Assessment of multiple salivary biomarkers during repetitive transcranial magnetic stimulation (rTMS) treatment for major depression.

Steroid hormones may serve as potential biomarkers of treatment response for major depressive disorder (MDD). Here, we assessed salivary levels of cortisol, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S), as well as α-amylase activity, across 30 sessions of bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in MDD patients. While rTMS significantly improved symptoms as measured by three different symptom scales, salivary biomarker levels and their ratios showed no significant changes across sessions. These results do not support the routine clinical use of these biomarkers as reliable indicators of treatment outcome during rTMS administration for MDD.

Neural Substrates and Circuits of Drug Addiction.

Drug addiction is a chronic relapsing disorder, and a significant amount of research has been devoted to understand the factors that contribute to the development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide an overview of various theories of addiction to drugs of abuse and the neurobiology involved in elements of the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the role of the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the contribution of these pathways and associated circuits to conditioned responses, drug craving, and loss of behavioral control that may underlie drug relapse. By enhancing the understanding of the neurobiological factors that mediate drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals.

Oxytocin Reduces Cocaine Cued Fos Activation in a Regionally Specific Manner.

Background: Oxytocin may be a possible treatment for multiple neuropsychiatric disorders, including cocaine addiction. Little is known about the site-specific effects of oxytocin on various drug addiction-related brain regions. Furthermore, sexually dimorphic effects of oxytocin on neural function in the addiction circuit have not been established. Here, we studied Fos expression following cocaine-cued reinstatement in both male and female rats. Methods: Male and female rats underwent self-administration, extinction, and reinstatement tests. On test days, rats were given oxytocin or vehicle, and lever pressing was measured in response to conditioned cocaine cues. Rats were perfused and Fos staining measured in the central amygdala, medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Fos/oxytocin double labeling occurred in the paraventricular nucleus of the hypothalamus. Results: Rats reinstated to cocaine cues relative to extinction responding and oxytocin reduced cocaine seeking. Oxytocin combined with contingent cue presentations increased Fos+ oxytocin cell bodies within the paraventricular nucleus of the hypothalamus relative to vehicle. Fos expression robustly increased in the central amygdala following oxytocin administration. Oxytocin reversed cue-induced Fos expression in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus. Central oxytocin infusion also attenuated reinstated cocaine seeking. Conclusions: Oxytocin decreased reinstated cocaine seeking, increased Fos activation in the paraventricular nucleus of the hypothalamus and central amygdala, but normalized cue-induced Fos activation in the medial prefrontal cortex, nucleus accumbens core, and subthalamic nucleus, thereby demonstrating regionally specific activation patterns. No sex differences were seen for the effects of oxytocin on cocaine seeking and Fos activation, indicating that oxytocin acts on similar central neural circuits critical to reinstated cocaine seeking in both males and females.

Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand.

BACKGROUND: Evidence indicates that oxytocin, an endogenous peptide well known for its role in social behaviors, childbirth, and lactation, is a promising addiction pharmacotherapy. We employed a within-session behavioral-economic (BE) procedure in rats to examine oxytocin as a pharmacotherapy for methamphetamine (meth) addiction. The BE paradigm was modeled after BE procedures used to assess motivation for drugs in humans with addiction. The same BE variables assessed across species have been shown to predict later relapse behavior. Thus, the translational potential of preclinical BE studies is particularly strong. METHODS: We tested the effects of systemic and microinfused oxytocin on demand for self-administered intravenous meth and reinstatement of extinguished meth seeking in male and female rats using a BE paradigm. Correlations between meth demand and meth seeking were assessed. RESULTS: Female rats showed greater demand (i.e., motivation) for meth compared with male rats. In both male and female rats, meth demand predicted reinstatement of meth seeking, and systemic oxytocin decreased demand for meth and attenuated reinstatement to meth seeking. Oxytocin was most effective at decreasing meth demand and seeking in rats with the strongest motivation for drug. Finally, these effects of systemic oxytocin were mediated by actions in the nucleus accumbens. CONCLUSIONS: Oxytocin decreases meth demand and seeking in both sexes, and these effects depend on oxytocin signaling in the nucleus accumbens. Overall, these data indicate that development of oxytocin-based therapies may be a promising treatment approach for meth addiction in humans.

Chronic methamphetamine self-administration disrupts cortical control of cognition.

Methamphetamine (meth) is one of the most abused substances worldwide. Chronic use has been associated with repeated relapse episodes that may be exacerbated by cognitive impairments during drug abstinence. Growing evidence demonstrates that meth compromises prefrontal cortex activity, resulting in persisting attentional and memory impairments. After summarizing recent studies of meth-induced cognitive dysfunction using a translationally relevant model of self-administered meth, this review emphasizes the cortical brain changes contributing to cognitive dysregulation during abstinence. Finally, we propose the use of cognitive enhancers during abstinence that may promote a drug-free state by reversing cortical dysfunction linked with prolonged meth abuse.

Regional Brain Activity in Abstinent Methamphetamine Dependent Males Following Cue Exposure.

BACKGROUND: Neuroimaging of drug-associated cue presentations has aided in understanding the neurobiological substrates of craving and relapse for cocaine, alcohol, and nicotine. However, imaging of cue-reactivity in methamphetamine addiction has been much less studied. METHOD: Nine caucasian male methamphetamine-dependent subjects and nine healthy controls were scanned in a Phillips 3.0T MRI scan when they viewed a randomized presentation of visual cues of methamphetamine, neutral objects, and rest conditions. Functional Imaging data were analyzed with Statistical Parametric Mapping software 5 (SPM 5). RESULTS: Methamphetamine subjects had significant brain activation in the ventral striatum and medial frontal cortex in comparison to meth pictures and neutral pictures in healthy controls (p<0.005, threshold 15 voxels). Interestingly the ventral striatum activation significantly correlated with the days since the last use of meth (r=-0.76, p=0.017). No significant activity was found in healthy control group. CONCLUSION: The preliminary data suggest that methamphetamine dependent subjects, when exposed to methamphetamine-associated visual cues, have increased brain activity in ventral striatum, caudate nucleus and medial frontal cortex which subserve craving, drug-seeking, and drug use.

Cocaine and methamphetamine induce opposing changes in BOLD signal response in rats.

BACKGROUND: Neuroimaging studies in psychostimulant addicts have reported functional neural activity changes in brain regions involved in relapse. However, the difference between the effects of the psychostimulants methamphetamine and cocaine on neuronal activity in a similar setting not been clarified. Since studies in humans are limited by the inability to study the initial impact of psychostimulant drugs, we addressed this issue in a rat model. OBJECTIVE: Here, we report methamphetamine and cocaine-induced blood-oxygen-level dependent (BOLD) signal change using functional magnetic resonance imaging (fMRI) in rats receiving drug for the first time during the imaging session. METHODS: Twenty-three male Long Evans rats underwent fMRI imaging and received an intravenous infusion of methamphetamine, cocaine, or saline. Anatomical and pharmacological fMRI (pfMRI) were performed on a 7T BioSpec dedicated research MR scanner under isoflurane gas (1.5-2%). After collecting baseline data for 10min, rats received drug over the next 10min for a total 40min scan time. Data were then preprocessed and statistically analyzed in anatomically defined regions of interest (ROIs) that have been implicated in persistent drug seeking and relapse. RESULTS: Methamphetamine during the imaging session resulted in a sustained negative BOLD signal change in key regions of the relapse circuit, except for the prefrontal cortex. In contrast, cocaine evoked a positive or unchanged BOLD signal in these same regions. In all of the investigated ROIs, there were no changes in BOLD signal following saline. CONCLUSION: Acute methamphetamine and cocaine have distinct patterns of functional activity as measured by pfMRI.

Chronic methamphetamine self-administration alters cognitive flexibility in male rats.

RATIONALE: Methamphetamine (meth) addiction is a chronically relapsing disorder that often produces persistent cognitive deficits. These include decreased cognitive flexibility, which may prevent meth addicts from altering their habitual drug abuse and leave them more susceptible to relapse. Multiple factors including low rates of compliance with research study participation and varied drug use patterns make the relationship between cognitive flexibility and relapse difficult to establish in clinical populations. OBJECTIVES: Here, we combined an extended-access meth self-administration paradigm with an automated set-shifting task in rats to directly compare cognitive flexibility performance with meth-seeking behavior. METHODS: Rats were pre-trained on an automated visual discrimination task, followed by 14 days of extended access (6 h/day) of meth or sucrose self-administration. They were then tested in the set-shifting task on strategy shift and reversal and subsequently assessed for cue-induced reinstatement of meth seeking. RESULTS: Rats with a history of meth, but not sucrose, self-administration had selective deficits in reversal learning. Specifically, meth rats had an increase in the total number of errors and perseverative errors (corresponding to the old stimulus-reward association) following the reversal shift, which correlated with prior stable meth self-administration. However, no relationship was seen between errors during the reversal and cue-induced reinstatement. CONCLUSION: The lack of association between meth-induced reversal deficits and cue-induced reinstatement to meth seeking indicates that these two domains may constitute independent pathologies of meth addiction.

Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats.

Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females.

Failure to Recognize Novelty after Extended Methamphetamine Self-Administration Results from Loss of Long-Term Depression in the Perirhinal Cortex.

Exposure to methamphetamine (meth) can produce lasting memory impairments in humans and rodents. We recently demonstrated that extended access meth self-administration results in novel object recognition (NOR) memory deficits in rats. Recognition of novelty depends upon intact perirhinal (pRh) cortex function, which is compromised by meth-induced downregulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors. NMDA receptors containing this subunit have a critical role in pRh long-term depression (LTD), one of the primary physiological processes thought to underlie object recognition memory. We hypothesized that meth-induced downregulation of GluN2B receptors would compromise pRh LTD, leading to loss of NOR memory. We found that meth self-administration resulted in an inability to induce pRh LTD following 1 Hz stimulation, an effect that was reversed with bath application of the NMDA receptor partial agonist D-cycloserine (DCS). In addition, pRh microinfusion of DCS restored meth-induced memory deficits. Furthermore, blockade of GluN2B-containing NMDA receptors with Ro 25-6981 prevented DCS restoration of pRh LTD in meth subjects. Thus, targeting pRh LTD may be a promising strategy to treat meth-induced cognitive impairment.

Oxytocin differentially affects sucrose taking and seeking in male and female rats.

Oxytocin has a modulatory role in natural and drug reward processes. While the role of oxytocin in pair bonding and reproduction has been extensively studied, sex differences in conditioned and unconditioned behavioral responses to oxytocin treatment have not been fully characterized. Here, we determined whether male and female rats would show similar dose response curves in response to acute oxytocin on measures of locomotor activity, sucrose seeking, and sucrose intake. Male and freely cycling female rats received vehicle or oxytocin (0.1, 0.3, 1, 3mg/kg, IP) injections before behavioral tests designed to assess general motor activity, as well as sucrose self-administration and seeking. Lower doses of oxytocin decreased motor activity in a novel environment in females relative to males. Likewise, lower doses of oxytocin in females decreased responding for sucrose during maintenance of sucrose self-administration and reinstatement to sucrose-conditioned cues. However, sucrose seeking in response to a sucrose prime was only decreased by the highest oxytocin dose in both sexes. In general, oxytocin had similar effects in both sexes. However, females were more sensitive to lower doses of oxytocin than males. These findings are consistent with the notion that oxytocin regulates many of the same behaviors in males and females, but that the effects are typically more profound in females. Therapeutic use of oxytocin should include sex as a factor in determining dose regimens.

Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function.

BACKGROUND: Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. METHODS: In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. RESULTS: Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner. CONCLUSIONS: These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions.

Assessment of a proposed "three-criteria" cocaine addiction model for use in reinstatement studies with rats.

RATIONALE: Relapse is a primary obstacle in the treatment of addiction disorders, and as such, understanding this phenomenon is a major effort of clinical and preclinical studies of cocaine addiction. OBJECTIVE: A recently developed protocol uses laboratory rats to model cocaine addiction by examining three criteria of addiction-like behaviors (persistent seeking in the absence of drug, high motivation for drug, and resistance to punishment during drug seeking) to detect subjects that possess an addiction phenotype. We closely followed this protocol in order to detect rats possessing this addiction phenotype, with the goal of utilizing this model in future studies investigating potential therapies for relapse in human cocaine addicts. RESULTS: The majority of the rats used in this study exhibited multiple characteristics thought to be associated with addiction-like behavior in rats, including robust reinstatement to multiple stimuli and high motivation to obtain cocaine. However, no rats displayed the complete addiction phenotype as previously described, due to a complete lack of addiction-like behavior in all subjects on two of the three addiction criteria (drug seeking in the absence of drug and resistance to punishment). CONCLUSIONS: Our data highlight the independence of behavioral aspects of a rat addiction-like phenotype and suggest that some of these behavioral criteria may be altogether absent in some rat populations. Furthermore, our results suggest a closer review and analysis of some parameters used in this protocol and its global utility.

Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate N-methyl-D-aspartate receptor expression.

BACKGROUND: Chronic methamphetamine (meth) abuse in humans can lead to various cognitive deficits, including memory loss. We previously showed that chronic meth self-administration impairs memory for objects relative to their location and surrounding objects. Here, we demonstrate that the cognitive enhancer, modafinil, reversed this cognitive impairment independent of glutamate N-methyl-d-aspartate (GluN) receptor expression METHODS: Male, Long-Evans rats underwent a noncontingent (Experiment 1) or contingent (Experiment 2) meth regimen. After one week of abstinence, rats were tested for object-in-place recognition memory. Half the rats received either vehicle or modafinil (100mg/kg) immediately after object familiarization. Rats (Experiment 2) were sacrificed immediately after the test and brain areas that comprise the key circuitry for object in place performance were manually dissected. Subsequently, glutamate receptor expression was measured from a crude membrane fraction using Western blot procedures. RESULTS: Saline-treated rats spent more time interacting with the objects in changed locations, while meth-treated rats distributed their time equally among all objects. Meth-treated rats that received modafinil showed a reversal in the deficit, whereby they spent more time exploring the objects in the new locations. GluN2B receptor subtype was decreased in the perirhinal cortex, yet remained unaffected in the prefrontal cortex and hippocampus of meth rats. This meth-induced down regulation occurred whether or not meth experienced rats received vehicle or modafinil. CONCLUSIONS: These data support the use of modafinil for memory impairment in meth addiction. Further studies are needed to elucidate the neural mechanisms of modafinil reversal of cognitive impairments.

Fos expression induced by cocaine-conditioned cues in male and female rats.

Previous studies have shown that female rats exhibit different patterns of drug seeking during multiple phases of cocaine addiction when compared with males. However, the underlying mechanisms for these sex differences remain largely unknown. Here, we used a cocaine self-administration/reinstatement model to examine neuronal activation, as determined by Fos expression, following cue-induced reinstatement of cocaine seeking in male and female rats. Fos expression revealed both similarities between sexes in some brain regions, as well as selective sexually dimorphic patterns. As compared to no cue control subjects, conditioned cues induced higher Fos expression in the Cg1 region of the anterior cingulate cortex, but lower expression in the nucleus accumbens in both males and females. Females exhibited higher Fos expression than males in multiple brain regions, including the agranular insular cortex, dorsal medial caudate-putamen, nucleus accumbens shell, ventral tegmental area, dorsal subiculum, and ventral CA1 and CA3 regions of the hippocampus. Notably, only Fos expression in the prelimbic cortex, nucleus accumbens shell, basolateral amygdala, and ventral subiculum correlated positively with lever responding in response to conditioned cues across males and females. These findings indicate that while sexually dimorphic Fos activation does occur, the relationship between cue-induced cocaine seeking and neuronal activation may be similar for males and females in key brain regions of the relapse circuit.

Dysregulation of dopamine and glutamate release in the prefrontal cortex and nucleus accumbens following methamphetamine self-administration and during reinstatement in rats.

Methamphetamine (meth) addicts often exhibit enduring cognitive and neural deficits that likely contribute to persistent drug seeking and the high rates of relapse. These deficits may be related to changes in the prefrontal cortex (PFC) and its glutamatergic projections to the nucleus accumbens (NAc). Here, we performed in vivo microdialysis in the PFC and NAc in rats following either meth self-administration or yoked-saline control histories to assess baseline glutamate (GLU) levels, or reinstatement-evoked GLU and dopamine (DA) efflux in both regions simultaneously under cue-induced, meth-primed, or combined cues+meth reinstatement conditions. Our results show that meth self-administration (1) reduced basal GLU levels in both the dmPFC and NAc, (2) concurrently increased dmPFC and NAc GLU efflux during reinstatement, and (3) increased DA efflux in the dmPFC, but not in the NAc, under all reinstatement conditions when compared with yoked-saline controls. These data demonstrate for the first time that a history of psychostimulant self-administration alters GLU homeostasis not only in the NAc, but also in the dmPFC, its primary GLU projection source. Furthermore, combined cues+meth-primed reinstatement conditions produced the most pronounced increases in mPFC and NAc extracellular GLU, suggesting that the cue and meth prime conditions are additive in promoting reinstatement. Finally, increased efflux of DA in the dmPFC, but not in the NAc, across reinstatement conditions suggests that DA release in the dmPFC may be an important mediator of drug seeking initiated by multiple relapse triggers.

Low frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex transiently increases cue-induced craving for methamphetamine: a preliminary study.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) can temporarily interrupt or facilitate activity in a focal brain region. Several lines of evidence suggest that rTMS of the dorsolateral prefrontal cortex (DLPFC) can affect processes involved in drug addiction. We hypothesized that a single session of low-frequency rTMS of the left DLPFC would modulate cue-induced craving for methamphetamine (MA) when compared to a sham rTMS session. METHODS: In this single-blind, sham-controlled crossover study, 10 non-treatment seeking MA-dependent users and 8 healthy controls were randomized to receive 15 min of sham and real (1 Hz) DLPFC rTMS in two experimental sessions separated by 1h. During each rTMS session, participants were exposed to blocks of neutral cues and MA-associated cues. Participants rated their craving after each cue block. RESULTS: In MA users, real rTMS over the left DLPFC increased self-reported craving as compared to sham stimulation (17.86 ± 1.46 vs. 24.85 ± 1.57, p=0.001). rTMS had no effect on craving in healthy controls. One Hertz rTMS of the left DLPFC was safe and tolerable for all participants. CONCLUSIONS: Low frequency rTMS of the left DLPFC transiently increased cue-induced craving in MA participants. These preliminary results suggest that 1 Hz rTMS of the left DLPFC may increase craving by inhibiting the prefrontal cortex or indirectly activating subcortical regions involved in craving.

Inactivation of the lateral habenula reduces anxiogenic behavior and cocaine seeking under conditions of heightened stress.

Recent anatomical and functional studies have renewed interest in the lateral habenula (LHb), a critical brain region that works in an opponent manner to modulate aversive and appetitive processes. In particular, increased LHb activation is believed to drive anxiogenic states during stressful conditions. Here, we reversibly inactivated the LHb with GABA receptor agonists (baclofen/muscimol) in rats prior to testing in an open field, elevated plus maze, and defensive burying task in the presence or absence of yohimbine, a noradrenergic α2-receptor antagonist that acts as an anxiogenic stressor. In a second set of experiments using a cocaine self-administration and reinstatement model, we inactivated the LHb during extinction responding and cue-induced reinstatement of cocaine seeking in the presence or absence of yohimbine pretreatment. Inactivation of the LHb after yohimbine treatment attenuated anxiogenic behavior by increasing time spent in the open arms and reducing the time spent burying. Inactivation of the LHb also reduced cocaine seeking when cue-induced reinstatement occurred in the presence of yohimbine, but did not affect extinction responding or cue-induced reinstatement by itself. These data demonstrate that the LHb critically regulates states of heightened anxiety during both unconditioned behavior and conditioned appetitive processes.

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats.

RATIONALE: Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success. OBJECTIVES: The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration. METHODS: Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction. RESULTS: Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test. CONCLUSION: Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.

Sex differences in methamphetamine seeking in rats: impact of oxytocin.

Previous evidence in an animal model of drug self-administration and drug seeking showed that acute oxytocin decreased methamphetamine (meth) seeking in male rats, suggesting potential clinical efficacy for the treatment of psychostimulant addiction. However, based on the well-established role of oxytocin in reproduction and pair bond formation, it is important to know how this effect extrapolates to females. Here, we tested whether oxytocin (1mg/kg, IP) would decrease meth seeking in female rats across various stages of the estrous cycle (Experiment 1). Freely cycling Long Evans female rats self-administered meth (IV) in 2-h daily sessions, followed by daily extinction sessions. Following extinction, rats received oxytocin (0, 0.3, or 1mg/kg, IP) 30min before a meth priming injection (1mg/kg, IP) to assess reinstatement of meth seeking. Next, we examined the effects of oxytocin on motivated meth- and sucrose-taking and seeking in male and female rats. In separate experiments, males and females self-administered meth (Experiment 2) or sucrose (Experiment 3) until responding was stabilized along a fixed ratio (FR) 5 schedule of reinforcement. Subsequently, rats received either oxytocin or vehicle prior to self-administration along a progressive ratio (PR) schedule of reinforcement. Rats were subsequently tested for cue-, meth-, and stress-induced reinstatement after pretreatment with oxytocin or vehicle. While oxytocin reduced meth seeking in females, we found that estrous cycle stage (as determined from vaginal cytology) did not influence meth-primed reinstatement or the ability of oxytocin to decrease reinstatement of meth seeking. Oxytocin reduced PR responding for meth only in females. Females responded more than males during cue-induced reinstatement of meth and sucrose seeking, and oxytocin reduced this responding only in meth females. In both sexes, oxytocin attenuated meth seeking in response to a meth prime and yohimbine (a pharmacological stressor). The results suggest that oxytocin may have efficacy as a treatment of meth addiction in both sexes; however, females may show greater response to oxytocin treatment for the prevention of relapse.