Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement

Johnson, Amy; Thibeault, Kimberly C.; López, Alberto J.; Peck, Emily G.; Sands, L. Paul; Sanders, Christina; Kutlu, Munir Gunes; Calipari, Erin S.

doi:10.1038/s41386-019-0320-0

Cited by 63 publications

(48 citation statements)

References 52 publications

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“…Overall, this study by Johnson et al [5] highlights a fundamental but previously unexplored role played by the estrous cycle in promoting female vulnerability to addiction. Cocaine-paired cues-by virtue of being conditioned during pro/ estrus-gain heightened incentive motivational value that invigorates cocaine intake regardless of current estrous cycle status.…”

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confidence: 69%

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Females pay a higher price for addiction

Zlebnik

2019

Neuropsychopharmacol.

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confidence: 69%

“…In this issue, Johnson et al [5] examine whether estrous cycle stage at time of conditioning of cocaine cues influences the motivational impact of those cues on future cocaine selfadministration. Standard preclinical drug self-administration procedures often present cue lights and/or tones prior to or coincident with response-contingent i.v.…”

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confidence: 99%

Females pay a higher price for addiction

Zlebnik

2019

Neuropsychopharmacol.

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“…In practical contexts, rewards are generally weighed with potential negative consequences (7), requiring consideration of the value of a reward and of associated aversive outcomes. Sex-based differences in reward seeking and avoidance -developed over evolutionary history -offer an ideal model to explore bias and strategy in a behavioral task while providing insight into the neurobiological basis of information encoding (8)(9)(10)(11)(12). Previous work has shown that the schedule under which a stimulus is presented is more of a behavioral determinant than the stimulus itself (13,14); while these principles laid the ground-work for behavioral neuroscience, many of these fundamental findings are no longer considered when developing and designing behavioral models in animals.…”

Section: Introductionmentioning

confidence: 99%

A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies

Kutlu

Zachry

Brady

et al. 2019

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AbstractBackgroundSex is a critical biological variable in the neuropathology of psychiatric disease, and in many cases, women represent a vulnerable population. It has been hypothesized that sex differences in neuropsychiatric disorders are manifestations of differences in basic reward processing. However, preclinical models often present rewards in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes.MethodsWe developed a Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence. Mice are trained in a series of operant tasks. In phase 1, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. In phase 2, both discriminative stimuli are presented concurrently allowing us to parse innate behavioral strategies based on reward seeking and shock avoidance. Phase 3 is punished responding where a discriminative stimulus predicts that nose-poking for sucrose occurs concurrently with footshock, allowing for the assessment of how positive and negative outcomes are relatively valued.ResultsFemales prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. In cases where rules are uncertain, males and females employ different strategies, with females demonstrating bias for shock avoidance.ConclusionsThe MCOAT has broad utility for neuroscience research where pairing this task with recording and manipulation techniques will allow for the definition of the discrete information encoded within cellular populations. Ultimately, we show that making conclusions from unidimensional data leads to inaccurate generalizations about sex-specific behaviors that do not accurately represent ground truth.

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“…A plurality of studies, however, focus only on the male phenotype, as female subjects are either underpowered or excluded altogether [49]. As a result, there has been a recent emphasis in accurately and reliably assessing sex as a biological variable with regard to preclinical models of substance use disorder [50][51][52][53][54][55]. Here, we assessed the sexspecific effects of food pre-training and commonly employed performance criteria for inclusion in subsequent operant studies.…”

Section: Discussionmentioning

confidence: 99%

An optimized procedure for robust volitional drug intake in mice

et al. 2019

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Substance use disorder is a behavioral disorder characterized by volitional drug consumption, compulsive behavior, drug seeking, and relapse. Mouse models of substance use disorder allow for the use of molecular, genetic, and circuit level tools, which provide enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends entirely on the validity of the mouse models used. Self-administration models have long been considered the gold standard of preclinical addiction models, as they allow for volitional drug use, this providing strong face validity. In a series of experiments, we show that traditional mouse models of self-administration, where behavior is maintained on a fixed-ratio one schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery -demonstrating that it is impossible to determine when intake is and is not volitional. Further, when assessing inclusion criteria, we find a sex-bias in exclusion criteria where females that acquired food self-administration were eliminated when traditional criteria were applied. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pre-trained on food and behavior is maintained on a variable ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and eliminates sex bias in inclusion criteria. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple and novel approach to minimize these confounds with escalating variable-ratio schedules of reinforcement.

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Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement

Cited by 63 publications

References 52 publications

Females pay a higher price for addiction

Females pay a higher price for addiction

A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies

An optimized procedure for robust volitional drug intake in mice

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