Goal-directed learning is multidimensional and accompanied by diverse and widespread changes in neocortical signaling.

New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naïve to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus-response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca2+ imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of response-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.

Drug discrimination learning: Interoceptive stimulus control of behavior and its implications for regulated and dysregulated drug intake.

Drug discrimination research has generated rich evidence for the capacity of interoceptive drug stimuli to control behavior by serving as discriminative cues. Owing to its neuropharmacological specificity, drug discrimination learning has been widely used to characterize the stimulus effects and neuropharmacological underpinning of drugs. Apart from such utility, discriminative drug stimuli may help regulate drug use by disambiguating conditioned associations and post-intake outcomes. First, this review summarizes the evidence supporting interoceptive regulation of drug intake from the literature of exteroceptive discriminative control of drug-related behavior, effects of drug priming, and self-titration of drug intake. Second, an overview of interoceptive control of reward-seeking and the animal model of discriminated goal-tracking is provided to illustrate interoceptive stimulus control of the initiation and patterning of drug intake. Third, we highlight the importance of interoceptive control of aversion-avoidance in the termination of drug-use episodes and describe the animal model of discriminated taste avoidance that supports such a position. In bridging these discriminative functions of drug stimuli, we propose that interoceptive drug stimuli help regulate intake by disambiguating whether intake will be rewarding, nonrewarding, or aversive. The reflection and discussion on current theoretical formulations of interoceptive control of drug intake may further scientific advances to improve animal models to study the mechanisms by which interoceptive stimuli regulate drug intake, as well as how alterations of interoceptive processes may contribute to the transition to dysregulated drug use.

The Impact of Trained Conditions on the Generalization of Learning Gains Following Voice Discrimination Training.

Auditory training can lead to notable enhancements in specific tasks, but whether these improvements generalize to untrained tasks like speech-in-noise (SIN) recognition remains uncertain. This study examined how training conditions affect generalization. Fifty-five young adults were divided into "Trained-in-Quiet" (n = 15), "Trained-in-Noise" (n = 20), and "Control" (n = 20) groups. Participants completed two sessions. The first session involved an assessment of SIN recognition and voice discrimination (VD) with word or sentence stimuli, employing combined fundamental frequency (F0) + formant frequencies voice cues. Subsequently, only the trained groups proceeded to an interleaved training phase, encompassing six VD blocks with sentence stimuli, utilizing either F0-only or formant-only cues. The second session replicated the interleaved training for the trained groups, followed by a second assessment conducted by all three groups, identical to the first session. Results showed significant improvements in the trained task regardless of training conditions. However, VD training with a single cue did not enhance VD with both cues beyond control group improvements, suggesting limited generalization. Notably, the Trained-in-Noise group exhibited the most significant SIN recognition improvements posttraining, implying generalization across tasks that share similar acoustic conditions. Overall, findings suggest training conditions impact generalization by influencing processing levels associated with the trained task. Training in noisy conditions may prompt higher auditory and/or cognitive processing than training in quiet, potentially extending skills to tasks involving challenging listening conditions, such as SIN recognition. These insights hold significant theoretical and clinical implications, potentially advancing the development of effective auditory training protocols.

Cognitive performance of grey mouse lemurs (Microcebus murinus) during a discrimination learning task: Effect of the emotional valence of stimuli.

Emotions are omnipresent in many animals' lives. It is a complex concept that encompasses physiological, subjective, behavioural and cognitive aspects. While the complex relationship between emotion and cognition has been well studied in humans and in some nonhuman primates, it remains rather unexplored for other nonhuman primate species, such as lemurs. In our study, we evaluated the performance of N = 48 grey mouse lemurs (Microcebus murinus) in a discrimination learning task using visual emotional stimuli. We tested whether the type of visual stimulus (positive, negative or neutral) influenced the cognitive performance of mouse lemurs. Individuals had to learn to discriminate between two platforms according to the associated visual stimuli and to jump to the target platform (leading to a reward). Our main finding was that emotional stimuli, whether positive or negative in valence, impaired cognitive performance when used as a target. Specifically, the lowest success rate occurred when the target was associated with the emotional stimuli, and the highest success rate occurred when it was associated with neutral stimuli. Our results show a similar pattern to that found in other primate species and support the adaptive role of emotion. Our results also support that individual differences could be a factor impacting the relation between emotion and cognition. This study is the first to explore how emotions interfere with the cognitive abilities of a lemur species and highlights the importance of acknowledging emotion in mouse lemurs as well as studying the emotion-cognition interaction in a wider range of primate species.

Amygdala and Cortex Relationships during Learning of a Sensory Discrimination Task.

During learning of a sensory discrimination task, the cortical and subcortical regions display complex spatiotemporal dynamics. During learning, both the amygdala and cortex link stimulus information to its appropriate association, for example, a reward. In addition, both structures are also related to nonsensory parameters such as body movements and licking during the reward period. However, the emergence of the cortico-amygdala relationships during learning is largely unknown. To study this, we combined wide-field cortical imaging with fiber photometry to simultaneously record cortico-amygdala population dynamics as male mice learn a whisker-dependent go/no-go task. We were able to simultaneously record neuronal populations from the posterior cortex and either the basolateral amygdala (BLA) or central/medial amygdala (CEM). Prior to learning, the somatosensory and associative cortex responded during sensation, while amygdala areas did not show significant responses. As mice became experts, amygdala responses emerged early during the sensation period, increasing in the CEM, while decreasing in the BLA. Interestingly, amygdala and cortical responses were associated with task-related body movement, displaying significant responses ∼200 ms before movement initiation which led to licking for the reward. A correlation analysis between the cortex and amygdala revealed negative and positive correlation with the BLA and CEM, respectively, only in the expert case. These results imply that learning induces an involvement of the cortex and amygdala which may aid to link sensory stimuli with appropriate associations.

Increased Generalization, Stronger Acquisition, or Reduced Extinction? Investigation of the Mechanisms Underlying the Acquisition-in-Multiple-Contexts Effect.

Prior research has demonstrated that conducting acquisition in multiple contexts results in more responding to the point that it can even nullify the benefit of subsequent extinction in multiple contexts on reducing renewal of excitatory responding. The underlying mechanism to explain why this happens has not been systematically examined. Using self-reported expectancy of the outcome, the current study investigates three mechanisms that potentially explain why acquisition in multiple contexts results in more responding-greater generalization, stronger acquisition learning, or slower extinction learning. Participants (N = 180) received discriminative training with a conditioned stimulus (CS+) and outcome pairing and a CS- → noOutcome pairing in either one or three contexts. This was followed by either extinction treatment in a novel context or no extinction. Finally, testing occurred in the acquisition context, the extinction context, or a novel context. Stronger renewal of extinguished conditioned expectation was observed for participants who received CS+ → Outcome pairings in three contexts relative to one context. There was no effect of the number of contexts on the strength of the excitatory CS+ → Outcome association or degree of inhibitory learning that occurred during extinction. This suggests that generalization is the mechanism responsible for the adverse impact to extinction learning when acquisition is conducted in multiple contexts.

This or not that: select and reject control of relational responding in rats using a blank comparison procedure with odor stimuli.

The blank comparison (BLC) task was developed to assess stimulus relations in discrimination learning; that is, are subjects learning to "select" the correct stimulus (S+) or "reject" the incorrect stimulus (S-) or both? This task has been used to study exclusion learning, mostly in humans and monkeys, and the present study extends the procedure to rats. The BLC task uses an ambiguous stimulus (BLC+/-) that replaces S+ (in the presence of S-) and replaces S- (in the presence of S+). In the current experiment, four rats were trained to remove session-novel scented lids from sand-filled cups in a two-choice, simultaneous presentation procedure called the Odor Span Task (OST) before being trained on the BLC procedure using odors as the discriminative stimuli. The BLC training procedure utilized simple discrimination training (S+ and S-) and added select (S+ and BLC-) and reject (BLC+ and S-) trial types. All rats demonstrated accurate performance in sessions with both select and reject type trials. Next, BLC probe trials were interspersed in standard OST sessions to assess the form of stimulus control in the OST. Rats performed accurately on select type probe trials (similar to baseline OST performance) and also showed above chance accuracy on reject type trials. Thus, we demonstrated that rats could acquire an odor-based version of the BLC task and that both select and exclusion-based (reject) relations were active in the OST. The finding of exclusion in rats under the rigorous BLC task conditions confirms that exclusion-based responding is not limited to humans and non-human primates.

Auditory discrimination learning differentially modulates neural representation in auditory cortex subregions and inter-areal connectivity.

Changes in sound-evoked responses in the auditory cortex (ACtx) occur during learning, but how learning alters neural responses in different ACtx subregions and changes their interactions is unclear. To address these questions, we developed an automated training and widefield imaging system to longitudinally track the neural activity of all mouse ACtx subregions during a tone discrimination task. We find that responses in primary ACtx are highly informative of learned stimuli and behavioral outcomes throughout training. In contrast, representations of behavioral outcomes in the dorsal posterior auditory field, learned stimuli in the dorsal anterior auditory field, and inter-regional correlations between primary and higher-order areas are enhanced with training. Moreover, ACtx response changes vary between stimuli, and such differences display lag synchronization with the learning rate. These results indicate that learning alters functional connections between ACtx subregions, inducing region-specific modulations by propagating behavioral information from primary to higher-order areas.

Sex differences in extinction and reinstatement of nicotine discrimination in rats: The effects of reinforcer devaluation.

Nicotine functions effectively as an interoceptive operant discriminative stimulus (SD) that sets the occasion for voluntarily emitted behavior to be reinforced by biologically relevant outcomes (e.g., food). This has been demonstrated primarily with male rats. Far less is known about nicotine's operant SD functions in female rats. There are no reports of sex differences in extinction and recovery of the SD functions of nicotine, which may elucidate smoking cessation and relapse. In view of this, eight male and eight female rats were trained to nose poke differentially among quasirandomly intermixed sessions of food reinforcement variable interval (VI-30 s) and nonreinforcement in a go/no-go across session one-manipulanda operant drug discrimination procedure. For half the rats, presession administration of nicotine (0.30 mg/kg, subcutaneous) occasioned reinforcement sessions of nose pokes (i.e., SD); for the remaining rats, it occasioned nonreinforcement (SΔ). Saline sessions occasioned the opposite contingencies. Training was conducted first under feeding restriction and then under free feeding, which was then followed by extinction sessions that were also conducted with free feeding. During discrimination training, response rates for females did not differ from males when conducted under restricted feeding but did so during training and later extinction conducted under free feeding. Females also exhibited greater reinstatement of responding under the nicotine SD but not the SΔ. These data provide additional evidence for sex differences in rats with the discriminative stimulus functions of nicotine under low, but not high, food-drive states-and may have implications for sex/gender differences in smoking cessation and relapse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Disrupting dorsal hippocampus impairs category learning in rats.

Categorization requires a balance of mechanisms that can generalize across common features and discriminate against specific details. A growing literature suggests that the hippocampus may accomplish these mechanisms by using fundamental mechanisms like pattern separation, pattern completion, and memory integration. Here, we assessed the role of the rodent dorsal hippocampus (HPC) in category learning by combining inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and simulations using a neural network model. Using touchscreens, we trained rats to categorize distributions of visual stimuli containing black and white gratings that varied along two continuous dimensions. Inactivating the dorsal HPC impaired category learning and generalization, suggesting that the rodent HPC plays an important role during categorization. Hippocampal inactivation had no effect on a control discrimination task that used identical trial procedures as the categorization tasks, suggesting that the impairments were specific to categorization. Model simulations were conducted with variants of a neural network to assess the impact of selective deficits on category learning. The hippocampal inactivation groups were best explained by a model that injected random noise into the computation that compared the similarity between category stimuli and existing memory representations. This model is akin to a deficit in mechanisms of pattern completion, which retrieves similar memory representations using partial information.

AMPA and NMDA receptors in dentate gyrus mediate memory for sucrose in two port discrimination task.

Although the phenomenon of memory formation and recall associated with the use of psychotropic drugs has been extensively studied, mechanisms underlying memories for natural reward have not been clarified. Herein, we test the hypothesis that glutamatergic receptors in the dentate gyrus play a role in memories associated with sucrose. We used pellet self-administration protocol to generate memories in two-port nose-poke discrimination task using male Wistar rats. During non-rewarded probe trial, the conditioned animals readily discriminated the active port versus inactive port and showed massive increase in mRNA expression of AMPA receptor subunit genes (gria2, gria3) as well as c-Fos protein in the DG. Access to sweet pellet further enhanced c-Fos expression in the DG. However, animals pre-treated with AMPA receptor antagonist CNQX (intra-DG), on exposure to operant chamber (no pellet), showed decreased discrimination as well as c-Fos expression. We suggest that AMPA receptors in DG mediate recall and consolidation of memories associated with sucrose consumption. CNQX pre-treated animals, if presented with sweet pellet on nose poke, exhibited high discrimination index coupled with increased c-Fos expression. In these CNQX treated rats, the DI was again decreased following administration of NMDA receptor antagonist AP5. We suggest that, although AMPA receptors are blocked, the access to sweet pellet may induce surge of glutamate in the DG, which in turn may reinstate memories via activation of erstwhile silent synapses in NMDA dependant manner.

Merging meaningful classes and abstract equivalence classes by exclusion.

The current experiment assessed whether relating abstract stimuli with familiar pictures by exclusion would produce the formation of a meaningful equivalence class. Ten participants learned conditional discrimination relations with abstract stimuli and established equivalence classes (ABC classes). They then learned DA (D1A1, D2A2, and D3A3) conditional discriminations with written words as D stimuli; two words (D1 and D2) were meaningful stimuli in the participants verbal community ("Dentist" and "Baker"), whereas the third (D3) was a pseudoword ("Tabilu"). In testing trials, participants evidenced derived relations between pictures related preexperimentally to D1 and D2 with the experimental equivalence classes related to D1 and D2. For some participants, the decontextualized stimuli were a set of boat pictures (Condition 1), whereas for others they were a set of miscellaneous pictures (Condition 2). Participants in both conditions successfully matched decontextualized pictures (unrelated to dentist and baker contexts) to all abstract stimuli in the class related to D3 (exclusion responding). In Condition 1 the meaning reported to the word Tabilu was similar across participants, but in Condition 2 participants showed more variations to answer to the meaning of Tabilu. These results suggest that exclusion learning can occur under different stimulus control topographies.

Color discrimination repetition distorts color representations.

Perceptual learning is the improvement of perceptual performance after repeated practice on a perceptual task. Studies on perceptual learning in color vision are limited. In this study, we measured the impact of color discrimination repetitions at a specific base color on color perception for entire hues. Participants performed five sessions of color discrimination training (200 or 300 trials per session) over five days, at colors on either the negative or positive direction of the L-M color axis, based on group assignment. We administered three color perception assessments (unique hues, color category boundaries, and color appearance) before and after the sessions to evaluate perceptual changes after training. The results showed declines in color discrimination thresholds after training, as expected. Additionally, the training influenced outcomes across all three assessment types. After the training, the perceived color appearance changed near the trained color along the stimulus hue, and some of the unique hues and the color category boundaries moved significantly toward the trained color. These findings indicate that short-term repetitions of color discrimination training can alter color representations in the visual system, distorting color perception around the trained color.

Investigating individual learning behaviour of dogs during a yes/no detection task.

Detection dogs are frequently tested for their ability to detect a variety of targets. It is crucial to comprehend the processes for odour learning and the consequences of training on an expanding set of target scents on performance. To properly evaluate their ability to identify the target, the only true measure is the dogs' initial response to novel sources, since this excludes learning effects. In this study, we evaluated the individual learning processes of three detection dogs that were pre-trained to differentially respond to a faecal sample of a mare in oestrus (S+) and a faecal sample of the same mare in di-oestrus (S-). After reaching criterion during a test with known training samples, the dogs were tested for generalization to a novel source. Average responses to S+ and S- were calculated as a function of presentation sequence, and Signal Detection Theory was used to further analyse characteristic differences in learning. The results of this study suggest that the ability of individual scent detection dogs to learn within an olfactory discrimination test varies considerably. The information obtained in this study could be helpful for mitigation training. We show that through careful monitoring of individual learning processes, the strategy each dog followed becomes apparent: especially the observations on the dogs' responses to first encounters with novel sample sources. This provides us with more detailed information than the more traditional sensitivity and specificity measures and allows us to better predict the dog's capabilities.

Social demonstration of colour preference improves the learning of associated demonstrated actions.

We studied how different types of social demonstration improve house sparrows' (Passer domesticus) success in solving a foraging task that requires both operant learning (opening covers) and discrimination learning (preferring covers of the rewarding colour). We provided learners with either paired demonstration (of both cover opening and colour preference), action-only demonstration (of opening white covers only), or no demonstration (a companion bird eating without covers). We found that sparrows failed to learn the two tasks with no demonstration, and learned them best with a paired demonstration. Interestingly, the action of cover opening was learned faster with paired rather than action-only demonstration despite being equally demonstrated in both. We also found that only with paired demonstration, the speed of operant (action) learning was related to the demonstrator's level of activity. Colour preference (i.e. discrimination learning) was eventually acquired by all sparrows that learned to open covers, even without social demonstration of colour preference. Thus, adding a demonstration of colour preference was actually more important for operant learning, possibly as a result of increasing the similarity between the demonstrated and the learned tasks, thereby increasing the learner's attention to the actions of the demonstrator. Giving more attention to individuals in similar settings may be an adaptive strategy directing social learners to focus on ecologically relevant behaviours and on tasks that are likely to be learned successfully.

Learning enhances representations of taste-guided decisions in the mouse gustatory insular cortex.

Learning to discriminate overlapping gustatory stimuli that predict distinct outcomes-a feat known as discrimination learning-can mean the difference between ingesting a poison or a nutritive meal. Despite the obvious importance of this process, very little is known about the neural basis of taste discrimination learning. In other sensory modalities, this form of learning can be mediated by either the sharpening of sensory representations or the enhanced ability of "decision-making" circuits to interpret sensory information. Given the dual role of the gustatory insular cortex (GC) in encoding both sensory and decision-related variables, this region represents an ideal site for investigating how neural activity changes as animals learn a novel taste discrimination. Here, we present results from experiments relying on two-photon calcium imaging of GC neural activity in mice performing a taste-guided mixture discrimination task. The task allows for the recording of neural activity before and after learning induced by training mice to discriminate increasingly similar pairs of taste mixtures. Single-neuron and population analyses show a time-varying pattern of activity, with early sensory responses emerging after taste delivery and binary, choice-encoding responses emerging later in the delay before a decision is made. Our results demonstrate that, while both sensory and decision-related information is encoded by GC in the context of a taste mixture discrimination task, learning and improved performance are associated with a specific enhancement of decision-related responses.

Discriminative stimulus properties of Cannabis sativa terpenes in rats.

Cannabis is a pharmacologically complex plant consisting of hundreds of potentially active compounds. One class of compounds present in cannabis that has received little attention are terpenes. Traditionally thought to impart aroma and flavor to cannabis, it has become increasingly recognized that terpenes might exert therapeutic effects themselves. Several recent reports have also indicated terpenes might behave as cannabinoid type 1 (CB1) receptor agonists. This study aimed to investigate whether several terpenes present in cannabis produce discriminative stimulus effects similar to or enhance the effects of Δ 9 -tetrahydrocannabinol (THC). Subsequent experiments explored other potential cannabimimetic effects of these terpenes. Rats were trained to discriminate THC from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Substitution testing was performed with the CB receptor agonist JWH-018 and the terpenes linalool, limonene, γ-terpinene and α-humulene alone. Terpenes were also studied in combination with THC. Finally, THC and terpenes were tested in the tetrad assay to screen for CB1-receptor agonist-like effects. THC and JWH-018 dose-dependently produced responding on the THC-paired lever. When administered alone, none of the terpenes produced responding predominantly on the THC-paired lever. When administered in combination with THC, none of the terpenes enhanced the potency of THC, and in the case of α-humulene, decreased the potency of THC to produce responding on the THC-paired lever. While THC produced effects in all four tetrad components, none of the terpenes produced effects in all four components. Therefore, the terpenes examined in this report do not have effects consistent with CB1 receptor agonist properties in the brain.

The generalization-across-dimensions model applied to conditional temporal discrimination.

Can simple choice conditional-discrimination choice be accounted for by recent quantitative models of combined stimulus and reinforcer control? In Experiment 1, two sets of five blackout durations, one using shorter intervals and one using longer intervals, conditionally signaled which subsequent choice response might provide food. In seven conditions, the distribution of blackout durations across the sets was varied. An updated version of the generalization-across-dimensions model nicely described the way that choice changed across durations. In Experiment 2, just two blackout durations acted as the conditional stimuli and the durations were varied over 10 conditions. The parameters of the model obtained in Experiment 1 failed adequately to predict choice in Experiment 2, but the model again fitted the data nicely. The failure to predict the Experiment 2 data from the Experiment 1 parameters occurred because in Experiment 1 differential control by reinforcer locations progressively decreased with blackout durations, whereas in Experiment 2 this control remained constant. These experiments extend the ability of the model to describe data from procedures based on concurrent schedules in which reinforcer ratios reverse at fixed times to those from conditional-discrimination procedures. Further research is needed to understand why control by reinforcer location differed between the two experiments.

Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats.

RATIONALE: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects. OBJECTIVES: Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting. METHODS: Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design. RESULTS: The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated. CONCLUSIONS: Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.

Generalization of a positive-feature interoceptive morphine occasion setter across the rat estrous cycle.

INTRODUCTION: Interoceptive stimuli elicited by drug administration acquire conditioned modulatory properties of the induction of conditioned appetitive behaviours by exteroceptive cues. This effect may be modeled using a drug discrimination task in which the drug stimulus is trained as a positive-feature (FP) occasion setter (OS) that disambiguates the relation between an exteroceptive light conditioned stimulus (CS) and a sucrose unconditioned stimulus (US). We previously reported that females are less sensitive to generalization of a FP morphine OS than males, so we investigated the role of endogenous ovarian hormones in this difference. METHODS: Male and female rats received intermixed injections of 3.2 mg/kg morphine or saline before each daily training session. Training consisted of 8 presentations of the CS, each followed by access to sucrose on morphine, but not saline sessions. Following acquisiton, rats were tested for generalization of the morphine stimulus to 0, 1.0, 3.2, and 5.4 mg/kg morphine. Female rats were monitored for estrous cyclicity using vaginal cytology throughout the study. RESULTS: Both sexes acquired stable drug discrimination. A gradient of generalization was measured across morphine doses and this behaviour did not differ by sex, nor did it differ across the estrous cycle in females. CONCLUSIONS: Morphine generalization is independent of fluctuations in levels of sex and endogenous gonadal hormones in females under these experimental conditions.