Developmental exposure to 17-α-hydroxyprogesterone caproate disrupts decision-making in adult female rats: A potential role for a dopaminergic mechanism.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1-P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms.

Chronic high-dose testosterone impairs economic decision making, but has no effect on memory in male rats.

The goal is to understand consequences of anabolic-androgenic steroid (AAS) abuse on cognitive function, using rats as a model. Economic decision making was evaluated in an operant test of effort value discounting, where subjects choose between 2 levers that deliver large and small rewards differing in maximum value and reward contrast. The hypothesis is that chronic high-dose testosterone increases preference for large rewards. Male rats were treated chronically with testosterone (7.5 mg/kg) or vehicle. Initially, all rats preferred the large reward lever when large and small rewards remained fixed at 3 and 1 sugar pellets, respectively. When different reward values were introduced, and with increasing response requirements, testosterone-treated rats made fewer responses for the large reward, and increased omissions. They earned fewer rewards overall. To determine if testosterone impairs memory, rats were tested for recognition memory with the novel object recognition and social transmission of food preference tasks, and for spatial memory with the radial arm maze and Morris water maze. There was not effect of chronic high-dose testosterone on any memory task. These results suggest that testosterone shifts economic decision making towards larger rewards even when they are disadvantageous, but does not alter memory in rats.

Effort-based decision making in response to high-dose androgens: role of dopamine receptors.

INTRODUCTION: Anabolic-androgenic steroids (AAS) are performance-enhancing drugs used by both world-class and rank-and-file athletes. AAS abuse has been linked with risky decision-making, ranging from drunk driving to abusing multiple drugs. Our lab uses operant behavior in rats to test the effects of AAS (testosterone) on decision making. In our previous study, testosterone caused rats to work harder for food reward during an effort discounting (ED) task. ED is sensitive to dopamine in the nucleus accumbens, and AAS alter accumbens dopamine receptor expression. Accordingly, we determined if testosterone increases response to dopamine receptor antagonists during ED. METHODS: Rats were treated chronically with high-dose testosterone (7.5 mg/kg; n = 9) or vehicle (n = 9). We measured baseline preference for the large reward in an ED task, where rats choose between a small easy reward (one lever press for one sugar pellet) and a large difficult reward (2, 5, 10, or 15 presses for three pellets). Preference for the large reward was measured after administration of D1-like (SCH23390, 0.01 mg/kg) or D2-like (eticlopride, 0.06 mg/kg) receptor antagonists. RESULTS: At baseline, testosterone- and vehicle-treated rats showed similar preference for the large reward lever (FR5, testosterone: 68.6 ± 9.7% and vehicle: 85.7 ± 2.5%). SCH23390 reduced large reward preference significantly in both groups (FR5, testosterone: 41.3 ± 9.2%; vehicle: 49.1 ± 8.2%; F(1,16) = 17.7; P < 0.05). Eticlopride decreased large reward preference in both groups, but more strongly in testosterone-treated rats (FR5: testosterone: 37.0 ± 9.7%; vehicle: 56.3 ± 7.8%; F(1,16) = 35.3; P < 0.05). CONCLUSION: Testosterone increases response to dopamine D2-like receptor blockade, and this contributes to previously observed changes in decision-making behaviors.

Developmental exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate, disrupts the mesocortical serotonin pathway and alters impulsive decision-making in rats.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to women at risk for preterm birth during a critical period of fetal development for mesocortical pathways. Yet, little information is available regarding the potential effects of 17-OHPC on the developing fetal brain. In rat models, the mesocortical serotonin pathway is sensitive to progestins. Progesterone receptor (PR) is expressed in layer 3 pyramidal neurons of medial prefrontal cortex (mPFC) and in serotonergic neurons of the dorsal raphe. The present study tested the hypothesis that exposure to 17-OHPC during development disrupts serotonergic innervation of the mPFC in adolescence and impairs behavior mediated by this pathway in adulthood. Administration of 17-OHPC from postnatal days 1-14 decreased the density of SERT-ir fibers within superficial and deep layers and decreased the density of synaptophysin-ir boutons in all layers of prelimbic mPFC at postnatal day 28. In addition, rats exposed to 17-OHPC during development were less likely to make impulsive choices in the Delay Discounting task, choosing the larger, delayed reward more often than controls at moderate delay times. Interestingly, 17-OHPC exposed rats were more likely to fail to make any choice (i.e., increased omissions) compared to controls at longer delays, suggesting disruptions in decision-making. These results suggest that further investigation is warranted in the clinical use of 17-OHPC to better inform a risk/benefit analysis of progestin use in pregnancy.

Performance on a modified signal detection task of attention is impaired in male and female rats following developmental exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate.

Based on evidence that the developing mesocortical dopamine pathway is sensitive to progestins, in the present study we tested the hypothesis that attention, a fundamental component of successful cognitive behavior, is disrupted by developmental exposure to the synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC). To assess attentional impairments, a modified signal detection task was utilized with three stimulus modalities: compound (light and tone), light alone, and tone alone, for four stimulus durations (2, 0.5, 0.25, 0.125 s). Adult rats were trained to push one lever if they detected the stimulus, and another lever if the stimulus was not presented. 17-OHPC animals were able to attend to the task, as evidenced by similar correct responses as controls. However, as the task became increasingly difficult at shorter durations, 17-OHPC animals made significantly more omissions compared to controls, suggesting that 17-OHPC treatment may disrupt attentional processes and/or delay response time. These findings add to the current body of literature demonstrating that exposure to 17-OHPC during development produces deficits in cognitive behavior in adulthood. These results may inform potential risks associated with 17-OHPC treatment in pregnant women with a history of preterm delivery who are commonly recipients of such treatment.

Cooperative responses in rats playing a 2 × 2 game: Effects of opponent strategy, payoff, and oxytocin.

The present study tested cooperation in rats playing a 2 × 2 game (2 players, 2 responses) in an operant chamber, where players choose to cooperate or defect without knowledge of their partner's choice. We evaluated cooperative responses in rats (Subjects) playing different games [iterated Prisoner's Dilemma (IPD), Stag Hunt] with a Stooge partner utilizing different response strategies [Tit-for-tat (TFT), Win-stay, Lose-shift (WSLS), Random], and we determined the effects of oxytocin (OT). IPD trial outcomes and payoffs included mutual cooperation (reward, R, 3 sugar pellets each), mutual defection (punishment, P, 1 pellet each), or unilateral defection (temptation, T, 5 pellets) and cooperation (sucker, S, 0 pellets). Stag Hunt was similar, except that T = 2 pellets. We hypothesized that Subjects would make more cooperative responses when playing Stag Hunt vs IPD, when playing IPD with a Stooge using TFT vs WSLS or Random, and when treated with OT. At baseline, Subjects' overall likelihood of cooperation was unaffected by the game (IPD vs SH) or by the Stooges' response strategy (TFT, WSLS, Random). Cooperative responses earned Subjects more pellets, except when playing with a Stooge using a random strategy. Trial outcomes (R, T, S or P) also varied by game and strategy, although the mutual defection (P) was the most common. Systemic pretreatment with OT increased Subjects' cooperative responses, resulting in fewer P and more R outcomes. In particular, IPD-Random Subjects were more cooperative, even at the expense of earning fewer pellets. These results demonstrate that OT increases cooperative behavior in rats playing 2 × 2 games.

Developmental exposure to 17α-hydroxyprogesterone caproate impairs adult delayed reinforcement and reversal learning in male and female rats.

Women with a history of unexplained miscarriage are frequently prescribed the synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC) during the middle trimester of pregnancy. However, little is known about the long-term behavioural effects of 17-OHPC. Work in rodents suggests that the developing brain is sensitive to progestins. Neonatal 17-OHPC impairs adult performance in set-shifting and delay discounting. The present study tested the effects of 17-OHPC (0.5 mg kg-1 ) or vehicle administration from postnatal days 1-14 on cognitive function in adulthood in rats. Cognitive function was assessed in males and females (n = 8-10 per group) by operant responding for sugar pellets, measuring delayed reinforcement or reversal learning. For delayed reinforcement, the rat must wait 15 seconds for pellets after responding on a lever. Delay is signalled by a light or is unsignalled. For reversal learning, the rat must respond on the lever under a stimulus light, and then learn to respond on the unlit lever. For delayed reinforcement, rats earned more pellets under signalled vs unsignalled conditions. Likewise, males made more responses and earned more pellets compared to females. Under signalled conditions, 17-OHPC-treated rats earned fewer pellets than controls. For reversal learning, the results were similar. Females required more trials than males to respond correctly for the new rule, and 17-OHPC-treated rats required more trials than controls. This suggests that 17-OHPC exposure during development may impair cognitive function. Considering that questions have been raised as to the efficacy of 17-OHPC to prevent miscarriage, it may be necessary to rethink the use of progestin therapy during pregnancy.

Sex Differences and Estrous Influences on Oxytocin Control of Food Intake.

Central oxytocin potently reduces food intake and is being pursued as a clinical treatment for obesity. While sexually dimorphic effects have been described for the effects of oxytocin on several behavioral outcomes, the role of sex in central oxytocin modulation of feeding behavior is poorly understood. Here we investigated the effects of sex, estrous cycle stage, and female sex hormones (estrogen, progesterone) on central oxytocin-mediated reduction of food intake in rats. Results show that while intracerebroventricular (ICV) oxytocin potently reduces chow intake in both male and female rats, these effects were more pronounced in males than in females. We next examined whether estrous cycle stage affects oxytocin's food intake-reducing effects in females. Results show that ICV oxytocin administration significantly reduces food intake during all estrous cycle stages except proestrous, suggesting that female sex hormones may modulate the feeding effects of oxytocin. Indeed, additional results reveal that estrogen, but not progesterone replacement, in ovariectomized rats abolishes oxytocin-mediated reductions in chow intake. Lastly, oxytocin receptor mRNA (Oxtr) quantification (via quantitative PCR) and anatomical localization (via fluorescent in situ hybridization) in previously established sites of action for oxytocin control of food intake revealed comparable Oxtr expression between male and female rats, suggesting that observed sex and estrous differences may be based on variations in ligand availability and/or binding. Overall, these data show that estrogen reduces the effectiveness of central oxytocin to inhibit food intake, suggesting that sex hormones and estrous cycle should be considered in clinical investigations of oxytocin for obesity treatment.

Anabolic-androgenic steroid abuse and cognitive impairment: Testosterone IMPAIRS biconditional task performance in male rats.

Our goal is to understand the consequences of anabolic-androgenic steroid (AAS) abuse on cognitive function, using rats as a model. There is relatively little research on how AAS abuse impacts cognition. In the present study, rats were tested for their ability to use contextual information to guide decision-making in biconditional discrimination. The Stroop task is a classic human test for contextual decision-making. In rodents, biconditional discrimination challenges subjects to use contextual cues in the operant chamber to resolve the correct lever response when auditory and visual cues are incongruent. The hypothesis is that chronic high-dose testosterone impairs biconditional discrimination. Rats were trained in 24 trials/day over 14 days, in alternating sessions with each environment. On a flat floor with houselight illuminated, auditory cues (clicker vs tone) signified the active lever. On a barred floor with no light, visual cues from 2 stimulus lights (constant vs blinking) identified the active lever. Rats treated chronically with testosterone (7.5 mg/kg) were unimpaired in task acquisition, and all rats learned to select the correct lever in response to auditory or visual cues. During extinction, controls made significantly more correct than incorrect responses in congruent trials (p < 0.05 by paired t-test), but testosterone-treated rats failed to show a similar preference. This was reflected by significant interactions of drug x cue agreement (F1,18 = 5.21, p < 0.05) and drug x cue agreement x response accuracy (F1,18 = 8.95, p < 0.05). These results suggest that testosterone impairs cognitive flexibility, and demonstrates potential for AAS abuse to impair cognitive function in humans.

Anabolic-androgenic steroids and cognitive effort discounting in male rats.

Anabolic-androgenic steroids (AAS) are drugs of abuse that impair behavior and cognition. In a rodent model of AAS abuse, testosterone-treated male rats expend more physical effort, by repeatedly pressing a lever for a large reward in an operant discounting task. However, since modern society prioritizes cognitive over physical effort, it is important to determine if AAS limit cognitive effort. Here we tested the effects of AAS on a novel cognitive-effort discounting task. Each operant chamber had 3 nose-pokes, opposite 2 levers and a pellet dispenser. Rats pressed a lever to illuminate 1 nose-poke; they responded in the illuminated nose-poke to receive sugar pellets. For the 'easy' lever, the light remained on for 1 s, and a correct response earned 1 pellet. For the 'hard' lever, the light duration decreased from 1 s to 0.1 s across 5 blocks of trials, and a correct response earned 4 pellets. As the duration of the nose-poke light decreased, all rats decreased their choice of the hard lever in a modest discounting curve. Task accuracy also decreased significantly across the 5 blocks of trials. However, there was no effect of testosterone on choice of the hard lever or task accuracy. Antagonism of dopamine D1 or D2 receptors had no effect on lever choice or task accuracy. However, serotonin depletion significantly decreased preference for the hard lever, and impaired task accuracy. Thus, physical effort discounting depends on dopamine activity, while cognitive effort discounting task is sensitive to serotonin. AAS impair physical effort discounting, but not cognitive effort discounting.

Androgen Regulation of the Mesocorticolimbic System and Executive Function.

Multiple lines of evidence indicate that androgens, such as testosterone, modulate the mesocorticolimbic system and executive function. This review integrates neuroanatomical, molecular biological, neurochemical, and behavioral studies to highlight how endogenous and exogenous androgens alter behaviors, such as behavioral flexibility, decision making, and risk taking. First, we briefly review the neuroanatomy of the mesocorticolimbic system, which mediates executive function, with a focus on the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Second, we present evidence that androgen receptors (AR) and other steroid receptors are expressed in the mesocorticolimbic system. Using sensitive immunohistochemistry and quantitative polymerase chain reaction (qPCR) techniques, ARs are detected in the VTA, NAc, mPFC, and OFC. Third, we describe recent evidence for local androgens ("neuroandrogens") in the mesocorticolimbic system. Steroidogenic enzymes are expressed in mesocorticolimbic regions. Furthermore, following long-term gonadectomy, testosterone is nondetectable in the blood but detectable in the mesocorticolimbic system, using liquid chromatography tandem mass spectrometry. However, the physiological relevance of neuroandrogens remains unknown. Fourth, we review how anabolic-androgenic steroids (AAS) influence the mesocorticolimbic system. Fifth, we describe how androgens modulate the neurochemistry and structure of the mesocorticolimbic system, particularly with regard to dopaminergic signaling. Finally, we discuss evidence that androgens influence executive functions, including the effects of androgen deprivation therapy and AAS. Taken together, the evidence indicates that androgens are critical modulators of executive function. Similar to dopamine signaling, there might be optimal levels of androgen signaling within the mesocorticolimbic system for executive functioning. Future studies should examine the regulation and functions of neurosteroids in the mesocorticolimbic system, as well as the potential deleterious and enduring effects of AAS use.

Anabolic-androgenic steroids alter decision making in a balanced rodent model of the Iowa gambling task.

Anabolic-androgenic steroid (AAS) abuse is implicated in maladaptive decision making such as increased risk taking and problem gambling. Endogenous testosterone correlates with economic risk taking in both the stock market (Coates & Herbert, 2008) and in the laboratory, as measured by the Iowa Gambling Task (Stanton, Liening, & Schultheiss, 2011). Additionally, AAS use has been associated with problem gambling behavior in adolescents (Proimos, DuRant, Pierce, & Goodman, 1998). Thus, AAS may impair economic decision making. However, studies of human AAS users cannot control for preexisting risky behavior or normalize androgen levels. Accordingly, the present study investigated AAS effects on decision making in rats using a novel, balanced rodent model of the IGT. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water) sc, and trained to work for sugar pellets in an operant chamber equipped with 4 levers, each associated with a different schedule of reward magnitude (number of pellets), probability, and punishment (time-out) duration. By RM-ANOVA, there was a main effect of lever (F3,78 = 25.33, p < .05), such that all rats preferred lever L4 offering a large reward (4 pellets), but with low probability (45%) and a long (35 sec) time-out. There was also a significant interaction of testosterone × lever (F3,78 = 2.78, p < .05), with testosterone increasing preference for L4 and decreasing preference for the other levers, relative to vehicle-treated controls. These data extend our previous findings of altered decision making in AAS-treated rats, and suggest that AAS may alter economic decision making in human users. (PsycINFO Database Record

Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors.

BACKGROUND: Anabolic-androgenic steroid abuse is implicated in maladaptive behaviors such as impaired cognition in humans. In a rat model, our lab has shown that testosterone decreases preference for a large/uncertain reward in probability discounting. Other studies have shown that androgens decrease dopamine D1 and D2 receptors in the nucleus accumbens shell, a region important for decision-making behavior in probability discounting. Thus, we attempted to restore selection of the large/uncertain reward in testosterone-treated rats by administering the D2 receptor agonist quinpirole or the D1 receptor agonist SKF81297 and testing probability discounting. METHODS: Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for probability discounting after injections of saline, 0.1 and 0.5 mg/kg of quinpirole or SKF81297. Rats chose between a small/certain reward (1 sugar pellet, 100% probability) and a large/uncertain reward (4 pellets, decreasing probability: 100, 75, 50, 25, 0%). RESULTS: Testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls after saline injection. However, acute injection with 0.1 mg/kg quinpirole increased large/uncertain reward preference in testosterone-treated rats only, indicated by a testosterone × quinpirole interaction. At 0.5 mg/kg, quinpirole increased large/uncertain reward preference in all rats. Acute injection with SKF81297 at 0.1 or 0.5 mg/kg rescued large/uncertain reward preference in testosterone-treated rats by eliminating the difference between groups. CONCLUSIONS: It appears that altered probability discounting behavior in testosterone-treated rats is due to both decreased D1 and D2 receptor function.

Prosocial effects of prolactin in male rats: Social recognition, social approach and social learning.

Prolactin (PRL) and oxytocin (OT) are pituitary hormones essential for lactation, but also promote sexual behavior. OT stimulates social behaviors, such as recognition, approach, and learning, but less is known about PRL in these behaviors. Since PRL and OT have complementary functions in reproduction, we hypothesized that PRL increases social recognition, approach, and learning. Male Long-Evans rats received ovine PRL (oPRL; 0.5, 2.0 or 5.0mg/kg), the PRL antagonist bromocriptine (0.1, 3.0 or 5.0mg/kg) or saline 20 mins before testing for recognition of familiar vs. unfamiliar stimulus males. Saline controls preferred the unfamiliar male (p<0.05), while bromocriptine blocked this preference. oPRL did not increase preference. To measure social approach, we determined if PRL restores approach 2h after defeat by an aggressive male. Defeated rats avoided the aggressive male. 2mg/kg oPRL, before or after defeat, restored approach towards the aggressive male (p<0.05). In non-defeated rats, oPRL or 3mg/kg bromocriptine had no effect. To determine if PRL increases social learning, we tested social transmission of food preference. Rats choose between two unfamiliar flavors, one of which they have previously been exposed to through interaction with a demonstrator rat. Vehicle controls preferred chow with the demonstrated flavor over the novel flavor. oPRL-treated rats were similar. Bromocriptine-treated rats failed to show a preference. When tested one week later, only oPRL-treated rats preferred the demonstrated flavor. The results suggest that PRL is required for social recognition and learning, and that increasing PRL enhances social memory and approach, similar to OT.

Sex differences and hormonal modulation of ethanol-enhanced risk taking in rats.

BACKGROUND: Ethanol (EtOH) intake correlates with increased risk-taking, and sex differences exist in both EtOH use and risk-taking in humans and rats. However, the interaction of sex and gonadal hormones to affect risk-taking under the influence of EtOH has not been determined. This was the focus of the current study. METHODS: Adult Long-Evans rats (n=18 males and females) were gonadectomized and received hormone replacement at physiologic levels or blank implants (n=7-9/group). Risk-taking was assessed with probability discounting, requiring rats to choose between a small/certain reward and a large/uncertain reward delivered with decreasing probability throughout each daily session. Before testing, rats received saline or EtOH (0.5 or 1.0g/kg) ip. RESULTS: In males, EtOH increased preference for the large/uncertain reward lever (F2,28=10.462, p<0.05). However, there was no effect of EtOH on lever preference in females (F1,30=0.914, p>0.05). At baseline, ORCHX+T males showed a greater preference for the large/uncertain reward lever then ORCHX males (F1,14=13.805, p<0.05). In females only, EtOH decreased choice latency relative to baseline (F1,10=7.25, p<0.05). EtOH decreased loss sensitivity in both sexes, with all rats exhibiting decreased lose-shift ratios (males: F2,18=5.10, p<0.05; females F2,10=4.37, p<0.05). CONCLUSIONS: These results show that EtOH, sex, and hormones interact to influence decision making. EtOH increases risk taking in males, but not in females. However, EtOH selectively decreases choice latency in females, and decreases loss sensitivity in both sexes. These findings are relevant to understanding human behavior, particularly in adolescents who experience increased hormone levels and often drink EtOH and engage in risky behavior.

Male rats play a repeated donation game.

While previous studies have demonstrated direct and generalized reciprocity in female Norway rats [26], the present study determined if unrelated male laboratory rats respond on behalf of a partner in an iterated sequential game. Pairs of rats worked for food reward in an operant chamber, where participants alternated as Donor and Responder in successive trials. In each trial, the Donor chose between variable and constant reward levers, where the constant reward lever delivered 1 pellet, and the variable reward lever triggered insertion of Responder lever(s); the Donor received 2 pellets when the Responder made any response. In forced-choice constant (FC) trials, the Responder also received 1 pellet for responding on the constant reward lever. In forced-choice variable (FV) trials, the Responder received no pellets for responding on the variable reward lever. In free-choice (FR) trials, the Responder chose between constant (1 pellet) and variable reward levers (0 pellets). With their cagemate, rats earned 61.4±2.0 pellets (64.0±2.1% of 96 possible pellets). As Donor in FC trials, rats preferred the variable reward lever, and the Responder responded frequently. In FV trials, Donor preference for the variable reward lever declined as Responder lever responses decreased. In FR trials, rats alternated responding on variable and constant reward levers as Donor and Responder, respectively. When paired with a new partner, there was no effect on Donor responses, but responses by the Responder decreased in the FV block. Similar effects were observed when paired with a maximally-cooperative stooge. Importantly, rats did not adjust their behavior as Donor to receive more pellets. Results suggest that unrelated male rats will work on behalf of a partner, and that their behavior is sensitive to familiarity, and to cooperative responses by their partner.

Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats.

Recent studies have demonstrated that anabolic-androgenic steroids (AAS) modify cognitive processes such as decision making and behavioral flexibility. However, the neural mechanisms underlying these AAS-induced cognitive changes remain poorly understood. The mesocorticolimbic dopamine (DA) system, particularly the nucleus accumbens (Acb), is important for reward, motivated behavior, and higher cognitive processes such as decision making. Therefore, AAS-induced plasticity in the DA system is a potential structural substrate for the observed cognitive alterations. High doses of testosterone (the most commonly-used AAS) increase dendritic spine density in limbic regions including the amygdala and hippocampus. However, effects on Acb are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically for 8weeks with high-dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc. Brains were stained by Golgi-Cox to analyze neuronal morphology in medium spiny neurons of the shell region of Acb (AcbSh). Eightweeks of testosterone treatment significantly decreased spine density in AcbSh compared to brains of vehicle-treated rats (F1,14=5.455, p<0.05). Testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results show that AAS alter neuronal morphology in AcbSh by decreasing spine density throughout the dendritic tree, and provides a potential mechanism for AAS to modify cognition and decision-making behavior.

Cooperation in rats playing the iterated Prisoner's Dilemma game.

Humans and animals show cooperative behaviour, but our understanding of cooperation among unrelated laboratory animals is limited. A classic test of cooperation is the iterated Prisoner's Dilemma (IPD) game, where two players receive varying payoffs for cooperation or defection in repeated trials. To determine whether unrelated rats cooperate in the IPD, we tested pairs of rats making operant responses to earn food reward in 25 trials/day. The operant chamber was bisected by a metal screen with a retractable lever and pellet dispenser on each side. When levers extended, rats had 2 s to respond. Mutual cooperation (Reward) delivered three pellets each, mutual defection (Punishment) provided no pellets, and unilateral defection (Temptation) gave five pellets to the defector, while the partner (Sucker) received none. In eight pairs of males (RM-) and females (RF-), cooperation was defined by withholding a response. In seven pairs of RM+ males, cooperation was defined by responding on the lever. In males, food restriction significantly inhibited both cooperation and pellets received. There was no effect of dominance status. Males and females made similar numbers of responses under ad libitum feeding. However, neither food restriction nor dominance status affected responses in females. Rats were subsequently tested for reciprocity in 24 alternating trials/day. A response on the lever within 5 s delivered three pellets to the partner. Females made significantly more responses for their cage-mate than males. Responses within pairs were significantly correlated for males, but not for females. For both sexes, responses declined significantly when paired with an unfamiliar partner who never reciprocated ('bad stooge'). These results demonstrate that rats working for food show cooperation in IPD and direct reciprocity. Their responses depend on food availability and responses of their partner.

Social housing conditions and oxytocin and vasopressin receptors contribute to ethanol conditioned social preference in female mice.

Social behavior modulates response to alcohol. Because oxytocin (OXT) and vasopressin (AVP) contribute to rewarding social behavior, the present study utilized a genetic strategy to determine whether OXT and AVP receptors (OXTR, AVPR1a) are essential for female mice to demonstrate a conditioned social preference for ethanol. The study compared wild-type (WT) and knock-out (KO) females lacking either Oxtr or Avpr1a in a conditioned social preference (CSP) test. KO females and WT females from Het-Het crosses were pair-housed: KO and WT(ko). WT females from Het-WT crosses were pair-housed: WT(wt). Test mice received 2g/kg ethanol or saline ip, and were paired four times each with one stimulus female (CS-) after saline, and with another female (CS+) following ethanol. After pairing, the time spent with CS+ and CS- females was measured. WT(wt) females showed conditioned preference for the CS+ female paired with ethanol, demonstrated by greater interaction time (p<0.05). In both KO lines, ethanol significantly reduced interaction with the CS+ female (p<0.05), and there was no change in interaction for WT(ko) females. Response to odors by habituation-dishabituation was unaffected in both KO lines, and the response to a hypnotic dose of ethanol also was the same as in WT mice. However, anxiety, measured as time on the open arms of the elevated plus maze, was reduced in KO(Oxtr) females compared with WT(wt). The results suggest that Oxtr and Avpr1a are required for conditioned effects of an ethanol-associated social stimulus. The lack of CSP in WT(ko) females suggests that the quality of social interactions during postnatal and postweaning life may modulate development and expression of normal social responses.

Anabolic-androgenic steroids and decision making: Probability and effort discounting in male rats.

Anabolic-androgenic steroid (AAS) abuse is implicated in maladaptive behaviors such as increased aggression and risk taking. Impaired judgment due to changes in the mesocorticolimbic dopamine system may contribute to these behavioral changes. While AAS are known to influence dopamine function in mesocorticolimbic circuitry, the effects on decision making are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for cost/benefit decision making in two discounting paradigms. Rats chose between a small reward (1 sugar pellet) and a large discounted reward (3 or 4 pellets). Probability discounting (PD) measures sensitivity to reward uncertainty by decreasing the probability (100, 75, 50, 25, 0%) of receiving the large reward in successive blocks of each daily session. Effort discounting (ED) measures sensitivity to a work cost by increasing the lever presses required to earn the large reward (1, 2, 5, 10, 15 presses). In PD, testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls. However, during ED, testosterone-treated rats selected the large/high effort reward significantly more than controls. These studies show that testosterone has divergent effects on different aspects of decision making. Specifically, testosterone increases aversion to uncertainty but decreases sensitivity to the output of effort for reward. These results have implications for understanding maladaptive behavioral changes in human AAS users.