Analysis of Wastewater Samples to Explore Community Substance Use in the United States: Pilot Correlative and Machine Learning Study.

BACKGROUND: Substance use disorder and associated deaths have increased in the United States, but methods for detecting and monitoring substance use using rapid and unbiased techniques are lacking. Wastewater-based surveillance is a cost-effective method for monitoring community drug use. However, the examination of the results often focuses on descriptive analysis. OBJECTIVE: The objective of this study was to explore community substance use in the United States by analyzing wastewater samples. Geographic differences and commonalities of substance use were explored. METHODS: Wastewater was sampled across the United States (n=12). Selected drugs with misuse potential, prescriptions, and over-the-counter drugs and their metabolites were tested across geographic locations for 7 days. Methods used included wastewater assessment of substances and metabolites paired with machine learning, specifically discriminant analysis and cluster analysis, to explore similarities and differences in wastewater measures. RESULTS: Geographic variations in the wastewater drug or metabolite levels were found. Results revealed a higher use of methamphetamine (z=-2.27, P=.02) and opioids-to-methadone ratios (oxycodone-to-methadone: z=-1.95, P=.05; hydrocodone-to-methadone: z=-1.95, P=.05) in states west of the Mississippi River compared to the east. Discriminant analysis suggested temazepam and methadone were significant predictors of geographical locations. Precision, sensitivity, specificity, and F1-scores were 0.88, 1, 0.80, and 0.93, respectively. Finally, cluster analysis revealed similarities in substance use among communities. CONCLUSIONS: These findings suggest that wastewater-based surveillance has the potential to become an effective form of surveillance for substance use. Further, advanced analytical techniques may help uncover geographical patterns and detect communities with similar needs for resources to address substance use disorders. Using automated analytics, these advanced surveillance techniques may help communities develop timely, tailored treatment and prevention efforts.

Unique SARS-CoV-2 Variants, Tourism Metrics, and B.1.2 Emergence in Early COVID-19 Pandemic: A Correlation Analysis in South Dakota.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which is the source of the coronavirus disease 2019 (COVID-19), was declared a pandemic in the March of 2020. Travel and tourism were severely impacted as restrictions were imposed to help slow the disease spread, but some states took alternative approaches to travel restrictions. This study investigated the spread of COVID-19 in South Dakota during the early pandemic period to better understand how tourism affected the movement of the virus within the region. Sequences from the fall of 2020 were retrieved from public sources. CDC and other sources were used to determine infections, deaths, and tourism metrics during this time. The data were analyzed using correlation and logistic regression. This study found that the number of unique variants per month was positively correlated with hotel occupancy, but not with the number of cases or deaths. Interestingly, the emergence of the B.1.2 variant in South Dakota was positively correlated with increased case numbers and deaths. Data show that states with a shelter-in-place order were associated with a slower emergence of the B.1.2 variant compared to states without such an order, including South Dakota. Findings suggest complex relationships between tourism, SARS-CoV-2 infections, and mitigation strategies. The unique approach that South Dakota adopted provided insights into the spread of the disease in areas without state-wide restrictions. Our results suggest both positive and negative aspects of this approach. Finally, our data highlight the need for future surveillance efforts, including efforts focused on identifying variants with known increased transmission potential to produce effective population health management.

Using wastewater to overcome health disparities among rural residents.

The SARS-CoV-2 pandemic highlighted the need for novel tools to promote health equity. There has been a historical legacy around the location and allocation of public facilities (such as health care) focused on efficiency, which is not attainable in rural, low-density, United States areas. Differences in the spread of the disease and outcomes of infections have been observed between urban and rural populations throughout the COVID-19 pandemic. The purpose of this article was to review rural health disparities related to the SARS-CoV-2 pandemic while using evidence to support wastewater surveillance as a potentially innovative tool to address these disparities more widely. The successful implementation of wastewater surveillance in resource-limited settings in South Africa demonstrates the ability to monitor disease in underserved areas. A better surveillance model of disease detection among rural residents will overcome issues around the interactions of a disease and social determinants of health. Wastewater surveillance can be used to promote health equity, particularly in rural and resource-limited areas, and has the potential to identify future global outbreaks of endemic and pandemic viruses.

Changes in buprenorphine visits in frontier and remote locations: Effects of the SARS-CoV-2 pandemic.

Background: The pandemic has changed many aspects of healthcare, including the treatment of people with opioid use disorder with buprenorphine. Prior to the pandemic, rural health disparities existed in the accessibility of this treatment. Rural and frontier areas of the United States, particularly the Great Plains, had few or no providers of this evidence-based treatment. This study aimed to investigate how access to buprenorphine changed in the Great Plains during the pandemic. Methods: This retrospective observational study compared the number of weekly patient appointments resulting in a buprenorphine prescription for 55 weeks before the start of the SARS-CoV-2 pandemic and 55 weeks after. Electronic health records of the largest rural health provider in the Great Plains were queried. Patients were categorized as coming from a frontier location or a non-frontier location based on the home address provided at the visit. The USDA defines frontier as communities that are small and distant from urban centers. Time series analysis was utilized to understand changes in weekly visits during this period. Results: A significant increase in weekly buprenorphine visits occurred after the pandemic's start. Further, females and people from frontier locations had significantly higher numbers of buprenorphine visits. Conclusions: In an area of the country with low pre-existing access to buprenorphine treatment for opioid use disorder, increases in buprenorphine visits were found after the pandemic began. This was particularly true of females who reside in frontier areas. Pandemic-related changes may have reduced barriers to this critical treatment, especially among rural populations.

Population Health Metrics During the Early Stages of the COVID-19 Pandemic: Correlative Pilot Study.

BACKGROUND: COVID-19 has caused nearly 1 million deaths in the United States, not to mention job losses, business and school closures, stay-at-home orders, and mask mandates. Many people have suffered increased anxiety and depression since the pandemic began. Not only have mental health symptoms become more prevalent, but alcohol consumption has also increased during this time. Helplines offer important insight into both physical and mental wellness of a population by offering immediate, anonymous, cheap, and accessible resources for health and substance use disorders (SUD) that was unobstructed by many of the mandates of the pandemic. Further, the pandemic also launched the use of wastewater surveillance, which has the potential for tracking not only population infections but also consumption of substances such as alcohol. OBJECTIVE: This study assessed the feasibility of using multiple public surveillance metrics, such as helpline calls, COVID-19 cases, and alcohol metabolites in wastewater, to better understand the need for interventions or public health programs in the time of a public health emergency. METHODS: Ethanol metabolites were analyzed from wastewater collected twice weekly from September 29 to December 4, 2020, in a Midwestern state. Calls made to the helpline regarding housing, health care, and mental health/SUD were correlated with ethanol metabolites analyzed from wastewater samples, as well as the number of COVID-19 cases during the sampling period. RESULTS: Correlations were observed between COVID-19 cases and helpline calls regarding housing and health care needs. No correlation was observed between the number of COVID-19 cases and mental health/SUD calls. COVID-19 cases on Tuesdays were correlated with the alcohol metabolite ethyl glucuronide (EtG). Finally, EtG levels were negatively associated with mental health/SUD helpline calls. CONCLUSIONS: Although helpline calls provided critical services for health care and housing-related concerns early in the pandemic, evidence suggests helpline calls for mental health/SUD-related concerns were unrelated to COVID-19 metrics. Instead, COVID metrics were associated with alcohol metabolites in wastewater. Although this research was formative, with continued and expanded monitoring of population metrics, such as helpline usage, COVID-19 metrics, and wastewater, strategies can be implemented to create precision programs to address the needs of the population.

Engaging Undergraduate Students in Substance Use and Related Mental Health Disorders Research within South Dakota: A Review of the Summer Program for Undergraduate Research in Addiction (SPURA).

BACKGROUND: The Summer Program for Undergraduate Research in Addiction (SPURA) at the University of South Dakota provides research opportunities to better understand substance use and related mental health disorders. The program was initiated in 2014 from funding from the National Institute on Drug Abuse with a mission to provide high-quality mentorship and research experiences for undergraduate students, including those underrepresented in science, technology, engineering, and math. METHODS: Students from the University of South Dakota were recruited to participate in this program. Survey responses and demographic information were collected from the students. RESULTS: During the first five years, 37 students completed the program. Many of these students were underrepresented in science. Of the students that had completed their undergraduate degree at the time of the last survey, most students either continued their education in a health professional or graduate program, or were employed in a career related to mental health or substance use. CONCLUSIONS: The current report reflects upon the outcomes of the program and future directions. With continued effort, SPURA will provide critical education for future leaders and health care professionals on topics related to substance use and mental health disorders, resulting in a greater number of advocates for those afflicted by substance use.

The emergence of cardiac changes following the self-administration of methamphetamine.

BACKGROUND: Clinical observations suggest an association between methamphetamine (METH) use and cardiovascular disease, but preclinical studies are lacking. The purpose of the current study was to explore changes in left ventricular function as a potential precursor to cardiovascular disease in a rodent model of METH use. METHODS: Male rats were allowed to self-administer either METH or saline for 9 d. On the day following the 4th and 9th self-administration sessions, an echocardiogram was performed to assess left-ventricular parameters under basal conditions and following a low-dose of METH (1 mg/kg). RESULTS: A low challenge dose of METH resulted in subtle but statistically significant changes in cardiac function during the echocardiogram in both the METH and saline self-administering groups. Further, differences in left-ventricular parameters such as stroke volume and heart rate were observed between METH and saline groups following the 9th self-administration session. Finally, supervised machine learning correctly predicted the self-administration group assignment (saline or METH) using cardiac parameters following the 9th self-administration session. CONCLUSIONS: The findings of the current study suggest the heart, specifically the left ventricle, is sensitive to METH. Overall, these findings and emerging clinical observations highlight the need for research to investigate the effects of METH use on the heart.

Interaction of stress and stimulants in female rats: Role of chronic stress on later reactivity to methamphetamine.

Previous research in humans and animals suggests that prior exposure to stress alters responsivity to drugs of abuse, including psychostimulants. Male rats show an augmented striatal dopamine response to methamphetamine following exposure to chronic unpredictable stress (CUS). Compared to males, female rats have been shown to be highly sensitive to the effects of stimulants and stress independently, however few studies have examined the interaction between stress and stimulants in female rats. Therefore, the current study investigated whether prior exposure to chronic stress potentiated the behavioral and neurochemical responses to an acute injection of methamphetamine in female rats. Adult female Sprague-Dawley rats were either exposed to CUS or left undisturbed (control) and then two weeks later received an injection of 1.0 or 7.5 mg/kg methamphetamine. Based on open field findings, a subsequent group of rats were exposed to CUS or left undisturbed and then two weeks later received 7.5 mg/kg methamphetamine and either dopamine efflux in the dorsal striatum or nucleus accumbens was measured or methamphetamine and amphetamine levels were measured in the brain and plasma. Female rats exposed to CUS traveled greater distances in the open field immediately following an injection of 7.5 mg/kg, but not 1.0 mg/kg, of methamphetamine and then showed high levels or stereotypy similar to control rats. Animals exposed to CUS had significantly greater increases in dorsal striatum dopamine following an acute injection of 7.5 mg/kg methamphetamine compared to control rats, but not in the nucleus accumbens. These differences were not due to group differences in levels of methamphetamine or amphetamine in the brain or plasma. The current findings demonstrate stress-augmented neurochemical responses to a dose of methamphetamine, similar to that self-administered, which increases understanding of the cross-sensitization between stress and methamphetamine in females.

Optogenetic inhibition of the medial prefrontal cortex reduces methamphetamine-primed reinstatement in male and female rats.

Preclinical findings suggest sex-differences exist in drug-seeking behavior following methamphetamine (METH) self-administration. The medial prefrontal cortex (mPFC), is thought to contribute to the reinstatement of drug-seeking in males. Glutamatergic neurons project from the prelimbic portion of the mPFC to various brain regions modulating activity including the nucleus accumbens; thus the prelimbic region of the mPFC is thought to contribute to drug-seeking behaviors. Although studied in males, little research has investigated the role of the mPFC in females. The purpose of this study was to investigate if the prelimbic portion of the mPFC plays a role in METH-seeking behavior in both male and female rats. Animals were allowed to self-administer METH, and underwent extinction and two reinstatement sessions. Reinstatement sessions were counterbalanced such that optogenetic inhibition targeting the prelimbic cortex of the mPFC occurred only during one reinstatement session. Results revealed an increase in METH consumption during self-administration in male and female animals. During extinction, lever-pressing behavior decreased as training progressed. Under sham conditions, female rats exhibited significantly higher drug-seeking behavior during reinstatement. However, when optogenetic inhibition was applied, both male and female animals significantly decreased drug-seeking. In both males and females, the prelimbic portion of the mPFC plays an important role in drug-seeking behavior as related to METH-seeking.

Behavioral and Serotonergic Changes in the Frontal Cortex Following Methamphetamine Self-Administration.

BACKGROUND: Methamphetamine use is associated with a variety of negative health outcomes, including psychosis. The frontal cortex serotonin receptors are thought to contribute to psychosis-like behaviors. This study investigated changes in serotonergic markers in the frontal cortex following methamphetamine self-administration and hallucinogenic drug-induced behavior. METHODS: Consistent with previously published studies, freely cycling male and female rats were allowed to self-administer methamphetamine (males: 0.12 mg/infusion; females: 0.09 mg/infusion) or saline (10 µL) for 7 days. On the day following self-administration or following 10 days of extinction training, animals were given the serotonin 2A/2C agonist, 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (2 mg/kg, i.p.), and head twitches were analyzed. Autoradiography was also used to assess serotonin receptors and transporters in the frontal cortex following self-administration. RESULTS: Methamphetamine self-administration led to an increase in DOI-induced head-twitch behavior compared to saline only on the day following self-administration. Increases in serotonin receptors in the orbitofrontal cortex and decreases in serotonin transporters in the orbitofrontal cortex and infralimbic cortex were observed following methamphetamine self-administration as assessed by autoradiography. CONCLUSIONS: Methamphetamine self-administration was associated with serotonergic alterations in the frontal cortex, which may underlie behavioral changes related to methamphetamine-associated psychosis.

The neurochemical consequences of methamphetamine self-administration in male and female rats.

BACKGROUND: Methamphetamine (METH) is an addictive substance that is used in both males and females. Few preclinical studies have focused on understanding sex-differences in the neurochemical consequences of contingent METH. The purpose of the current study was to investigate potential sex-differences in the neurochemical consequences of METH self-administration. METHODS: Male and female adult rats were given extended access to METH or saline self-administration for 7d. Following self-administration, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine transporter (DAT) were assessed via western blotting. RESULTS: Male and female rats had similar METH intake. METH self-administration reduced striatal DAT in both sexes, but only males that self-administered METH had elevated hippocampal BDNF levels. CONCLUSIONS: Sex-differences exist in the neurochemical consequences of METH self-administration. These differences may lead to sex-specific vulnerability to the toxic effects of METH.

The Persistent Neurotoxic Effects of Methamphetamine on Dopaminergic and Serotonergic Markers in Male and Female Rats.

OBJECTIVE: Methamphetamine (METH) is a highly addictive substance abused world-wide in both males and females. Preclinical studies in male rodents suggest that large-dose exposure to METH can lead to persistent neurotoxic consequences to various brain regions. However, little research has focused on the potential role of sex in the neurotoxic consequences of METH exposure. METHODS: The current study exposed male and female rats to large-doses of METH (4 injections of 7.5 mg/kg) or saline. Hyperthermia was promoted in the females exposed to METH such that similar hyperthermia occurred in males and females. Rats were sacrificed 8 d later and neurochemical changes were assessed in the striatum, hippocampus, frontal cortex and olfactory bulbs. RESULTS: Results revealed that male and female rats exposed to METH had similar decreases in dopamine (DA) transporter (DAT) immunoreactivity in the striatum, serotonin (5-HT) content and 5-HT transporter (SERT) function in the hippocampus, and 5-HT content in the frontal cortex. However, female rats exposed to METH had greater decreases in 5-HT content in the olfactory bulbs compared to sex-matched controls while male rats exposed to METH did not significantly differ from sex-matched controls. CONCLUSIONS: These findings suggest that when similar hyperthermia is maintained between male and female rats exposed to METH, the neurotoxic effects of METH were similar in some, but not all brain regions.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease.

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4ß2 and α6ß2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4ß2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6ß2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4ß2 and/or α6ß2 expression, and that both age of onset and duration of nicotine exposure affect this protection.

Nicotine Administration Attenuates Methamphetamine-Induced Novel Object Recognition Deficits.

BACKGROUND: Previous studies have demonstrated that methamphetamine abuse leads to memory deficits and these are associated with relapse. Furthermore, extensive evidence indicates that nicotine prevents and/or improves memory deficits in different models of cognitive dysfunction and these nicotinic effects might be mediated by hippocampal or cortical nicotinic acetylcholine receptors. The present study investigated whether nicotine attenuates methamphetamine-induced novel object recognition deficits in rats and explored potential underlying mechanisms. METHODS: Adolescent or adult male Sprague-Dawley rats received either nicotine water (10-75 µg/mL) or tap water for several weeks. Methamphetamine (4 × 7.5mg/kg/injection) or saline was administered either before or after chronic nicotine exposure. Novel object recognition was evaluated 6 days after methamphetamine or saline. Serotonin transporter function and density and α4ß2 nicotinic acetylcholine receptor density were assessed on the following day. RESULTS: Chronic nicotine intake via drinking water beginning during either adolescence or adulthood attenuated the novel object recognition deficits caused by a high-dose methamphetamine administration. Similarly, nicotine attenuated methamphetamine-induced deficits in novel object recognition when administered after methamphetamine treatment. However, nicotine did not attenuate the serotonergic deficits caused by methamphetamine in adults. Conversely, nicotine attenuated methamphetamine-induced deficits in α4ß2 nicotinic acetylcholine receptor density in the hippocampal CA1 region. Furthermore, nicotine increased α4ß2 nicotinic acetylcholine receptor density in the hippocampal CA3, dentate gyrus and perirhinal cortex in both saline- and methamphetamine-treated rats. CONCLUSIONS: Overall, these findings suggest that nicotine-induced increases in α4ß2 nicotinic acetylcholine receptors in the hippocampus and perirhinal cortex might be one mechanism by which novel object recognition deficits are attenuated by nicotine in methamphetamine-treated rats.

Effect of low doses of methamphetamine on rat limbic-related neurotensin systems.

Administration of methamphetamine (METH) alters limbic-related (LR) neurotensin (NT) systems. Thus, through a D1-receptor mechanism, noncontingent high doses (5-15 mg kg(-1)), and likely self-administration, of METH appears to reduce NT release causing its accumulation and an elevation of NT-like immunoreactivity (NTLI) in limbic-related NT pathways. For comparison, we tested the effect of low doses of METH, that are more like those used in therapy, on NTLI in the core and shell of the nucleus accumbens (NAc and NAs), prefrontal cortex (PFC), ventral tegmental area (VTA), the lateral habenula (Hb) and basolateral amygdala (Amyg). METH at the dose of 0.25 mg kg(-1) in particular, but not 1.00 mg kg(-1), decreased NTLI concentration in all of the LR structures studied, except for the prefrontal cortex; however, these effects were rapid and brief being observed at 5 h but not at 24 h after treatment. In all of the LR areas where NTLI levels were reduced after the low dose of METH, the effect was blocked by pretreatment with either a D1 or a D2 antagonist. Thus, opposite to high doses like those associated with abuse, the therapeutic-like low-dose METH treatment induced reduction in NT tissue levels likely reflected an increase in NT release and a short-term depletion of the levels of this neuropeptide in LR structures, manifesting features comparable to the response of basal ganglia NT systems to similar low doses of METH.

Prior methamphetamine self-administration attenuates the dopaminergic deficits caused by a subsequent methamphetamine exposure.

Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose "binge" METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposure of METH or saline (so as to assess the impact of prior METH self-administration), or were sacrificed without a subsequent METH exposure (i.e., to assess the status of the rats at what would have been the initiation of the binge METH treatment). Results revealed that METH self-administration per se decreased striatal dopamine (DA) transporter (DAT) function and DA content, as assessed 16 h after the last self-administration session. Exposure to a binge METH treatment beginning at this 16-h time point decreased DAT function and DA content as assessed 1 h after the binge METH exposure: this effect on DA content (but not DAT function) was attenuated if rats previously self-administered METH. In contrast, 24 h after the binge METH treatment prior METH self-administration: 1) attenuated deficits in DA content, DAT function and vesicular monoamine transporter-2 function; and 2) prevented increases in glial fibrillary acidic protein and DAT complex immunoreactivity. These data suggest that changes 24 h, but not 1 h, after binge METH exposure are predictive of tolerance against the persistence of neurotoxic changes following binge METH exposures.

Persistent behavioral and neurochemical sensitization to an acute injection of methamphetamine following unpredictable stress.

Prior research in humans and animals suggest that exposure to chronic stress alters the response to drugs of abuse, increasing vulnerability to drug addiction. Chronic unpredictable stress (CUS) has been shown to augment the increase of dopamine in the striatum when challenged with high doses of methamphetamine immediately following stress exposure, however it is not known whether this neurochemical stress-sensitization continues after the cessation of the stressors or if behavioral sensitization is also present. Therefore, the current study examined the immediate and delayed effects of CUS on methamphetamine-induced behaviors and striatal dopamine levels. Male rats were exposed to 10 days of CUS and then tested in either an open field box to assess locomotion or underwent in vivo microdialysis to measure striatal dopamine levels immediately following CUS or after a 1-2 week delay. All rats exposed to CUS showed a potentiated locomotor response immediately following an acute injection of 7.5mg/kg methamphetamine compared to non-stressed control rats. Both groups of CUS rats also showed augmented dopamine release and rectal temperatures following methamphetamine with prolonged increases in the CUS rats tested after a delay. These results suggest that CUS increases the sensitivity of a rat to a single injection of methamphetamine and that the increased sensitivity persists for up to 2 weeks following the last stressor.

Neurochemical and behavioral effects of chronic unpredictable stress.

Chronic stress can influence behaviors associated with medial prefrontal cortex (mPFC) function, such as cognition and emotion regulation. Dopamine in the mPFC is responsive to stress and modulates its behavioral effects. The current study tested whether exposure to 10 days of chronic unpredictable stress (CUS) altered the effects of acute elevation stress on dopamine release in the mPFC and on spatial recognition memory. Male rats previously exposed to CUS or nonstressed controls were tested behaviorally, underwent microdialysis to assess mPFC dopamine levels or underwent blood sampling for corticosterone analysis. Dopamine in the mPFC significantly increased in both groups during acute elevation stress compared with baseline levels, but the level was attenuated in CUS rats compared with controls. Control rats exposed to elevation stress immediately before the T-maze test showed impaired performance, whereas CUS rats did not. No group differences were observed in general motor activity or plasma corticosterone levels following elevation stress. The present results indicate that prior exposure to this CUS procedure reduced dopamine release in the mPFC during acute elevation stress and prevented the impairment of performance on a spatial recognition test following an acute stressor. These findings may contribute to an understanding of the complex behavioral consequences of stress.

Methamphetamine self-administration attenuates hippocampal serotonergic deficits: role of brain-derived neurotrophic factor.

Preclinical studies suggest that prior treatment with escalating doses of methamphetamine (METH) attenuates the persistent deficits in hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter (SERT) function resulting from a subsequent 'binge' METH exposure. Previous work also demonstrates that brain-derived neurotrophic factor (BDNF) exposure increases SERT function. The current study investigated changes in hippocampal BDNF protein and SERT function in rats exposed to saline or METH self-administration prior to a binge exposure to METH or saline. Results revealed that METH self-administration increased hippocampal mature BDNF (mBDNF) immunoreactivity compared to saline-treated rats as assessed 24 h after the start of the last session. Further, mBDNF immunoreactivity was increased and SERT function was not altered in rats that self-administered METH prior to the binge METH exposure as assessed 24 h after the binge exposure. These results suggest that prior exposure to contingent METH increases hippocampal mBDNF, and this may contribute to attenuated deficits in SERT function.