Enhanced heroin self-administration and distinct dopamine adaptations in female rats.

Increasing evidence suggests that females are more vulnerable to the harmful effects of drugs of abuse, including opioids. Additionally, rates of heroin-related deaths substantially increased in females from 1999 to 2017 [1], underscoring the need to evaluate sex differences in heroin vulnerability. Moreover, the neurobiological substrates underlying sexually dimorphic responding to heroin are not fully defined. Thus, we evaluated male and female Long Evans rats on acquisition, dose-responsiveness, and seeking for heroin self-administration (SA) as well as using a long access model to assess escalation of intake at low and high doses of heroin, 0.025 and 0.1 mg/kg/inf, respectively. We paired this with ex vivo fast-scan cyclic voltammetry (FSCV) in the medial nucleus accumbens (NAc) shell and quantification of mu-opioid receptor (MOR) protein in the ventral tegmental area (VTA) and NAc. While males and females had similar heroin SA acquisition rates, females displayed increased responding and intake across doses, seeking for heroin, and escalation on long access. However, we found that males and females had similar expression levels of MORs in the VTA and NAc, regardless of heroin exposure. FSCV results revealed that heroin exposure did not change single-pulse elicited dopamine release, but caused an increase in dopamine transporter activity in both males and females compared to their naïve counterparts. Phasic-like stimulations elicited robust increases in dopamine release in heroin-exposed females compared to heroin-naïve females, with no differences seen in males. Together, our results suggest that differential adaptations of dopamine terminals may underlie the increased heroin SA behaviors seen in females.

Acquisition of remifentanil self-administration: Enhanced in female rats but no effect of adolescent stress exposure.

Animal models of acquisition have been vital in shaping our understanding of vulnerability factors that influence susceptibility to drugs of abuse. Decades of research substantiates a number of biological, environmental, and behavioral factors that predict vulnerability - many of which have been important in the development of early intervention efforts in humans. The goal of the present study was to examine the acquisition of a synthetic opioid derivative in 66 adult male and female Long-Evans rats following histories of stress exposure during adolescence. Stress-exposed rats were subjected to a mild stress paradigm, which included alternating exposure to synthetic fox feces and physical restraint for eight days. Following stress induction and assessment, all rats were implanted with intravenous catheters in order to self-administer remifentanil (1 µm/kg/infusion) with no prior operant training. Acquisition of remifentanil self-administration was measured over 15 days. Findings indicate that regardless of stress condition, female rats acquired remifentanil self-administration sooner and emitted more active lever presses than males. Stress exposed animals exhibited increased anxiety-like response compared to the control group following exposure to stress, operationalized as decreased exploratory behavior on an Elevated Plus Maze. However, these effects were not expressed as significant differences in self-administration by stress. Together, these findings indicate that sex differences are evident in remifentanil self-administration.

Behavioral economic demand as a unifying language for addiction science: Promoting collaboration and integration of animal and human models.

The intersection of pharmacological, psychological, and economic theory within behavioral economics has helped advance an understanding of substance use disorder. A notable contribution of this approach is the conceptualization of reinforcement from a behavioral economic demand perspective. Demand analyses provide a multidimensional view of reinforcement in which distinct behavioral mechanisms are measured that impact decision making and drug consumption. This review describes the state of research on behavioral economic demand as a common language for addiction science researchers across varied model systems and stages of a translational continuum. We first provide an overview of the theoretical concepts and procedures used to evaluate demand in animal and human models. The potential for demand to serve as a common language for diverse research groups in psychopharmacology and addiction science (e.g., those evaluating neurobehavioral outcomes, medications development, clinical practice) is then described. An overview is also provided of existing empirical studies that, while small in number, suggest good linguistic and conceptual overlap between animal and human demand models when studying biological, environmental, and pharmacological individual difference vulnerabilities underlying drug-taking behavior. Refinement of methodological procedures and incorporation of more nuanced environmental features should help improve correspondence between animal and human demand studies as well as clinical translation of such findings. Our hope is that this review and commentary ultimately serves as inspiration for new collaborative efforts involving behavioral economic demand between animal and human researchers who share a common goal of improving substance use treatment outcomes and broader psychological wellbeing. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The influence of sex and estrous cyclicity on cocaine and remifentanil demand in rats.

The application of behavioral economic demand theory in addiction science has proved useful for evaluating individual characteristics underlying abuse liability. Two factors that have received comparably little attention within this literature are sex and gonadal hormones. We determined cocaine and remifentanil demand in male and female rats using a within-session procedure. Cocaine and remifentanil demand were evaluated for 15 consecutive days using a balanced, crossover design that randomized drug order. This design allowed for the evaluation of temporal and exposure effects on two independent dimensions of demand, unconstrained demand (Q0 ) and demand elasticity (α). Estrous cyclicity was tracked to determine the contribution of phase to demand. No overall sex differences were observed. Increased unconstrained demand for cocaine and remifentanil was observed in females during periods in which estrogen was high (eg, estrus phase). Unconstrained remifentanil demand escalated over the 15-day testing period, but escalation was not observed for cocaine or for demand elasticity. A significant exposure effect was also observed in which greater prior remifentanil intake increased unconstrained cocaine demand and reduced cocaine demand elasticity. These effects were directionally specific as no significant effects of prior cocaine exposure were observed on remifentanil demand measures. These data suggest that unconstrained demand and demand elasticity do not differ between male and female subjects; however, that unconstrained demand is associated with estrous cyclicity. These findings also suggest that opioid exposure enhances subsequent demand for psychomotor stimulants, which may be important when considering recent increases in nonmedical prescription opioid use in the United States.

Multiprobe Nuclear Imaging of the Cystic Fibrosis Lung as a Biomarker of Therapeutic Effect.

Background: Nuclear imaging biomarkers illustrate unique aspects of lung physiology and are useful for assessing therapeutic effects in cystic fibrosis (CF) lung disease. We have developed a multiprobe method to simultaneously measure mucociliary clearance (MCC) and paracellular absorption (ABS). MCC is a direct measure of mucus clearance. ABS has been related to airway surface liquid (ASL) absorption through previous in vitro studies. Methods: We describe baseline factors affecting MCC and ABS using data from a retrospective baseline group (n = 22) and the response of the measures to inhaled 7% hypertonic saline (HS) and dry powder mannitol using data from a prospective response group (n = 7). A retrospective healthy control group (n = 15) is also described. The baseline and control groups performed single measurements of MCC/ABS. The response group performed baseline measurements of MCC/ABS and measurements after each intervention. Results: ABS was correlated (Spearman's ρ = 0.51, p = 0.06) to sweat chloride, a systemic measure of cystic fibrosis transmembrane conductance regulator (CFTR) function, whereas MCC was not. Baseline MCC was depressed after Pseudomonas aeruginosa infection as we have previously described. MCC provided a more sensitive indication of therapeutic effect and indicated improved clearance with mannitol compared with HS. Conclusion: MCC provides a useful and well-established means of testing therapies directed at improving mucus clearance in the lung. ABS may provide a means of detecting local changes in ASL absorption and CFTR function in the lung. Both are useful tools for studying the key aspects of CF lung pathophysiology (ASL hyperabsorption and MCC depression) that link the basic genetic defects of CF to disease manifestations in the lung.

Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats.

RATIONALE: Preclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity. OBJECTIVES: The purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats. METHODS: Female rats were obtained during late adolescence and divided into two groups. Resistance exercise rats were trained to climb a vertical ladder wearing a weighted vest; sedentary control rats were placed repeatedly on the ladder oriented horizontally on its side. All rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. mRNA expression in the NAc core and shell was examined following behavioral testing. RESULTS: Resistance exercise significantly decreased heroin self-administration, resulting in a downward shift in the dose-effect curve. Resistance exercise also reduced mRNA expression for mu opioid receptors and dopamine D1, D2, and D3 receptors in the NAc core. Resistance exercise increased mRNA expression of dopamine D5 receptors in the NAc shell and increased mRNA expression of brain-derived neurotrophic factor (exons I, IIB, IIC, IV, VI, IX) in the NAc core. CONCLUSIONS: These data indicate that resistance exercise decreases the positive reinforcing effects of heroin and produces changes in opioid and dopamine systems in the NAc of heroin-exposed rats.

Adolescent d-amphetamine exposure enhances the acquisition of cocaine self-administration in male and female rats.

Diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) has risen drastically over the past 20 years in the United States and abroad. Amphetamine-based prescription stimulants are the most prescribed treatment for ADHD and the diversion of these drugs has also increased. Reports indicate 61% of individuals with an ADHD medication prescription have sold or shared their medication. Exposure to prescription stimulants, especially for those without an ADHD diagnosis, may increase susceptibility to drugs of abuse. The present study aimed to model ADHD medication misuse during adolescence in male and female rats. The primary dependent measure was the acquisition of intravenous cocaine self-administration. Male and female, Long-Evans rats were exposed to d-amphetamine (0.7 mg/kg, i.p.) or saline in adolescence (35-41 days old), during which locomotor activity was measured. At approximately 75 days old, animals were implanted with jugular catheters. All animals then entered a 15-day acquisition procedure with no prior operant training. Finally, following acquisition all animals responded on a progressive-ratio (PR) schedule to obtain 0, 0.1, 0.3, and 1.0 mg/kg/infusion cocaine. Animals exposed to amphetamine acquired cocaine self-administration faster than saline-exposed controls when the acquisition criterion was operationally defined as two consecutive days with 12 infusions or greater. Discrete-time hazard modeling also found amphetamine exposure to increase the likelihood of acquiring cocaine self-administration. There were no differences detected during PR testing. These data suggest that individuals with histories of prescription stimulant misuse may be at increased risk to use other drugs of abuse. (PsycINFO Database Record

Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis.

AIM: Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. METHOD: In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. RESULTS: Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. CONCLUSIONS: The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways.

The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats.

RATIONALE: Preclinical studies indicate that gonadal hormones are important determinants of drug self-administration. To date, little is known about the influence of sex and estrous cycle on drug self-administration in ecologically relevant social contexts. OBJECTIVE: The objective of this study was to examine the role of sex and estrous cycle in a rat model during cocaine and heroin self-administration with male-female and female-female social dyads. METHODS: Male and female virgin rats were trained to self-administer cocaine and heroin in operant conditioning chambers that permitted two rats to self-administer concurrently, but prevented physical contact. Experiment 1 examined cocaine self-administration on a progressive ratio schedule in male-female dyads. Experiments 2 and 3 examined heroin self-administration on a fixed ratio schedule in male-female dyads at constant and varying doses, respectively. Experiment 4 examined heroin self-administration in female-female dyads on a fixed ratio schedule. RESULTS: Cocaine-maintained breakpoints increased by ∼17 % in females during estrus, but remained consistent in males. Heroin self-administration decreased by ∼70 % during proestrus in females whether they were isolated, housed with males, or housed with females. Heroin self-administration was lower in males than females under some conditions and was not consistently associated with the responding of females. CONCLUSIONS: Cocaine and heroin self-administration is influenced by the estrous cycle in females when in the presence of a male partner. As a novel finding, these data illustrate that heroin self-administration is reduced in females during proestrus regardless of the social context tested. Finally, these data suggest that drug self-administration in males is only minimally influenced by the hormonal status of a female partner.

The effects of social contact on cocaine intake under extended-access conditions in male rats.

Social learning theories of drug use propose that drug use is influenced by the behavior of peers. We previously reported that cocaine self-administration under limited-access conditions can be either facilitated or inhibited by social contact, depending on the behavior of a peer. The purpose of this study was to determine whether social contact influences cocaine self-administration under conditions that are more representative of problematic patterns of drug use. Male rats were assigned to either isolated or pair-housed conditions in which a social partner either had access to cocaine or did not have access to cocaine. Pair-housed rats were tested in custom-built operant conditioning chambers that allowed both rats to be tested simultaneously in the same chamber. In Experiment 1, rats were tested for 14 consecutive days during daily 6-hr test sessions. In Experiment 2, different doses of cocaine were tested in 23-hr test sessions conducted every 3 days. All groups of rats escalated their cocaine intake in Experiment 1; however, pair-housed rats with a partner without access to cocaine had lower levels of intake throughout the 14 days of testing. In Experiment 2, pair-housed rats with a partner without access to cocaine had lower levels of cocaine intake than did rats with a partner with access to cocaine, and this effect was observed at all doses of cocaine tested. These data indicate that the behavior of a social partner (i.e., whether or not that partner is also self-administering cocaine) influences cocaine self-administration under conditions that model problematic patterns of drug use. (PsycINFO Database Record

Intravenous Prenatal Nicotine Exposure Alters METH-Induced Hyperactivity, Conditioned Hyperactivity, and BDNF in Adult Rat Offspring.

In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth weight in offspring, but it can also negatively influence neurodevelopmental outcomes in later stages of life, such as an increased incidence of obesity and drug abuse. Animal models demonstrate that prenatal nicotine (PN) alters the development of the mesocorticolimbic system, which is important for organizing goal-directed behavior. In the present study, we determined whether intravenous (IV) PN altered the initiation and/or expression of methamphetamine (METH)-induced locomotor sensitization as a measure of mesocorticolimbic function in adult rat offspring. We also determined whether PN and/or METH exposure altered protein levels of BDNF (brain-derived neurotrophic factor) in the nucleus accumbens, the dorsal striatum, and the prefrontal cortex of adult offspring. BDNF was of interest because of its role in the development and maintenance of the mesocorticolimbic pathway and its ability to modulate neural processes that contribute to drug abuse, such as sensitization of the dopamine system. Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline, 3×/day on gestational days 8-21. Testing was conducted when offspring reached adulthood (around postnatal day 90). Following 3 once daily habituation sessions the animals received a saline injection and baseline locomotor activity was measured. PN and prenatal saline (PS)-exposed offspring then received 10 once daily injections of METH (0.3 mg/kg) to induce locomotor sensitization. The animals received a METH injection (0.3 mg/kg) to assess the expression of sensitization following a 14-day period of no injections. A day later, all animals were injected with saline and conditioned hyperactivity was assessed. Brain tissue was harvested 24 h later. PN animals habituated more slowly to the activity chambers compared to PS controls. PN rats treated with METH showed significant enhancement of locomotor behavior compared to PS rats following acute and repeated injections; however, PN did not produce differential initiation or expression of behavioral sensitization. METH produced conditioned hyperactivity, and PN rats exhibited a greater conditioned response of hyperactivity relative to controls. PN and METH exposure produced changes in BDNF protein levels in all three regions, and complex interactions were observed between these two factors. Logistic regression revealed that BDNF protein levels, throughout the mesocorticolimbic system, significantly predicted the difference in the conditioned hyperactive response of the animals: both correlations were significant, but the predicted relationship between BDNF and context-elicited activity was stronger in the PN (r = 0.67) compared to the PS rats (r = 0.42). These findings indicate that low-dose PN exposure produces long-term changes in activity and enhanced sensitivity to the locomotor effects of METH. The enhanced METH-induced contextual conditioning shown by the PN animals suggests that offspring of in utero tobacco smoke exposure have greater susceptibility to learn about drug-related conditional stimuli, such as the context. The PN-induced alterations in mesocorticolimbic BDNF protein lend further support for the hypothesis that maternal smoking during pregnancy produces alterations in neuronal plasticity that contribute to drug abuse vulnerability. The current findings demonstrate that these changes are persistent into adulthood.

The effects of resistance exercise on cocaine self-administration, muscle hypertrophy, and BDNF expression in the nucleus accumbens.

BACKGROUND: Exercise is associated with positive outcomes in drug abusing populations and reduces drug self-administration in laboratory animals. To date, most research has focused on aerobic exercise, and other types of exercise have not been examined. This study examined the effects of resistance exercise (strength training) on cocaine self-administration and BDNF expression, a marker of neuronal activation regulated by aerobic exercise. METHODS: Female rats were assigned to either exercising or sedentary conditions. Exercising rats climbed a ladder wearing a weighted vest and trained six days/week. Training consisted of a three-set "pyramid" in which the number of repetitions and resistance varied across three sets: eight climbs carrying 70% body weight (BW), six climbs carrying 85% BW, and four climbs carrying 100% BW. Rats were implanted with intravenous catheters and cocaine self-administration was examined. Behavioral economic measures of demand intensity and demand elasticity were derived from the behavioral data. BDNF mRNA expression was measured via qRT-PCR in the nucleus accumbens following behavioral testing. RESULTS: Exercising rats self-administered significantly less cocaine than sedentary rats. A behavioral economic analysis revealed that exercise increased demand elasticity for cocaine, reducing consumption at higher unit prices. Exercising rats had lower BDNF expression in the nucleus accumbens core than sedentary rats. CONCLUSIONS: These data indicate that resistance exercise decreases cocaine self-administration and reduces BDNF expression in the nucleus accumbens after a history of cocaine exposure. Collectively, these findings suggest that strength training reduces the positive reinforcing effects of cocaine and may decrease cocaine use in human populations.

The effects of physical activity on impulsive choice: Influence of sensitivity to reinforcement amount and delay.

Impulsive choice is a diagnostic feature and/or complicating factor for several psychological disorders and may be examined in the laboratory using delay-discounting procedures. Recent investigators have proposed using quantitative measures of analysis to examine the behavioral processes contributing to impulsive choice. The purpose of this study was to examine the effects of physical activity (i.e., wheel running) on impulsive choice in a single-response, discrete-trial procedure using two quantitative methods of analysis. To this end, rats were assigned to physical activity or sedentary groups and trained to respond in a delay-discounting procedure. In this procedure, one lever always produced one food pellet immediately, whereas a second lever produced three food pellets after a 0, 10, 20, 40, or 80-s delay. Estimates of sensitivity to reinforcement amount and sensitivity to reinforcement delay were determined using (1) a simple linear analysis and (2) an analysis of logarithmically transformed response ratios. Both analyses revealed that physical activity decreased sensitivity to reinforcement amount and sensitivity to reinforcement delay. These findings indicate that (1) physical activity has significant but functionally opposing effects on the behavioral processes that contribute to impulsive choice and (2) both quantitative methods of analysis are appropriate for use in single-response, discrete-trial procedures.

Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung.

Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis.

The effects of a shared history of drug exposure on social choice.

Selection theories of drug use propose that individuals choose or self-select into peer groups on the basis of perceived similarities with other group members with regard to their beliefs, attitudes, and histories of drug use. The purpose of the present study was to determine whether a shared history of drug exposure would influence choice of a social partner. Adolescent male rats were treated with either cocaine (3.0 mg/kg, intraperitoneally) or saline and their preference for a cocaine-treated rat or a saline-treated rat was measured in a partner preference test. Next, a series of conditioning trials were conducted in which rats were paired with a cocaine-treated and a saline-treated partner on alternating days for 10 days. Finally, a second partner preference test was conducted, in which preference for cocaine-treated and saline-treated partners was reassessed. Relative to baseline, rats showed an increase in the amount of time they spent with their similarly treated partner, and this effect was driven by cocaine-treated rats increasing the amount of time spent in proximity to their cocaine-treated partner after conditioning. These findings support a selection model of drug use by showing that a shared history of drug exposure is sufficient to establish a social preference for one individual over another.

Cocaine self-administration in social dyads using custom-built operant conditioning chambers.

BACKGROUND: Traditionally, the analysis of intravenous drug self-administration is limited to conditions in which subjects are tested in isolation. This limits the translational appeal of these studies because drug use in humans often occurs in the presence of others. NEW METHOD: We used custom-built operant conditioning chambers that allowed social dyads visual, olfactory, auditory, and limited tactile contact while concurrently self-administering cocaine. Male rats were trained to respond according to a fixed interval schedule of reinforcement (with a limited hold) in order to determine if patterns of cocaine (0.75mg/kg/infusion) self-administration became more similar over time in social pairs. Cocaine self-administration was tested across five days according to a 10-min fixed interval schedule (with a 5-min limited hold). Quarter-life values (time at which 25% of responses were emitted per interval) were analyzed using intraclass correlations. RESULTS: The total number of reinforcers obtained did not vary across the five days of testing; however, quarter-life values became progressively more similar between individuals within the social dyads. COMPARISON WITH EXISTING METHODS: Standard operant conditioning chambers are unable to assess responding in multiple animals due to their small size, the need to prevent subjects from responding on the lever of their partner, and the need to prevent infusion lines from entangling. By using custom-built social operant conditioning chambers, we assessed the effects of social contact on cocaine self-administration. CONCLUSION: Social operant conditioning chambers can be used as a preclinical method to examine social influences on drug self-administration under conditions that approximate human substance use.

Exercise decreases speedball self-administration.

AIMS: Epidemiological studies report that individuals who exercise are less likely to abuse drugs. Preclinical studies report that exercise, in the form of treadmill or wheel running, reliably decreases the self-administration of psychomotor stimulants and opioids. To date, preclinical studies have only examined the effects of exercise on responding maintained by individual drugs and not by combinations of multiple drugs. This limits the translational appeal of these studies because polydrug abuse is common among substance abusing populations. The purpose of this study was to examine the effects of exercise on the self-administration of speedball, a combination of cocaine and heroin that is frequently encountered in intravenous drug abusing populations. MAIN METHODS: Female rats were obtained at weaning and assigned to sedentary or exercising conditions. Sedentary rats were housed in standard cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed in similar cages with an activity wheel. After 6weeks, rats were implanted with intravenous catheters and trained to self-administer cocaine, heroin, and dose combinations of cocaine and heroin (i.e., speedball) on a progressive ratio schedule of reinforcement. KEY FINDINGS: Doses of speedball maintained greater levels of responding than corresponding doses of cocaine and heroin alone. Importantly, responding maintained by cocaine, heroin, and speedball was lower in exercising rats than sedentary rats. SIGNIFICANCE: These data indicate that exercise decreases the self-administration of speedball and suggest that exercise may reduce the abuse of drug combinations that have traditionally been resistant to treatment.

IV prenatal nicotine exposure increases the reinforcing efficacy of methamphetamine in adult rat offspring.

BACKGROUND: Maternal smoking during pregnancy is correlated with increased substance use in offspring. Research using rodent models shows that gestational nicotine exposure produces enduring alterations in the neurodevelopment of motivational systems, and that rats prenatally treated with nicotine have altered motivation for drug reinforcement on fixed-ratio (FR) schedules of reinforcement. OBJECTIVE: The present study investigated methamphetamine (METH) self-administration in adult offspring prenatally exposed to intravenous (IV) nicotine or saline using a progressive-ratio (PR) schedule of reinforcement. METHODS: Pregnant rats were administered IV prenatal saline (PS) or nicotine (PN; 0.05mg/kg/infusion), 3×/day during gestational days 8-21. At postnatal day 70, offspring acquired a lever-press response for sucrose (26%, w/v; FR1-3). Rats were trained with METH (0.05mg/kg/infusion), and following stable FR responding, animals were tested using a progressive-ratio (PR) schedule for three different doses of METH (0.005, 0.025, and 0.05mg/kg/infusion). RESULTS: METH infusion, active lever presses, and the ratio breakpoint are reported. PN-exposed animals exhibited more METH-maintained responding than PS controls, according to a dose×prenatal treatment interaction (e.g., infusions). PN rats self-administered more METH infusions between the range of 0.025 and 0.05, but not for the 0.005mg/kg/infusion dose. CONCLUSIONS: IV PN-exposure produced enhanced motivation to self-administer METH. These findings indicate that pregnant women who smoke tobacco may impart neurobiological changes in offspring's motivational systems that render them increasingly vulnerable to drug abuse during adulthood.

The effects of social learning on the acquisition of cocaine self-administration.

BACKGROUND: Social learning models of substance use propose that drug-use behaviors are learned by observing and mimicking the behavior of others. The aim of this study was to examine the acquisition of cocaine self-administration in three groups of experimentally naïve rats: rats that were tested in isolation, rats that were tested in the presence of another rat that had access to cocaine and had previously been trained to self-administer cocaine, and rats that were tested in the presence of another rat that did not have access to cocaine. METHODS: Male rats were reared in isolated or pair-housed conditions and implanted with intravenous catheters. Pair-housed rats were then assigned to drug-experienced or drug-naïve conditions. In the drug-experienced condition, one rat of each pair was trained to self-administer cocaine in isolation before the reintroduction of its partner. In the drug-naïve condition, one rat of each pair did not have access to cocaine for the duration of the study. For each group, the acquisition of cocaine self-administration was measured over 15 days in rats with access to cocaine but no prior operant training. RESULTS: Rats tested with a drug-experienced partner were faster to acquire cocaine self-administration and emitted more active lever presses than rats tested with a cocaine-naïve partner. Data for the isolated control group fell between the other two groups on these measures. CONCLUSION: These data indicate that the acquisition of cocaine self-administration can either be facilitated or inhibited by social contact. Collectively, these results support a social learning model of substance use.