== Mean (SEM) scores of Fos immunoreactive cells in eight brain regions of male (left panels) and female (right panels) rats given 14 days of chronic cocaine or chronic saline following long maternal separations, brief maternal separations, or animal facility rearing. doses of cocaine Monoammoniumglycyrrhizinate did not differ among rearing conditions, but the training dose cue lasted longer in LMS. Distinct generalization and ED50profiles were found between male rearing conditions for all dopamine compounds. While BMS females had higher cocaine ED50estimates, no other differences were found in females. LMS males and females, as well as AFR females, had significant increases in Fos expression after cocaine in a region-specific manner. No differences were found with other rearing groups. == Conclusion == Early environmental variables altered the stimulus effects (in a sex-dependent manner) as well as the neuronal responsiveness to cocaine, which may be mediated by the dopamine system. Keywords:Maternal separation, Discriminative-stimulus effects, Drug discrimination learning, Cocaine, Dopamine generalization, Time course, Immediate-early gene c-Fos Subjective effects are considered important Monoammoniumglycyrrhizinate in drug acceptability and the likelihood of continued drug use. Drug discrimination (DD) studies have been useful as a preclinical model for studying the subjective effects of a number of psychoactive compounds from various drug classes. As a pharmacological tool, DD has demonstrated remarkable specificity for receptor mechanisms on which the training drug is thought to work, allowing for pharmacological characterization of the neurotransmitter system(s) involved in its discriminable effects (seeAtor and Griffiths 2003;Solinas et al. 2006). DD may also be useful as an in vivo approach to studying molecular alterations in response to environmental events and how they relate to the interoceptive cue of a pharmacological challenge such as a training drug (seeColpaert 1999). Thus, just as generalization studies with selective compounds can be used to determine the subjective effects profile of a training drug, we may be able to use this same principle to assess mechanisms responsible for alterations in the discriminative cue due to environmental challenges. A characterization of this kind may be important for determining a Monoammoniumglycyrrhizinate specific receptors role in populations that display behaviors that are characteristic of addiction or other psychopathologies. Early life stress models such as maternal separation (MS) have been developed in an attempt to model early adverse events in humans (e.g., abuse, neglect, etc) that have been associated with increased vulnerability to addiction (seeDube et al. 2003;Felitti et al. 1998;Teicher et al. 2006). Our initial investigation (experiment 1, described in this report) attempted to characterize responses to cocaine using a DD procedure in animals with varying degrees of MS, e.g., animal-facility-reared (AFR), brief maternal separation (BMS), and long maternal separation (LMS), during early preweaning. Given the importance of dopamine (DA) in the cocaine discriminative stimulus (seeMcKenna and Ho 1980;Barrett and Appel 1989;Terry et al. 1994;Katz et al. 2000), we reasoned Monoammoniumglycyrrhizinate that previously reported differences in DAergic functioning following differential rearing conditions (rats with extended separation periods show hyperdopaminergic presynaptic responses;Hall et al. 1999; see alsoMoffett et al. 2006b) would result in differences in the acquisition of the discrimination, with a more rapid acquisition in LMS and AFR rats (compared to BMS), as well as a leftward shift in the doseresponse curve for cocaine indicative of greater sensitivity to the drug. Also, to test the relative roles of dopamine receptor subtypes in the cocaine training condition, a dopamine transporter inhibitor and a D1- and a D2-like agonist were tested for generalization (or substitution) to the cocaine cue. If the reported differences in receptor binding and expression (LMS have lower DAT, D1, and D3receptor densities, compared to BMS; seeBrake et al. 2004;Meaney et al. 2002;Ploj et al. 2003) have a functional consequence in behavior elicited by cocaine, we may expect different relative roles of these subtypes in cocaine-like responses. Cue sensitivity was then further tested with a pretreatment manipulation to compare the onset and duration of cocaines stimulus effects in animals with different MS histories. In experiment 2, cocaine-induced neuronal activation IFI30 using the protein c-Fos in animals subjected to BMS, AFR, and LMS was measured in brain areas associated with the reinforcing, motor stimulating, and discriminative effects of psychostimulants (seeWise 1998;Zeng et al. 2004) to assess if any differences found in sensitivity to the discriminative cue of cocaine would be associated with differential Fos activation. == Materials and methods == == Subjects == A total of 36 SpragueDawley rats (n=6/rearing condition/sex) served as subjects in experiment 1 (drug discrimination), and 42 rats (n=67/rearing condition/sex) served in experiment 2 (cocaine-induced Fos expression). All experimental subjects were derived from 21 primiparous females purchased from Harlan SpragueDawley (Indianapolis, IN, USA). Monoammoniumglycyrrhizinate All experimental manipulations took place between 1300 hours and 1600 hours in the light.