"begin":2991,"end":2992},"obj":"12445722"},{"id":"15061865-12445713-12857710","span":{"begin":3312,"end":3313},"obj":"12445713"},{"id":"15061865-11919664-12857711","span":{"begin":3314,"end":3315},"obj":"11919664"},{"id":"15061865-12629161-12857712","span":{"begin":3316,"end":3317},"obj":"12629161"},{"id":"15061865-11027236-12857713","span":{"begin":3353,"end":3354},"obj":"11027236"},{"id":"15061865-11351937-12857714","span":{"begin":3355,"end":3356},"obj":"11351937"},{"id":"15061865-12457265-12857715","span":{"begin":3781,"end":3783},"obj":"12457265"},{"id":"15061865-12589383-12857716","span":{"begin":3784,"end":3786},"obj":"12589383"},{"id":"15061865-12629161-12857717","span":{"begin":3837,"end":3838},"obj":"12629161"},{"id":"15061865-11027236-12857718","span":{"begin":3839,"end":3840},"obj":"11027236"},{"id":"15061865-11323267-12857719","span":{"begin":4139,"end":4141},"obj":"11323267"},{"id":"15061865-11323267-12857720","span":{"begin":4293,"end":4295},"obj":"11323267"},{"id":"15061865-10789947-12857721","span":{"begin":4465,"end":4467},"obj":"10789947"},{"id":"15061865-9105587-12857722","span":{"begin":4565,"end":4567},"obj":"9105587"},{"id":"15061865-10525751-12857723","span":{"begin":4673,"end":4675},"obj":"10525751"},{"id":"15061865-10484959-12857724","span":{"begin":4806,"end":4808},"obj":"10484959"},{"id":"15061865-9247267-12857725","span":{"begin":5127,"end":5129},"obj":"9247267"},{"id":"15061865-11323267-12857726","span":{"begin":5378,"end":5380},"obj":"11323267"},{"id":"15061865-10789947-12857726","span":{"begin":5378,"end":5380},"obj":"10789947"}],"text":"Background\nReinforcement-mediated associative learning, or the ability to ascribe deterministic relationships between environmental stimuli that signal the probability of receiving a primary reinforcer (e.g. food), has been divided into 3 components or stages [1]. The first, unlearned stage is the organism's experience with a primary reinforcer that elicits some unlearned/innate physiological response (e.g. palatability of a food or satiety). The second phase involves the attachment of salience to external stimuli (discriminative stimuli) that signal whether the delivery of a primary reinforcer will or will not occur based on some emitted behavior (e.g. a rodent lever presses for food pellets only when a stimulus light is illuminated in an operant chamber). Finally, there is the maintenance of associative learning relationships over time (a stimulus light always signifies a food pellet is available subsequent to a lever press) [see refs. [1,2] for review]. Berridge and Robinson [1] have proposed that dopamine plays a pivotal role in the second phase of reinforcement-mediated associative learning by molding the \"incentive salience\" or learned motivational properties of conditioned stimuli. In support of this view are several studies demonstrating that the disruption of dopamine signaling via acute blockade of dopamine receptors with dopamine receptor antagonists [3-9] or 6-OHDA lesions [1,10,11] do not disrupt phase 1, the palatability or primary reinforcing characteristics of a natural reinforcer (e.g. palatability) but disrupt phase 2, the formation of incentive salience.\nDopamine signaling is mediated at the cellular level by two major subclasses of G-protein coupled receptors that are referred to as D-1 like (D1aR, D1b/5R) or D-2 like (D2R, D3R, D4R) [12,13]. Although individual genes code for each dopamine receptor subtype, there is considerable pharmacological overlap between D1-like and D2-like receptors. Several studies have used pharmacological manipulations to investigate the contribution of dopamine receptor subtypes in various stages of associative learning [1,2,14]. Currently it is held that excitatory dopamine D1Rs mediate the acquisition and expression of several conditioned behaviors involving food reinforcers [e.g. [6,7]] as well as responding for conditioned cues predictive of cocaine delivery [9] – consistent with the interpretation that D1R mediated signaling might modulate the maintenance of stimulus-response outcomes. Despite a growing literature demonstrating disrupted associative learning following acute manipulations of dopamine D1R signaling during acquisition of associative learning tasks with food [e.g. [6,7]], the actual contribution of D2R-mediated signaling on acquisition and maintenance of associative learning in rodents is unresolved.\nWhile D2R antagonists have been used in the context of rodent associative learning paradigms, their lack of receptor subtype specificity [13] and motor-disrupting effects [6,8] have prevented a rigorous examination of the actual role this dopamine receptor subtype plays in associative and reversal learning in the context of an operant behavior. Past experiments seeking to explore the possible involvement of dopamine D2Rs in associative learning have utilized low to moderate doses of drugs [2,5,6] and site-specific administration [7,9] in order to avoid the confounding effect that locomotor disruption associated with acute D2R blockade can have on learning performance in rodents. Besides their lack of receptor subtype specificity, an acute exposure to commercially available D2 receptor antagonists fails to completely block signaling mediated solely by D2Rs. Moreover, acute dosing does not recapitulate the marked learning deficits produced in rodents [15,16] by chronic exposure to dopamine D2R antagonists [6,7].\nThe influence of dopamine D2R-mediated signaling on reversal learning is also poorly understood. Reversal learning can be conceptualized as the ability to recognize an unexpected consequence to a previously established associative learning rule and then alter response strategies accordingly [17,18]. Reversal learning in rodents can serve as an index of learning adaptability and alertness that correlates with human attentional-shift paradigms [17,18]. Additionally, a previous report demonstrated that excitotoxic lesions of terminal field targets of mesocortical dopamine have been shown to disrupt reversal learning [19]. Administration of the D2R/D3R antagonist, sulpiride, impairs spatial reversal leaning in mice [20] and has also been shown to impair attention and the cognitive performances of healthy human volunteers [21]. Moreover an inverse relationship between lower dopamine D2R levels and compulsive behavior in human subjects has been reported [22]. Taken together these findings suggest that D2R-mediated signaling could play a critical role in reversal learning but are insufficient to prove it.\nIn an effort to establish the contribution of dopamine D2 receptor-mediated signaling to associative and non-spatial reversal learning in adult mice, we compared mice [23] that had developed in the complete absence of all functional dopamine D2 receptors (D2R-/-) to wild-type littermates (D2R+/+) in a go/no-go operant learning procedure that measures primary reinforcement, sensory processing, and reversal learning [17-19]. Here we report that dopamine D2R-mediated signaling must be intact if a mouse is to efficiently learn to associate a food reinforcer with a specific odor and then adaptively disengage inappropriate behavioral strategies following the reversal of reinforcement contingencies."}