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Introduction: There are numerous pharmacologic treatments for opioid use disorder (OUD), but none that directly target the underlying addictive effects of opioids. Oxytocin, a peptide hormone produced in the paraventricular nucleus of the hypothalamus (PVN), has been investigated as a potential therapeutic for OUD. Promising preclinical and clinical results have been reported, but the brain region(s) and mechanism(s) by which oxytocin impacts reward processes remain undetermined. Methods: Here, we assess peripherally administered oxytocin’s impacts on cued reinstatement of heroin seeking following forced abstinence and its effects on neuronal activation in the PVN and key projection regions. We also examine how DREADD-mediated activation or inhibition of oxytocinergic PVN neurons alters cued heroin seeking and social interaction. Results: As predicted, peripheral oxytocin administration successfully decreased cued heroin seeking on days 1 and 30 of abstinence. Oxytocin administration also led to increased neuronal activity within the PVN and the central amygdala (CeA). Activation of oxytocinergic PVN neurons with an excitatory (Gq) DREADD did not impact cued reinstatement or social interaction. In contrast, suppression with an inhibitory (Gi) DREADD reduced heroin seeking on abstinence day 30 and decreased time spent interacting with a novel conspecific. Discussion: These findings reinforce oxytocin’s therapeutic potential for OUD, the basis for which may be driven in part by increased PVN-CeA circuit activity. Our results also suggest that oxytocin has distinct signaling and/or other mechanisms of action to produce these effects, as inhibition, but not activation, of oxytocinergic PVN neurons did not recapitulate the suppression in heroin seeking.

Empathy is an innate ability to understand the emotional states of others along with the motivation to improve it. It has evolved over time into highly complex behaviors, the basis of which can be described using the Perception Action Model (PAM), where shared affect promotes an action that eliminates the distress of both the passive “Target” and, by extension, the active “Observer.” There are myriad biological variables that may modulate empathic behavior, including sex, sensory modalities, and neural activity. In the following studies, using our lab’s model of social contact-independent targeted helping, we first tested whether sex differences exist in helping behavior. Next, we explored sex differences in sensory and affective signaling, including the impact of direct visualization of a distressed conspecific and the type of ultrasonic vocalizations (USV) made between animal pairs during the task. Finally, we examined the neural activity of multiple cortical and subcortical regions of interest across time during targeted helping between males and females. We show both sexes exhibit similar helping behavior, but sensory and affective signaling differs between sexes. Further, changes in neural activity exhibited distinct sex-specific patterns across time. Our results indicate sex differences are not a ubiquitous presence in targeted helping. Instead, it is likely sex differences may be a convergent phenomenon in which the behavior is similar, but the underlying biological mechanisms are distinct. These results lay the groundwork for future studies to explore the similarities and differences that drive empathic behavior in both males and females.

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this review, we discuss our efforts, as well as other's efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra peptide D-Phe-D-Phe-D-Nle-D-Arg-NH

Empathy is a complex phenomenon critical for group survival and societal bonds. In addition, there is mounting evidence demonstrating empathic behaviors are dysregulated in a multitude of psychiatric disorders ranging from Autism Spectrum Disorder (ASD), Substance Use Disorders (SUD), and personality disorders. Therefore, understanding the underlying drive and neurobiology of empathy is paramount for improving the treatment outcomes and quality of life for individuals suffering from these psychiatric disorders. While there is a growing list of human studies, there is still much about empathy to understand, likely due to both its complexity and the inherent limitations of imaging modalities. It is therefore imperative to develop, validate, and utilize rodent models of empathic behaviors as translational tools to explore this complex topic in ways human research cannot. This review outlines some of the more prevailing theories of empathy, lists some of the psychiatric disorders with disrupted empathic processes, describes rat and mouse models of empathic behaviors currently used, and discusses ways in which these models have elucidated social, environmental, and neurobiological factors that may modulate empathy. The research tools afforded to rodent models will provide an increasingly clear translational understanding of empathic processes and consequently result in improvements in care for those diagnosed with any one of many psychiatric disorders.

Empathy, the ability to perceive the affective state of another, is a complex process that is integral to many of the prosocial behaviors expressed in humans and across the animal kingdom. Research into the behavioral and neurobiological underpinnings of empathic behaviors has increased in recent years. Growing evidence suggests changes in empathy may contribute to a myriad of psychiatric illnesses, including substance use disorder (SUD). Indeed, both clinical and preclinical research in SUD demonstrates a strong relationship between drug taking or relapse events and changes to empathic behavior. Further, there is significant overlap in the underlying neural substrates of these complex behaviors, including the insula, paraventricular nucleus of thalamus (PVT), and the paraventricular nucleus of the hypothalamus (PVN). In this review, we will discuss our current understanding of the interplay between empathic behaviors and SUD. We will also examine the underlying neurobiology that may regulate this interaction, focusing specifically on the insula, PVT, and PVN. Finally, we discuss the biologic and therapeutic importance of taking empathic processes into consideration when discussing SUD.

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

Exposure to acute stress can increase vulnerability to develop or express many psychiatric disorders, including post-traumatic stress disorder. We hypothesized that stress-induced psychiatric vulnerability is associated with enduring neuroplasticity in the nucleus accumbens core because stress exposure can alter drug addiction-related behaviors that are associated with accumbens synaptic plasticity. We used a single 2-h stress session and 3 weeks later exposed male and female rats to stress-conditioned odors in a modified defensive burying task, and quantified both active and avoidant coping strategies. We measured corticosterone, dendritic spine and astrocyte morphology in accumbens, and examined reward sensitivity using a sucrose two-bottle choice and operant sucrose self-administration. Exposure to stress odor increased burying (active coping) and immobility (avoidant coping) in the defensive burying task in female and male rats. Systemic corticosterone was transiently increased by both ongoing acute restraint stress and stress-conditioned odors. Three weeks after administering acute restraint stress, we observed increased dendritic spine density and head diameter, and decreased synaptic association with astroglia and the astroglial glutamate transporter, GLT-1. Exposure to conditioned stress further increased head diameter without affecting spine density or astroglial morphology, and this increase by conditioned stress was correlated with burying behavior. Finally, we found that stress-exposed females have a preference for sweet solutions and higher motivation to seek sucrose than stressed male rats. We conclude that acute stress produced enduring plasticity in accumbens postsynapses and associated astroglia. Moreover, conditioned stress odors induced active behavioral coping strategies that were correlated with dendritic spine morphology.

Oxytocin attenuates cocaine-seeking when administered both systemically and directly into the nucleus accumbens core . This effect is blocked by intra-accumbens antagonism of mGlu2/3 and, together with our finding that intra-accumbens oxytocin increases glutamate concentrations in this brain region, indicates that pre-synaptic regulation of glutamate release by oxytocin influences cocaine relapse. However, mGlu2/3 receptors also regulate dopamine release in the nucleus accumbens . Here we aimed to determine whether systemic oxytocin increases glutamate and dopamine concentrations in the nucleus accumbens core of cocaine-experienced and cocaine-naive male and female rats. A subset of rats self-administered cocaine (0.5 mg/kg/infusion) and then underwent extinction training for 2–3 weeks. Rats were implanted with microdialysis probes in the accumbens core and samples were collected for a baseline period, and following saline (1 mL/kg), and oxytocin (1 mg/kg, IP) injections. Locomotion was assessed during microdialysis. In cocaine-experienced rats, oxytocin increased glutamate concentrations in the accumbens core to the same extent in males and females but only increased dopamine concentrations in male rats. Oxytocin did not alter glutamate levels in cocaine-naive rats. Oxytocin did not produce sedation. These results extend previous findings that systemic oxytocin increases nucleus accumbens dopamine in a sex-specific manner in cocaine-experienced rats. These data are the first to find that systemic oxytocin increases nucleus accumbens glutamate after cocaine experience, providing a mechanism of action by which oxytocin attenuates the reinstatement of cocaine seeking in both male and female rats.

Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following 2-hour cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate ‘overflow’ during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glialglutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.

RationaleMethamphetamine (METH) induces changes in the glutamatergic system and elicits cellular alterations in the cortico-accumbens circuit.ObjectiveWhile there is a body of literature on the effects of METH on dopaminergic transmission, there is a gap in knowledge regarding the effects of a high dose of METH on synaptic glutamatergic neurotransmission, specifically in brain regions involved in goal directed behavior (nucleus accumbens core; NAc core) and executive functions (prefrontal cortex;PFC).MethodsIn order to fill that gap we assessed synaptic glutamatergic transmission using a well established METH administration regime (4 × 4 mg/kg ip at 2 hr intervals) followed by 7 days of abstinence. Rats were then sacrificed and whole cell and field recordings were performed in the NAc core and medial PFC.ResultsMETH treatment elicited a significant decrease in paired pulse ratio in NAc core and a significant increase in AMPA/NMDA ratio driven by increases in AMPA currents. On the other hand, there were no significant changes in measures of synaptic glutamate in the PFC.ConclusionThese results suggest that a high dose of METH treatment followed by a period of abstinence elicits significant increases in indices of glutamatergic transmission in the NAc core with no detectable changes in mPFC, denoting that neurons and glutamate terminals in this limbic region have a higher susceptibility to a neurotoxic METH regime.

The neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signalling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signalling to reduce METH self-administration and reinstatement of METH-seeking behaviours. Male and female Sprague-Dawley rats underwent surgery for jugular catheterisation and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue- and METH-induced reinstatement of METH-seeking. Oxytocin treatment robustly attenuated METH intake in both sexes, and SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV decreased the suppressing effects of oxytocin on cue- and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8. Our data suggest that vagus nerve signalling is required for the inhibitory effects of peripherally administered oxytocin on METH self-administration and reinstatement, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has implications for the use of oxytocin as a therapy for METH use disorder for both sexes.

Background Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues. Further, the nucleus accumbens core has strong glutamatergic innervation from numerous regions including the prefrontal cortex. Thus, we hypothesize that oxytocin regulates presynaptic glutamate terminals in the nucleus accumbens core, thereby affecting reinstatement. Methods To begin to evaluate this hypothesis, we examined the effects of intra-nucleus accumbens core oxytocin on extracellular glutamate levels in this region. We next determined if direct infusion of oxytocin into the nucleus accumbens core could attenuate cued reinstatement of cocaine seeking in a manner dependent on metabotropic glutamate 2/3 receptors. Finally, we tested if site-specific application of oxytocin in the prefrontal cortex reduced cued reinstatement of cocaine seeking. Results We found an increase in nucleus accumbens core extracellular glutamate for several minutes following reverse dialysis of oxytocin. In male and female rats with a history of cocaine self-administration, site-specific application of oxytocin in the nucleus accumbens core and prefrontal cortex had opposing effects, decreasing and increasing cued reinstatement, respectively. The mGlu2/3 antagonist LY-341495 reversed oxytocin’s ability to attenuate cued reinstatement. Conclusions While the precise mechanism by which oxytocin increases nucleus accumbens core glutamate is yet to be determined, the present results clearly support oxytocin mediation of glutamate neurotransmission in the nucleus accumbens core that impacts cued cocaine seeking.

Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.

Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin’s effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions. Reinstatement tests consisted of systemic (Experiment 1) or site-specific application of the drugs into the NAcore (Experiments 2 and 3). Before reinstatement sessions, rats received LY341495, an mGluR2/3 antagonist, or its vehicle followed by a second infusion/injection of oxytocin or saline. As expected, both males and females reinstated lever pressing to meth associated cues, and LY341495 alone did not impact this behavior. Oxytocin injected systemically or infused into the NAcore decreased cued meth seeking. Importantly, combined LY341495 and oxytocin administration restored meth cued reinstatement. Interestingly, neither oxytocin nor LY341495 impacted sucrose-cued reinstatement, suggesting distinct mechanisms between meth and sucrose. These findings were consistent between males and females. Overall, we report that oxytocin reduced responding to meth-associated cues and blocking presynaptic mGluR2/3 reversed this effect. Further, oxytocin’s effects were specific to meth cues as NAcore oxytocin was without an effect on sucrose cued reinstatement. Results are discussed in terms of oxytocin receptor localization in the NAcore and modulation of presynaptic regulation of glutamate in response to drug associated cues.

Females are at higher risk for certain opioid addictive behaviors, but the influence of ovarian hormones is unknown. In our rat model of heroin self-administration, females exhibited higher relapse rates that correlated with rates of heroin seeking on the first extinction session. We administered estradiol alone, or in combination with progesterone, 30 min prior to the first extinction session in freely cycling, heroin-seeking female rats. Although neither treatment produced long-term effects on relapse, each treatment regulated distinct aspects of heroin seeking. Estradiol treatment enhanced extinction memory retention, whereas the combination treatment acutely reduced expression of heroin seeking.

RATIONALE: There is a robust relationship between anxiety disorders, including post traumatic stress disorder (PTSD) and substance abuse. In fact, 30–50% of people seeking treatment for substance abuse have a comorbid diagnosis for PTSD. Heroin use is at epic proportions in the United States and is commonly used by people with co-occurring PTSD symptoms and substance use disorder. OBJECTIVES: Here we combined animal assays of acute restraint stress and contingent heroin self-administration (SA) to study co-morbidity between stress disorders and opioid use disorder, and identify shifts in anxiety-like behaviors following stress and/or heroin in response to a stress-conditioned cue. Our objective for this approach was to determine the long-term impact of acute restraint stress and heroin self-administration on stress reactivity and basic reward processes. METHODS: We used 2-h acute restraint stress paired with an odor stimulus to condition a stress cue (CS) for testing of subsequent stress reactivity in a burying task, and reinstatement and extinction to heroin seeking. Rats were also tested for social place preference for measures of social reward and anxiety-like behaviors. RESULTS: Stress rats exhibited multiple levels of disrupted behavior including enhanced acquisition of heroin intake and reinstatement in response to the stress CS, as well as delayed extinction in response to the stress CS. All rats developed a social place preference, but stress rats spent more time in nose-to-nose contact with the unfamiliar rat while heroin rats spent time exploring the chamber. In the burying task, stress shortened latencies to bury the CS, and increased burying and immobility in male and female rats relative to sham counterparts. CONCLUSIONS: Acute restraint stress results in anxiety-like behaviors and a stress associated cue is sufficient to reinstate extinguished heroin seeking. This project has the potential to elucidate the complex relationship between stress/anxiety disorders, including some PTSD-like characteristics, and the onset, maintenance, and relapse to heroin seeking.

Empathy, the capacity for shared emotional valence with others, can allow for cooperativity and social bonding between individuals. However, clinical studies indicate it is dysregulated in neuropsychiatric disorders like autism and addiction, making a translationally relevant model of empathy extremely important. The evolutionary basis of the empathic behaviors observed across numerous species can be described using the Perception Action Model (PAM), in which shared affect can promote an action that eliminates the distress of both the “Target” and, by extension, the “Observer”. Increasing evidence suggests rodents will work to reduce the distress of a conspecific, but current models of helping behavior are unable to completely parse apart whether the reported behavior is driven by empathy or social reward. The current study demonstrates, using a novel behavioral model, rats learn to aid a distressed conspecific in the absence of social reward, retain the task over time, and previous experience increases the rate of task acquisition. Further, our model suggests that empathic behavior is subject to low effort as compared to a social reward. We next validated the specificity of this model to study empathic processes, characterized the importance of both the Target’s level of distress and the impact of the Observer’s familiarity with the Target on empathic behavior. Overall, we believe this model adheres to the PAM of empathy by eliminating the influence of social interaction. Importantly, it can be used to directly evaluate the neurocircuitry of empathy and explore the interplay between blunted empathic behavior and neuropsychiatric disorders.

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this article, we discuss our efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH(2), such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered intravenously (i.v.); however, they are inactive when administered orally. Application of our laboratory’s proprietary nonnatural amino acid technology to CR665 produced derivatives that exhibit peripheral analgesic activity when dosed orally but do not promote CNS-based effects. Lead compound JT09 activates the kappaopioid receptor with EC(50)s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >33,400 fold. Results indicate that JT09 is approximately as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (addiction, sedation, dysphoria, tolerance, addiction). Thus, we propose that JT09 has potential for development as a novel analgesic. PERSPECTIVE: This article presents data supporting the analgesic properties of an orally available, peripherally-restricted, kappa-opioid agonist for peripheral pain. A potential out-patient pharmaceutical that acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects, could help reduce the current health care burden associated with prescription opioids.

World-wide methamphetamine (meth) use is increasing at a rapid rate; therefore, it has become increasingly important to understand the synaptic changes and neural mechanisms affected by drug exposure. In rodents, 6-hr access to contingent meth results in an escalation of drug intake and impaired cognitive sequelae typically associated with changes within the corticostriatal circuitry. There is a dearth of knowledge regarding the underlying physiological changes within this circuit following meth self-administration. We assessed pre- and postsynaptic changes in glutamate transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) following daily 6-hr meth self-administration. In the mPFC, meth caused postsynaptic adaptations in ionotropic glutamate receptor distribution and function, expressed as a decrease in AMPA/NMDA ratio. This change was driven by an increase in NMDA receptor currents and an increase in GluN2B surface expression. In the NAc, meth decreased the paired-pulse ratio and increased the frequency of spontaneous excitatory postsynaptic currents with no indication of postsynaptic changes. These changes in mPFC synapses and NAc activity begin to characterize the impact of meth on the corticostriatal circuitry.

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.

Preclinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge, we recorded from the prelimbic area of the prefrontal cortex (PL-PFC) of male and female rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during SA; however, female rats exhibit significant synaptic baseline differences when compared to males. Furthermore, females exhibited a significant increase in evoked excitatory currents. This increase in evoked glutamate was correlated with increases in NMDA currents and was not affected by application of a GluN2B selective blocker. We propose that METH SA selectively upregulates GluN2B-lacking NMDA receptors (NMDAR) in the PFC of female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females.

Interest for the use of oxytocin as a treatment for addiction began over 40years ago. Better known for its roles in parturition, lactation and pair bonding, oxytocin also has anxiolytic properties, reduces immune and inflammatory responses, and has a role in learning and memory. In this chapter, oxytocin effects on addiction processes are described by highlighting research findings that have used oxytocin within current preclinical animal models of addiction, relapse, or craving. First, we provide a brief background of the endogenous oxytocin system followed by descriptions of the behavioral models used to study addiction, including models of drug taking and seeking. Then we review recent preclinical studies that have used oxytocin as a therapeutic intervention throughout multiple stages of the addiction cycle from a behavioral and neurobiological perspective. These models encompass the entire range of the addiction cycle including acquisition and maintenance of drug taking, withdrawal and craving during periods of drug abstinence, and ultimately relapse. We then posit several theories about how oxytocin interacts with both drug and social reward, as well as presenting a mechanistic account of how specific oxytocin receptor localization may contribute to oxytocin's efficacy as an addiction therapeutic.

Prolonged use of methamphetamine (meth) has been associated with episodic memory deficits in humans, and preclinical rat models of meth self-administration indicate the memory deficits are a consequence of meth use. Others have suggested that the meth-induced memory deficits may promote a cyclical pattern of drug use, abstinence, and relapse, although preclinical evidence for this relationship is somewhat lacking. The memory deficits in preclinical models manifest as a loss of novel object recognition (NOR) memory. These deficits occur one to two weeks after cessation of meth use and involve the perirhinal cortex, a parahippocampal region essential to NOR memory. We hypothesized that a loss of perirhinal cortex function contributes to both the NOR memory deficits and increased vulnerability to relapse in a novel-cue reinstatement model. To test this, we attempted to restore NOR memory in meth rats using an excitatory Gq-DREADD in perirhinal neurons. Activation of these neurons not only reversed the meth-induced deficit in NOR memory, but also restored novelty salience in a novel-cue reinstatement model. Thus, perirhinal cortex functionality contributes to both memory deficits in relapse in a long-access model of meth self-administration in rats, and chemogenetic restoration of perirhinal function restores memory and reduces relapse.

Rats that have self-administered methamphetamine (meth) under long access, but not short access, conditions do not recognize novel objects. The perirhinal cortex is critical for novelty detection, and perirhinal metabotropic glutamate 5 receptors (mGlu5) are downregulated after long-access meth. The novel positive allosteric modulator (PAM) 1-(4-(2,4-difluorophenyl) piperazin-1-yl)-2-((4-fluorobenzyl)oxy)-ethanone, or DPFE, demonstrates improved solubility compared with other mGlu5 PAMs, thus allowing brain-site-specific pharmacological studies. Infusion of DPFE into perirhinal cortex restored novel object recognition in long-access meth rats. To investigate the impact of these cognitive enhancing effects on relapse, we tested the effects of DPFE infusions into perirhinal cortex on meth-seeking under two different test conditions. In the standard cue relapse test, perirhinal DPFE infusions did not alter meth-seeking in the presence of meth cues. However, in a novel cue relapse test, wherein animals were allowed to allocate responding between a novel cue and meth-conditioned cue, perirhinal DPFE infusions shifted the pattern of responding in long-access rats toward a profile resembling short-access rats, which respond equally for novel and meth cues. Perirhinal mGlu5 are thus a promising pharmacological target for the restoration of cognitive function in meth addicts. Targeting these receptors may also reduce relapse, particularly in situations where novel stimuli compete with conditioned stimuli for control over meth seeking.

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, 3 mg/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.

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 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.

Cocaine addiction is often characterized by a rigid pattern of behavior in which cocaine users continue seeking and taking drug despite negative consequences associated with its use. As such, full acquisition and relapse of drug-seeking behavior may be attributed to a shift away from goal-directed responding and a shift towards the maladaptive formation of rigid and habit-like responses. This rigid nature of habitual responding can be developed with extended training and is typically characterized by insensitivity to changes in outcome value. The present study determined whether cocaine (primary reinforcer) and cocaine associated cues (secondary reinforcer) could be devalued in rats with different histories of cocaine self-administration. Specifically, rats were trained on two schedules of cocaine self-administration (long-access vs. short-access). Following training the cocaine reinforcer was devalued through three separate pairings of lithium chloride with cocaine infusions. Cocaine history did not have an impact on devaluation of cocaine-associated cues. However, the reinforcing properties of cocaine were devalued only in rats on a short-access cocaine schedule but not those trained on a long-access schedule. Taken together this pattern of findings suggests that, in short access rats, devaluation is specific to the primary reinforcer and not associative stimuli such as cues. Importantly, rats that received extended training during self-administration displayed insensitivity to outcome devaluation of the primary reinforcer as well as all associative stimuli, thus displaying rigid behavioral responding similar to behavioral patterns found in addiction. Alternatively, long access cocaine exposure may have altered the devaluation threshold.

Male rats escalate methamphetamine (meth) intake during long-access meth self-administration, show enhanced reinstatement of meth-seeking, and exhibit meth-induced memory impairments. However, the impact of long-access daily meth self-administration on reinstatement and cognitive dysfunction has not been assessed in females, even though clinical studies on meth addiction have shown differences between men and women. This study determined whether male and freely cycling female rats: (1) escalate meth intake in a 6-h daily-access period relative to 1-h access; (2) show different sensitivity to meth primed reinstatement after short- and long-access conditions; and (3) show deficits in novel object and object in place recognition memory. Male and female Long–Evans rats self-administered meth in limited (1-h/day) or extended (6-h/day) daily access sessions. After 21 days, meth access was discontinued, and rats entered an abstinence period. On the seventh and 14th days of abstinence, rats were assessed for recognition memory using tests for: (a) novel object recognition memory and (b) object-in-place memory. Rats were tested for reinstatement of meth-seeking following extinction of responding. Female rats self-administered more meth and escalated intake faster than males during extended, but not limited, daily access. Both males and females in the extended, but not limited, access groups showed memory deficits on both tasks. Female rats showed greater reinstatement to meth-seeking with lower doses of meth priming injections than males. Relative to males, females were equally susceptible to meth-induced memory deficits but exhibited higher meth intake and greater relapse to meth-seeking.

We assessed whether sign-tracking developed along with goal-tracking in a Pavlovian drug discrimination task. Rats had nicotine sessions intermixed with saline sessions. For nicotine sessions, 15-s illumination of a light near (Experiment 1) or far (Experiment 2) from the dipper receptacle was followed by sucrose. Saline sessions were similar to nicotine sessions except sucrose was withheld. Regardless of location, the light evoked goal-tracking only on nicotine sessions. Only rats with the light near the dipper developed sign-tracking.

The cysteine prodrug N-acetylcysteine (NAC) has been shown to reduce reinstatement of cocaine seeking by normalization of glutamatergic tone. However, enduring inhibition of cocaine seeking produced by NAC has not been explored under different withdrawal conditions. Thus, the present study determined whether chronic NAC administered during daily extinction training or daily abstinence after withdrawal from cocaine self-administration would reduce cocaine seeking. Rats self-administered intravenous cocaine during daily 2-h sessions for 12 days, followed by daily extinction or abstinence sessions. During this period, rats received daily injections of saline or NAC (60 or 100 mg/kg). Subsequently, rats were tested for cocaine seeking via conditioned cue, cue + cocaine-primed, and context-induced relapse. Chronic NAC administration blunted cocaine seeking under multiple experimental protocols. Specifically, NAC attenuated responding during cue and cue + cocaine-primed reinstatement tests after extinction and context, cue, and cue + cocaine relapse tests after abstinence. Protection from relapse by NAC persisted well after treatment was discontinued, particularly when the high dose was combined with extinction trials. The finding that NAC reduced cocaine seeking after drug treatment was discontinued has important implications for the development of effective antirelapse medications. These results support recent preclinical and clinical findings that NAC may serve as an effective treatment for inhibiting relapse in cocaine addicts.

Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N -acetylcysteine. N -acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N -acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.

The interoceptive stimulus effects of nicotine acquire control over behavior. This observation, among others, suggests that the stimulus effects of nicotine are important in the development and tenacity of tobacco dependence. Despite this importance, there has been little research examining whether non-reinforced presentations (extinction) of a ligand that share stimulus effects of nicotine will weaken responding controlled by nicotine. Rats were trained to discriminate nicotine (0.4 mg/kg) from saline using a discriminated goal-tracking task in which nicotine signaled intermittent access to sucrose; sucrose was withheld on saline sessions. Experiment 1 examined substitution for nicotine by ABT-418, nornicotine, epibatidine, varenicline, or cytisine in 4-min extinction tests. Experiments 2 to 5 [low dose nicotine (0.05 mg/kg), ABT-418, nornicotine, or varenicline, respectively] examined whether substitution for nicotine would persist if extinction tests were increased to 20 min and repeated daily for 6 days. Finally, generalization of this extinction back to the nicotine training stimulus was assessed. Full substitution in brief 4-min extinction tests was seen for ABT-418, nornicotine, epibatidine, varenicline, and cytisine. Low-dose nicotine, ABT-418, nornicotine, and varenicline, evoked only a partial ‘nicotine-like’ response in the first 20-min extinction test. With repeated extinction, only low-dose nicotine, nornicotine, and varenicline continued to substitute. Extinction with nornicotine and varenicline transferred back to nicotine as indicated by a partial conditioned response to the training stimulus. Interpretations regarding ‘nicotine-like’ effects of a ligand depend on the nature of the test. Understanding the processes mediating transfer of extinction learning with potential pharmacotherapies may reveal new treatment targets.

Understanding and preventing relapse to drug use is one of the most difficult challenges faced by clinicians and practitioners in the struggle to help people remain abstinent. In this paper, we review basic preclinical research on forced abstinence periods that identify the neural substrates involved and neural adaptations that occur after a drug-free period. Our attention focuses on forced abstinence after self-administration because of its promise for translational research in the development of candidate medications to reduce relapse. This model requires subjects (often rats) to initially acquire drug self-administration. However, rather than extinguishing behavior with daily drug-free sessions as in the reinstatement model of drug seeking, subjects are removed from the self-administration situation and do not receive any exposure to the drug. Notably, the integrity of the drug-taking behavior and the drug-associated cues in the drug-taking environment are preserved because they are not experienced in the absence of the drug. Research shows time dependent increases in drug-seeking following forced abstinence periods. More so, neural substrates and adaptations within the mesocorticolimbic system and the nigrostriatal system have been identified that contribute to increased drug seeking following abstinence. From a translational perspective, behavioral and pharmacological treatment of substance use disorder often starts during this initial abstinence period (either forced or voluntary). The forced abstinence model simulates some of the features of this treatment situation and thus allows for the study of potential treatments that alter relapse of drug-seeking behaviors along with the accompanying neurobiological changes.

Vaccines to methamphetamine (meth) were designed by covalently attaching a meth hapten (METH) to peptide constructs that contained a conformationally biased, response-selective molecular adjuvant, YSFKPMPLaR (EP54). Rats immunized with EP54-containing meth vaccines generated serum antibody titers to authentic meth, an immune outcome that altered meth self-administration. Immunization increased meth self-administration suggesting pharmacokinetic antagonism. The ability of immune sera to bind a METH-modified target protein dramatically decreased during and shortly after the meth self-administration assay, suggesting effective sequestration of free meth. However, the binding ability of immune sera to the METH-modified target protein was recovered 34 days after meth-free clearance time.

Bupropion is a promising candidate medication for methamphetamine use disorder. As such, we used a preclinical model of drug-taking to determine the effects of bupropion on the reinforcing effects of methamphetamine (0.025, 0.05 or 0.1 mg/kg/infusion). Specificity was determined by investigating the effects of bupropion on responding maintained by sucrose. In the self-administration study, rats were surgically prepared with indwelling jugular catheters and trained to self-administer methamphetamine under an FR5 schedule. A separate group of rats was trained to press a lever for sucrose. Once responding stabilized, rats were pretreated with bupropion (0, 10, 30 and 60 mg/kg IP) 5 min before chamber placement in a unique testing order. Following acute testing, rats were then repeatedly pretreated with 30 and 60 mg/kg bupropion. Acute treatments of bupropion dose dependently reduced drug intake for 0.025 to 0.1 mg/kg methamphetamine; sucrose deliveries were only reduced with the high bupropion dose. Repeated exposure to 60 mg/kg bupropion before the session resulted in a consistent decrease in methamphetamine intake (0.05 and 0.1 mg/kg) and sucrose deliveries. Considered together, this pattern of findings demonstrates that bupropion decreases responding for methamphetamine, but the effects are only somewhat specific.

Bupropion reduces the subjective effects and cue-induced craving for methamphetamine in humans. Given these effects of bupropion on methamphetamine in humans and its widespread clinical use, a preclinical model of drug-taking was used to determine if pretreatment with bupropion would alter the acquisition of methamphetamine self-administration. During acquisition, rats were given saline or bupropion (30 or 60 mg/kg, IP) 5 min before a 60-min session. For the first 8 days, each response on the active lever produced an infusion of methamphetamine (0.025 mg/kg). Responding on the inactive lever had no programmed consequence. This FR1 schedule was then increased to an FR3 for 4 more days. In a parallel study, the identical procedures were used to test the impact of bupropion on sucrose-maintained responding. Bupropion pretreatment decreased the number of methamphetamine infusions and sucrose deliveries earned on an FR1 and FR3. However, bupropion pretreatment only delayed discrimination between the active and inactive levers in the methamphetamine self-administration rats. Discrimination between active and inactive levers was acquired in all groups in the sucrose experiment regardless of pretreatment condition. Combined, these results suggest that bupropion has a more general effect within the appetitive/reward system of the brain rather than having complete specificity for methamphetamine.

Access to novelty might provide an alternative learning history that competes with conditioned drug reward. We tested this suggestion in rats using a place conditioning procedure with cocaine and novelty. In Experiment 1, rats were conditioned with cocaine to prefer one side of an apparatus. In a subsequent phase, cocaine exposure continued; however, on the unpaired side, separate group of rats had access to novel objects, cocaine injections, or saline with no objects. Pairings with novel objects or cocaine shifted a preference away from the cocaine-paired environment during drug-free and drug-challenge tests. Experiment 2 tested novelty's impact when cocaine exposure was discontinued. The identical procedures were used except drug exposure ceased on the cocaine-paired side during the second phase. Both groups expressed a preference for the cocaine compartment. This preference was maintained for rats that did not have novel objects; however, rats that experienced novelty spent similar amounts of time in both compartments during both tests. Overall, the conditioned rewarding effects of novelty competed with those of cocaine as evidenced by a change in choice behaviors motivated by drug reward.

Past research has shown that when rats received 0.4mg base/kg nicotine paired reliably with intermittent sucrose delivery that anticipatory sucrose-seeking behavior (i.e., goal tracking) was differentially displayed in the nicotine state relative to intermixed saline sessions in which no sucrose was delivered. The present research extended this observation to a lower dose of nicotine (i.e., 0.2mg base/kg) and tested a state-dependent learning account of differential conditioned responding. According to this account, the increase in goal tracking on nicotine sessions reflects a chamber-sucrose association that is only recalled when in the nicotine state. We used a 2x2 factorial design in which rats received sucrose deliveries in one drug state (nicotine or saline) and were then tested in the same state (Nic-->Nic or Sal-->Sal) or a different state (Nic-->Sal or Sal-->Nic) after acquiring the conditioned response. A state-dependency account predicts disruption in conditioned goal tracking for rats that receive a shift in drug state on the test day. This disruption did not occur suggesting that differential control of conditioned responding by nicotine is more likely due to a direct excitatory association between the interoceptive cueing effects of nicotine and the appetitive qualities of sucrose.

People diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk to start smoking and have greater difficulty quitting. Nicotine, one of the principal addictive components of tobacco smoke, functioned as a conditioned stimulus (CS) for intermittent sucrose delivery in a Pavlovian drug discrimination task with rats. This study compared the ability of commonly prescribed ADHD medications (i.e., methylphenidate, atomoxetine, and bupropion) and additional dopamine reuptake inhibitors (i.e., cocaine and GBR 12909) to substitute for the CS effects of nicotine. Atomoxetine was also used to antagonize these CS effects. Rats acquired the discrimination as evidenced by increased dipper entries in nicotine (0.2 mg base/kg) sessions as compared with saline sessions. Nicotine generalization was dose dependent. Bupropion (10 and 20 mg/kg), methylphenidate (10 mg/kg), and cocaine (5 and 10 mg/kg) partially substituted for the 0.2 mg/kg nicotine CS. Atomoxetine did not substitute for the nicotine CS; however, atomoxetine (1 to 10 mg/kg) partially blocked nicotine's CS effects. These results suggest that atomoxetine, bupropion, and/or methylphenidate may be effective treatments for people diagnosed with ADHD and addicted to nicotine.

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.

In the present study, we examined whether exposing rats to manganese (Mn) during the preweanling period would affect basal or cocaine-induced locomotor activity in adulthood and reduce the number of striatal dopamine transporter binding sites. On postnatal day (PD) 1-21, rats were given oral supplements of vehicle or Mn chloride (250 or 750 microg/day). Striatal Mn and iron (Fe) accumulation as well as serum Fe levels were measured on PD 14, PD 21, and PD 90. Throughout the dosing period, rats were evaluated on standard measures of sensory and motor development. During adulthood, the basal and cocaine-induced locomotor activity of vehicle- and Mn-exposed rats was assessed using automated testing chambers. After completion of behavioral testing, striatal dopamine transporter binding sites were measured using [(3)H]GBR 12935. Results showed that early Mn exposure enhanced striatal Mn accumulation on PD 14 and PD 21, while depressing serum Fe levels on PD 21. Exposure to Mn on PD 1-21 did not affect striatal or serum Mn or Fe levels on PD 90. During the second postnatal week, Mn-exposed rat pups performed more poorly than controls on a negative geotaxis task, however basal motor activity of preweanling rat pups was not affected by Mn treatment. When tested in adulthood, basal locomotor activity of vehicle- and Mn-exposed rats also did not differ. In contrast, adult rats previously exposed to 750 microg/day Mn showed an enhanced locomotor response when challenged with 10 mg/kg cocaine. A different pattern of results occurred after treatment with a higher dose of the psychostimulant, because Mn-exposed rats showed an attenuated locomotor response when given 20 mg/kg cocaine. Importantly, Mn-exposed rats exhibited long-term reductions in striatal dopamine transporter binding sites. Considered together, these results indicate that postnatal Mn exposure has long-term behavioral and neurochemical effects that can persist into adulthood.

In adult rats, the partial D(2)-like agonist terguride acts as an antagonist at normosensitive D(2)-like post-synaptic receptors, while it acts as an agonist at the same receptors during states of low dopaminergic tone.The purpose of the present study was to determine whether partial D(2)-like agonists exhibit both antagonistic and agonistic actions during the preweanling period.In experiments 1 and 2 (examining the agonistic actions of terguride), preweanling rats were either given an escalating regimen of amphetamine to induce a state of amphetamine withdrawal or pretreated with the tyrosine hydroxylase inhibitor AMPT. Distance traveled was measured after rats were injected with saline, terguride (0.4-1.6 mg/kg), or the full D(2)-like receptor agonist NPA (0.01 mg/kg). In experiment 3 (examining the antagonistic actions of terguride), preweanling rats were pretreated with terguride 30 min before they were tested with saline, NPA (0.05 mg/kg), or amphetamine (1.5 mg/kg).NPA had an exaggerated locomotor activating effect when tested under conditions of amphetamine withdrawal, while the partial D(2)-like agonist did not enhance distance traveled under any circumstance. Similarly, NPA increased and terguride did not affect the distance-traveled scores of AMPT-pretreated rats. In experiment 3, terguride pretreatment significantly reduced the distance traveled of amphetamine-treated and NPA-treated rats.The behavioral evidence indicates that, during the preweanling period, terguride antagonizes D(2)-like post-synaptic receptors in a state of high dopaminergic tone; however, there is no evidence that terguride is capable of stimulating D(2)-like post-synaptic receptors during states of low dopaminergic tone.

Glutamatergic signaling in the medial prefrontal cortex (mPFC) plays a critical role in drug addiction and relapse. The mPFC is functionally subdivided into dorsal (prelimbic, PL) and ventral (infralimbic, IL) regions, and evidence suggests a differential role of these two divisions in the control of drug seeking and taking; however, there is a dearth of information on the cocaine-induced adaptations in PL- and IL-mPFC synaptic glutamate transmission and their regulation of behavioral responses to cocaine-associated stimuli. We tested male rats in a cocaine-induced conditioned place preference (CPP) paradigm. In vitro whole-cell recordings were performed at different abstinence intervals to investigate the neuroadaptations in synaptic glutamate transmission in PL- and IL-mPFC deep layer (5/6) pyramidal neurons. Our results show that in naïve animals, PL-mPFC neurons expressed higher frequency of spontaneous events (sEPSCs) than IL-mPFC neurons. Following cocaine-CPP and a short abstinence (SA) period (8 d), we observed decreases in the amplitude of sEPSCs in both mPFC regions. Longer abstinence periods (30 d), resulted in a sustained decrease in the frequency of sEPSCs and an increase in AMPA receptor rectification only in PL-mPFC neurons. In addition, PL-mPFC neurons expressed a decrease in the area under the curve of sEPSCs, suggesting altered receptor activation dynamics. Synaptic glutamate transmission was not significantly different between retested and naïve rats. These results suggest that retention of cocaine-CPP requires differential modulation of glutamate transmission between PL- and IL-mPFC neurons and that these adaptations are dependent on the abstinence interval and reexposure to the cocaine context.