"A robust and simple catheter connector assembly for long-term self-administration experiments".

Intravenous self-administration in rats is used widely to study the reinforcing effects of drugs and serves as the gold standard for assessing their use and misuse potential. One challenge that researchers often encounter when scaling up experiments is balancing the cost, time investment to construct, and robustness of each implanted catheter. These catheters include multiple components such as surgical meshing and a variety of entry ports designed to facilitate the connection of the rat to a catheter port tethering system. Other considerations include maintaining the catheters free of blockage during the extent of the drug self-administration experiment. These large-scale studies provide ample opportunity for the catheter system to fail. The failure and replacement of commercially purchased catheters leads to ballooning expenses, and the failure of in-lab manufactured catheters requires the manufacture of reserves, also increasing costs, as these handmade products are inherently more variable. We have developed a catheter system that combines a commercially available implantable back-mounted entry connector system with inexpensive medical items such as surgical mesh, sutures, and an air-tight back flow prevention system to bolster the overall success of self-administration experiments.•Method to bolster commercially available jugular catheter components for long-lasting self-administration experiments.•Reduces the overall cost per unit of self-administration experiments.•Easily assembled by laboratory students and staff.

Individual corticosterone response to intermittent swim stress predicts a shift in economic demand for ethanol from pre- stress to post-stress in male rats.

This study investigated the relationship between stress exposure and subsequent ethanol use, focusing on individual differences among male rats. We combined operant self-administration with behavioral economics to assess how intermittent swim stress affects ethanol consumption. This approach allowed for a nuanced analysis of the transition from regular ethanol intake to stress-induced escalation in economic demand. Results showed a consistent rise in ethanol demand post-stress among subjects, irrespective of exposure to actual swim stress or a sham procedure. This increase may result from a two-week abstinence or an inherent rise in demand over time. Significantly, we identified a direct link between post-stress corticosterone levels and the demand for ethanol, considering baseline levels. This correlation was particularly pronounced when examining the shifts in both corticosterone levels and demand for ethanol post-stress. However, neither post-stress corticosterone levels nor their change over time correlated significantly with changes in ethanol demand following a forced swim test that was administered 24 hours after the intermittent swim stress test. This suggests potential context-specific or stressor-specific effects. Importantly, pre-stress ethanol demand did not significantly predict the corticosterone response to stress, indicating that high ethanol-demand rats do not inherently exhibit heightened stress sensitivity. Our research brings to light the complex interplay between stress and ethanol consumption, highlighting the critical role of individual differences in this relationship. This research introduces a nuanced perspective, underscoring the need for future studies in the realm of stress and substance use to give greater consideration to individual variability.

Assessment of ethanol and nicotine interactions using a reinforcer demand modeling with grouped and individual levels of analyses in a long-access self-administration model using male rats.

Previous reports have indicated the reciprocal effects of nicotine and ethanol on their rewarding and reinforcing properties, but studies using methodological approaches resembling substance use in vulnerable populations are lacking. In our study, rats first self-administered ethanol, and their sensitivity to ethanol's reinforcing effects was assessed using a reinforcer demand modeling approach. Subsequently, rats were equipped with intravenous catheters to self-administer nicotine, and their sensitivity to nicotine's reinforcing effects was evaluated using the same approach. In the final phase, rats were allowed to self-administer ethanol and nicotine concurrently, investigating the influence of one substance on the rate of responding for the other substance. Group analyses revealed notable differences in demand among sucrose, sweetened ethanol, and ethanol-alone, with sucrose demonstrating the highest demand and ethanol-alone exhibiting greater sensitivity to changes in cost. At the individual level, our study finds significant correlations between rats' demand for sucrose and sweetened ethanol, suggesting parallel efforts for both substances. Our individual data also suggest interconnections in the elasticity of demand for sweetened ethanol and ethanol-alone, as well as a potential relationship in price response patterns between ethanol and nicotine. Furthermore, concurrent self-administration of ethanol and nicotine at the group level displayed reciprocal effects, with reduced responding for nicotine in the presence of ethanol and increased responding for ethanol in the presence of nicotine. This study provides valuable insights into modeling the co-use of ethanol and nicotine and assessing their interaction effects using reinforcer demand modeling and concurrent self-administration or noncontingent administration tests. These findings contribute to our understanding of the complex interplay between ethanol and nicotine and have implications for elucidating the underlying mechanisms involved in polydrug use.

Inactivation of posterior but not anterior dorsomedial caudate-putamen impedes learning with self-administered nicotine stimulus in male rats.

The rodent caudate-putamen is a large heterogeneous neural structure with distinct anatomical connections that differ in their control of learning processes. Previous research suggests that the anterior and posterior dorsomedial caudate-putamen (a- and p-dmCPu) differentially regulate associative learning with a non-contingent nicotine stimulus. The current study used bilateral NMDA-induced excitotoxic lesions to the a-dmCPu and p-dmCPu to determine the functional involvement of a-dmCPu and p-dmCPu in appetitive learning with contingent nicotine stimulus. Rats with a-dmCPu, p-dmCPu, or sham lesions were trained to lever-press for intravenous nicotine (0.03 mg/kg/inf) followed by access to sucrose 30 s later. After 1, 3, 9, and 20 nicotine-sucrose training sessions, appetitive learning in the form of a goal-tracking response was assessed using a non-contingent nicotine-alone test. All rats acquired nicotine self-administration and learned to retrieve sucrose from a receptacle at equal rates. However, rats with lesions to p-dmCPu demonstrated blunted learning of the nicotine-sucrose association. Our primary findings show that rats with lesions to p-dmCPu had a blunted goal-tracking response to a non-contingent nicotine administration after 20 consecutive days of nicotine-sucrose pairing. Our findings extend previous reports to a contingent model of nicotine self-administration and show that p-dmCPu is involved in associative learning with nicotine stimulus using a paradigm where rats voluntarily self-administer nicotine infusions that are paired with access to sucrose-a paradigm that closely resembles learning processes observed in humans.

Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement.

Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on motivation for a food reinforcer. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that (a) nicotine decreased economic demand for sucrose, (b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and (c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that had not been exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards.

Conditioned enhancement of the nicotine reinforcer.

This study was designed to assess whether nicotine can acquire additional reinforcing properties through associations with other rewards. To this end, rats self-administered nicotine-alone (0.01 mg/kg) or nicotine paired with access to sucrose during the conditioning phase. In the subsequent challenge phase, we tested the effect of nicotine-sucrose pairings on the reinforcing effects of nicotine using a progressive ratio schedule of reinforcement. Using this approach, we show that (a) rats in both paired and nicotine-alone conditions self-administered similar amounts of nicotine in the initial conditioning phase of the study when intake was limited to 10 infusions per session, (b) nicotine rapidly acquired control over goal-tracking behavior in the paired condition, (c) rats that had a history of nicotine and sucrose pairings worked harder and took more nicotine as measured on a progressive ratio using a distinct response form, and (d) conditioned goal-tracking evoked by nicotine did not show extinction when sucrose was no longer paired with nicotine over the 11 days of nicotine self-administration on a progressive ratio schedule of reinforcement. Overall, our results demonstrate that in addition to the multifaceted nature of nicotine stimulus that includes primary reinforcing effects, conditioned reinforcing effects, and reward enhancing effects, nicotine can also acquire additional reinforcing properties through associations with other rewards. This ability to acquire additional reinforcing properties through associative learning may contribute to the development and perpetuation of tobacco use disorder. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Assessment of individual differences in response to acute bupropion or varenicline treatment using a long-access nicotine self-administration model and behavioral economics in female rats.

Bupropion and varenicline are widely prescribed pharmacological treatments for smoking cessation. These treatments are only marginally effective in clinical populations but most preclinical studies show that they are effective in decreasing self-administration in rats on a group level. The present study investigated individual differences in responding to bupropion or varenicline in a preclinical model of long-access to nicotine (0.03 mg/kg/inf; 12 h/day) in female rats. Rats were first assessed for their individual economic demand for nicotine and for their individual performance in open field and elevated plus maze prior to nicotine access and during withdrawal. Rats were then tested for the acute effects of bupropion, varenicline, and yohimbine. We found that neither bupropion nor varenicline decreased responding for nicotine on test days. On the contrary, a moderate dose of bupropion (30 mg/kg) significantly increased responding for nicotine. We also found that rats with higher demand for nicotine were more sensitive to pretreatment with yohimbine which resulted in increased responding for nicotine during the dose-effect tests. Finally, we show that rats that had a higher demand for nicotine also were more persistent in seeking nicotine during extinction and reinstatement tests with nicotine or yohimbine as triggers. Our findings suggest that the length of access to daily nicotine may be an important factor underlying the response to pharmacological treatments like bupropion or varenicline. Future studies modeling chronic treatment approaches that include both sexes will be needed to further extend our findings.

Individual Vulnerability to Stress Is Associated With Increased Demand for Intravenous Heroin Self-administration in Rats.

Opioid use is a widespread epidemic, and traumatic stress exposure is a critical risk factor in opioid use and relapse. There is a significant gap in our understanding of how stress contributes to heroin use, and there are limited studies investigating individual differences underlying stress reactivity and subsequent stress-induced heroin self-administration. We hypothesized that greater individual vulnerability to stress would predict higher demand for heroin self-administration in a within-subjects rodent model of stress and heroin use comorbidity. Male rats were exposed to inescapable intermittent swim stress (ISS) and individual biological (corticosterone) or behavioral [open field, social exploration, and forced swim tests (FSTs)] measures were assessed before and after the stress episode. Individual demand for self-administered heroin (0.05 mg/kg/infusion; 12-h sessions) was assessed using a behavioral economics approach followed by extinction and reinstatement tests triggered by stress re-exposure, non-contingent cue presentations, and yohimbine (0, 1.0, or 2.5 mg/kg). We found that behavioral, biological, and a combination of behavioral and biological markers sampled prior to and after the stress episode that occurred weeks before the access to heroin self-administration predicted the magnitude of individual demand for heroin. Non-contingent presentation of cues, that were previously associated with heroin, reinstated heroin seeking in extinction. For the first time, we show that individual biological response to an ecologically relevant stressor in combination with associated behavioral markers can be used to predict subsequent economic demand for heroin.

Individual differences in responding to bupropion or varenicline in a preclinical model of nicotine self-administration vary according to individual demand for nicotine.

Bupropion and varenicline are the top two smoking cessation interventions that are marginally successful in increasing abstinence rates when compared to placebo. Although smokers vary in their history and pattern of tobacco use, there is a significant gap in addressing this individual variability with individually targeted treatments. The present study takes the initial step towards a better understanding of individual differences in treatment outcomes by assessing the effect of bupropion or varenicline on nicotine self-administration in rats. Rats were first assessed for their individual economic demand for sucrose and then for self-administered nicotine (0.03 mg/kg/inf; 2 h sessions). We then examined the effect of bupropion (0, 10, 30, 60 mg/kg) or varenicline (0, 0.1, 1.0, 3.0 mg/kg) pretreatment on individual rates of nicotine self-administration using progressive ratio schedule of reinforcement. Thereafter, rats were subjected to four rounds of extinction and reinstatement tests. We found that individual demand for sucrose did not predict individual demand for nicotine. Acute pretreatments with bupropion or varenicline were most effective at decreasing nicotine self-administration in rats that had a higher demand for nicotine. Rats with higher demand for nicotine also showed higher magnitude of responding in extinction and during nicotine-triggered reinstatement tests. Although the acute treatment protocol employed in this study is an important initial step towards a better understanding of individual treatment effects, future research modeling chronic treatment approaches will be needed to further extend our findings.

The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine-triggered reinstatement of female rats.

N-acetylcysteine and bupropion are two promising candidate medications for treatment of substance use disorder. The effects of N-acetylcysteine or bupropion on methamphetamine self-administration of female rats are not well understood. To fill this gap, this study assessed the effects of N-acetylcysteine (0, 30, 60, or 120 mg/kg) and bupropion (0, 10, 30, and 60 mg/kg) on methamphetamine self-administration of female rats across the natural estrous cycle. Following a completed dose-response curve, responding for methamphetamine self-administration was extinguished and the effects of N-acetylcysteine or bupropion on methamphetamine-triggered reinstatement was evaluated in separate experiments. N-acetylcysteine did not decrease responding maintained by methamphetamine or methamphetamine-triggered reinstatement. Bupropion significantly decreased methamphetamine self-administration and methamphetamine-triggered reinstatement in female rats with highest dose (60 mg/kg) also significantly decreasing general chamber activity. In a companion experiment, testing the effect of bupropion on responding maintained by sucrose, we confirmed non-specificity of bupropion's effects as bupropion also decreased responding for sucrose. Considered together, our findings suggest that while N-acetylcysteine has considerable promise for treatment of cocaine dependence it may not generalize to other stimulants like methamphetamine. Furthermore, although bupropion has been shown to effectively decrease methamphetamine self-administration, and presently methamphetamine-triggered reinstatement, its locomotor and reward suppressing effects warrant further investigation including both sexes.

Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus.

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a moderate stimulant and a mild reinforcer. Importantly, besides its unconditional effects, nicotine also has conditioned stimulus effects that may contribute to the tenacity of the smoking habit. Because the neurobiological substrates underlying these processes are virtually unexplored, the present study investigated the functional involvement of the dorsomedial caudate putamen (dmCPu) in learning processes with nicotine as an interoceptive stimulus. Rats were trained using the discriminated goal-tracking task where nicotine injections (0.4 mg/kg; SC), on some days, were paired with intermittent (36 per session) sucrose deliveries; sucrose was not available on interspersed saline days. Pre-training excitotoxic or post-training transient lesions of anterior or posterior dmCPu were used to elucidate the role of these areas in acquisition or expression of associative learning with nicotine stimulus. Pre-training lesion of p-dmCPu inhibited acquisition while post-training lesions of p-dmCPu attenuated the expression of associative learning with the nicotine stimulus. On the other hand, post-training lesions of a-dmCPu evoked nicotine-like responding following saline treatment indicating the role of this area in disinhibition of learned motor behaviors. These results, for the first time, show functionally distinct involvement of a- and p-dmCPu in various stages of associative learning using nicotine stimulus and provide an initial account of neural plasticity underlying these learning processes.

Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats.

BACKGROUND: Chronic methamphetamine intake has been shown to induce a neuroinflammatory state leading to significant changes in brain functioning including behavioral changes. These changes can persist for years after drug use is discontinued and likely contribute to the risk of relapse. A better understanding of inflammation responses associated with methamphetamine intake may help in designing novel and more efficacious treatment strategies. METHODS: Rats were trained to self-administer methamphetamine or saline on a variable ratio 3 schedule of reinforcement (25 days). This training was followed by 12 days of extinction (i.e., methamphetamine unavailable) during which rats received daily post-session administration of ibudilast (AV411; 2.5 or 7.5mg/kg) or saline. Following extinction, synaptosomes were isolated from the prefrontal cortex (PFC) and the differential pattern of synaptic proteins was assessed using mass spectrometry based proteomics. RESULTS: Treatment with ibudilast allowed for deeper extinction of active lever pressing. Quantitative mass spectrometry based proteomics on the PFC identified one potential hit; the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1). While methamphetamine intake was associated with reduced PEBP1 protein levels, treatment with ibudilast reversed this effect. Furthermore, decreased PEBP1 expression was correlated with subsequent activation of Raf-1, MEK, and ERK signaling components of the mitogen-activated protein kinase cascade (MAPK). Raf-1, MEK, and ERK expression levels were also attenuated by ibudilast treatment. CONCLUSION: PEBP1, given its synaptic localization and its role as a signaling molecule acting via the ERK/MAPK pathway, could be a potential therapeutic target mediating drug-seeking behaviors associated with neuroinflammation.

We know very little about the subjective effects of drugs in females.

Pharmaceutical companies assessing the nervous system effects of candidate therapeutics often use a behavioral assay in rodents that assesses the drug's subjective (internal stimulus) effects. Variants of this so-called "drug discrimination task" have also been widely used by basic scientist for more than 50 years to study the receptor actions of a host of ligands related to disease states and neuropathologies. Notably, most published research with this task has used male rats or mice. This situation is unfortunate and severely limits the utility of the research, given the well-documented differences between women and men on drug efficacy and safety, as well as known sex differences in the neural and behavioral effects of drugs. In this Viewpoint, we highlight the need for basic researchers, as well as pharmaceutical scientists, to include females in drug discrimination studies in a manner that allows detection and interpretation of potential sex differences.

Interoceptive conditioning with nicotine using extinction and re-extinction to assess stimulus similarity with bupropion.

Bupropion is an atypical antidepressant that increases long-term quit rates of tobacco smokers. A better understanding of the relation between nicotine and this first-line medication may provide insight into improving treatment. For all experiments, rats first had nicotine (0.4 mg base/kg) and saline session intermixed; intermittent access to sucrose only occurred on nicotine session. Nicotine in this protocol comes to differentially control "anticipatory" dipper entries. To more closely examine the overlap in the interoceptive stimulus effects of nicotine and bupropion, we assessed whether subsequent prolonged and repeated non-reinforced (extinction) sessions with the bupropion stimulus could weaken responding to nicotine (i.e., transfer of extinction). We also examined whether retraining the discrimination after initial extinction and then conducting extinction again (i.e., re-extinction) with bupropion would affect responding. We found that bupropion (20 and 30 mg/kg) fully substituted for the nicotine stimulus in repeated 20-min extinction sessions. The extent of substitution in extinction did not necessarily predict performance in the transfer test (e.g., nicotine responding unchanged after extinction with 20 mg/kg bupropion). Generalization of extinction back to nicotine was not seen with 20 mg/kg bupropion even after increasing the number of extinction session from 6 to 24. Finally, there was evidence that learning in the initial extinction phase was retained in the re-extinction phase for nicotine and bupropion. These findings indicate that learning involving the nicotine stimuli are complex and that assessment approach for stimulus similarity changes conclusions regarding substitution by bupropion. Further research will be needed to identify whether such differences may be related to different facets of nicotine dependence and/or its treatment.

Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats.

Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague-Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10-20. After 1, 4, or 8 days (i.e. on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol-pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least 8 days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up-regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side effects, including extrapyramidal symptoms.

Post-training cocaine exposure facilitates spatial memory consolidation in C57BL/6 mice.

In this study, we examined the ability of post-training injections of cocaine to facilitate spatial memory performance using the Morris water maze (MWM). We also investigated the role that hippocampal protein kinase A (PKA) and extracellular signal-regulated kinase 1/2 (ERK) signaling may play in cocaine-mediated spatial memory consolidation processes. Male and female C57BL/6 mice were first trained in a MWM task (eight consecutive trials) then injected with cocaine (0, 1.25, 2.5, 5, or 20 mg/kg), and memory for the platform location was retested after a 24 h delay. Cocaine had a dose-dependent effect on spatial memory performance because only the mice receiving 2.5 mg/kg cocaine displayed a significant reduction in latency to locate the platform. No sex differences in MWM performance were observed; however, females showed higher hippocampal levels of PKA when compared with males. A second experiment demonstrated that 2.5 mg/kg cocaine enhanced MWM performance only when administered within 2, but not 4 h after spatial training. We also found that cocaine (2.5 mg/kg) increased ERK2 phosphorylation within the hippocampus and one of its downstream targets (ribosomal S6 kinase), a mechanism that may be responsible, at least in part, for the enhanced cocaine-mediated spatial memory performance. Overall, these data demonstrate that a low dose of cocaine (2.5 mg/kg) administered within 2 h after training facilitates MWM spatial memory performance in C57BL/6 mice.

Disentangling the nature of the nicotine stimulus.

Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using "standard" testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more "standard" testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.

Conditioned response evoked by nicotine conditioned stimulus preferentially induces c-Fos expression in medial regions of caudate-putamen.

Nicotine has both unconditioned and conditioned stimulus properties. Conditioned stimulus properties of nicotine may contribute to the tenacity of nicotine addiction. The purpose of this experiment was to use neurohistochemical analysis of rapidly developing c-Fos protein to elucidate neurobiological loci involved in the processing of nicotine as an interoceptive conditioned stimulus (CS). Rats were injected (SC) in an intermixed fashion with saline or nicotine (16 sessions of each) and placed in conditioning chambers where they were given one of the three conditions depending on group assignment: (a) nicotine paired 100% of the time with intermittent access to sucrose (nicotine-CS condition), (b) nicotine and saline each paired 50% of the time with sucrose (chamber-CS condition), or (c) no sucrose US control (CS-alone condition). Rats in the nicotine-CS condition acquired the discrimination as evidenced by goal-tracking (ie, increased dipper entries before initial sucrose delivery) only on nicotine sessions. The chamber-CS condition showed goal-tracking on all sessions; no goal-tracking was seen in the CS-alone condition. On the test day, rats in each condition were challenged with saline or nicotine and later assessed for c-Fos immunoreactivity. In concordance with previous reports, nicotine induced c-Fos expression in the majority of areas tested; however, learning-dependent expression was specific to dorsomedial and ventromedial regions of caudate-putamen (dmCPu, vmCPu). Only rats in the nicotine-CS condition, when challenged with nicotine, had higher c-Fos expression in the dmCPu and vmCPu. These results suggest that medial areas of CPu involved in excitatory conditioning with an appetitive nicotine CS.

Acute and long-term response of dopamine nigrostriatal synapses to a single, low-dose episode of 3-nitropropionic acid-mediated chemical hypoxia.

The goal of the present investigation was to determine the persistence of striatal (DA) dopaminergic dysfunction after a mild chemically induced hypoxic event in Fisher 344 rats. To this end, we gave a single injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP; 16.5 mg/kg, i.p.) to 2-month old male F344 rats and measured various indices of striatal DA functioning and lipid peroxidation over a 3-month span. Separate groups of rats were used to measure rod walking, evoked DA release, DA content, malondialdehyde (MDA) accumulation, DA receptor binding, and tyrosine hydroxylase (TH) activity. The results showed that 3-NP exposure reduced most measures of DA functioning including motoric ability, DA release, and D(2) receptor densities for 1 to 3 months postdrug administration. Interestingly, DA content was reduced 1 week after 3-NP exposure, but rose to 147% of control values 1 month after 3-NP treatment. MDA accumulation, a measure of lipid peroxidation activity, was increased 24 h and 1 month after 3-NP treatment. 3-NP did not affect TH activity, suggesting that alterations in DA functioning were not the result of nigrostriatal terminal loss. These data demonstrate that a brief mild hypoxic episode caused by 3-NP exposure has long-term detrimental effects on the functioning of the nigrostriatal DA system.

Effects of repeated and acute aripiprazole or haloperidol treatment on dopamine synthesis in the dorsal striatum of young rats: comparison to adult rats.

The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10-20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70-80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring L-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment.