PT150 blocks the rewarding properties of ethanol and attenuates ethanol-induced reduction of egg laying in Coturnix quail.

RATIONALE: Alcohol use disorder (AUD) has been shown to be associated with a dysregulated stress system. Reducing the stress hormone corticosterone (CORT), that binds to glucocorticoid receptors, may attenuate the rewarding properties of drugs of abuse. However, the effect of blocking corticosterone receptors on ethanol reward has yet to be investigated. OBJECTIVES: The current study investigated whether the stress hormone receptor antagonist, PT150, would block the rewarding properties of ethanol via the glucocorticoid receptor system and attenuate other ethanol-induced effects. METHODS: A conditioned place preference (CPP) procedure was used to examine the rewarding properties of ethanol in an avian preclinical model. Ethanol was paired with the least preferred chamber. On alternate days, water was paired with the preferred chamber. After eight pairings, a place preference test was given that allowed subjects to have access to both chambers. Half of the subjects received PT150 prior to ethanol administration. The other half received vehicle. Time spent in each chamber during the preference tests, locomotor activity during the pairings, and egg production in female birds was recorded. RESULTS: Ethanol treatment resulted in a CPP and pretreatment of PT150 blocked the acquisition of the ethanol-induced place preference. Neither ethanol nor PT150 altered locomotor activity. Pretreatment of PT150 also increased egg production in female quail treated with ethanol. CONCLUSIONS: These findings suggest repeated ethanol pairings with visual cues can produce a CPP. Furthermore, pretreatment of PT150 may be a potential pharmacotherapy for blocking the rewarding properties of ethanol and may enhance egg production in female quail treated with ethanol.

Ethanol induces a dose-dependent conditioned place preference and conditioned place aversion in Japanese quail.

The conditioned place preference (CPP) paradigm is commonly used to investigate the motivational properties of drugs of abuse. Cues in the environment may become paired with these motivational properties and later result in drug seeking. Because many of these alcohol-paired cues are visual, Japanese quail may be a beneficial model to examine visual cue-induced alcohol seeking behavior. The aim of the present study was to examine the motivational properties of ethanol using a visual CPP model. During CPP, quail were given an initial preference test to determine their initially preferred chamber, during which time they could explore the entire chamber for 15 min. Following the initial preference test, quail were gavaged with their assigned treatment (water or 0.75 or 2.0 g/kg of ethanol) and were confined to their initially least preferred chamber every other conditioning day for 30 min. On alternate days, they were gavaged with water and confined to the preferred chamber for 30 min. After the 8th day of conditioning, a final preference test was given. Locomotor activity was also measured during conditioning. The findings indicated that quail that received the 0.75 g/kg ethanol developed a place preference to the ethanol-paired chamber, and that quail treated with 2 g/kg ethanol developed a place aversion to the ethanol-paired chamber. Additionally, locomotor activity was reduced in quail that received the high dose of ethanol. The findings suggest that both the rewarding and aversive properties of ethanol may be observable in this visual cue CPP model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Time will tell: Temporal processing in the sexual behavior system.

This paper describes several temporal factors that appear to play a role in sexual conditioning including the conditioned stimulus (CS)-unconditioned stimulus (US) interval, the C/T ratio, and trace conditioning. One commonality among these studies is the attention given to the stimuli and responses involved. This is contrary to traditional learning theories such as the general process theory. The general process theory is focused on identifying universal principles and commonalities of learning, without regard to the stimuli and responses involved. The research described in this paper has taken a different approach and made specific considerations of the stimuli and responses such as with the type of conditioned stimuli used and the use of more than one, and sometimes multiple, response measures with which to identify conditioned responding. The findings of these studies are best accounted for by the behavior systems approach. For example, one of the main findings is that during long-delay learning, a new conditioned response may emerge (increased locomotor activity) in lieu of a decrease or absence of the target conditioned response (approach behavior). The behavior systems approach accounts for this by describing the sexual behavior system as being on a continuum from consummatory behavior to focal search and general search. The nature of the conditioned response depends on where the CS is introduced along the continuum. This example and several other sexual conditioning experiments are described within this paper with an emphasis on their interpretation from a behavior systems perspective.

Sex differences in alcohol dehydrogenase levels (ADH) and blood ethanol concentration (BEC) in Japanese quail.

Ethanol is one of the most widely used and abused drugs. Following ethanol consumption, ethanol enters the bloodstream from the small intestine where it gets distributed to peripheral tissues. In the bloodstream, ethanol is cleared from the system by the liver. The primary metabolism of ethanol uses alcohol dehydrogenase (ADH). In mammals, females appear to have higher ADH activity in liver samples than males. The purpose of the first experiment was to analyze sex differences in ADH levels following 12 d of ethanol administration (i.e., water or 2 g/kg) in male and female quail. Following the last daily treatment of ethanol, quail were euthanized, their livers were extracted, and ADH was analyzed in liver homogenate samples. Results showed that female quail had higher ADH levels, heavier livers, and a greater liver to body weight ratio than male quail. In a second experiment, we aimed to develop a blood ethanol concentration (BEC) profile for both male and female quail. Quail were administered 0.75 or 2 g/kg of ethanol and blood was collected at 0.5, 1, 2, 4, 6, 8, 12, 24 h after gavage administration. Blood ethanol concentration was analyzed using an Analox. We found that quail had a fairly rapid increase in BECs followed by a steady and slow disappearance of ethanol from the blood samples. Female quail had a lower peak of ethanol concentration and a smaller area under the curve (AUC) than male quail. The current research suggests that higher ADH levels in female quail may be responsible for increased metabolism of ethanol. In general, quail appear to eliminate ethanol more slowly than rodents. Thus, as a model, they may allow for a prolonged window with which to investigate the effects of ethanol.

Repeated subcutaneous administration of PT150 has dose-dependent effects on sign tracking in male Japanese quail.

A devastating feature of drug dependence is the susceptibility of relapse (40-60%) after stretches of abstinence. In both animal and human research, it has been demonstrated that cues (e.g., levers, paraphernalia) associated with drug reward can instigate renewed drug taking. Research has shown animals that attend to a cue that predicts reward more than the location of reward delivery when the cue is present (sign trackers) have an increase in corticosterone (CORT), a primary stress hormone when compared with animals that do not sign track. This interaction of sign tracking and CORT implicate CORT's effects as a possible pharmacological target for cue-induced relapse behaviors. PT150 is a novel glucocorticoid receptor antagonist that reduces the effects of CORT. Previous research has shown that oral administration of 40 mg/kg PT150 reduced sign tracking. To better understand dose-dependent effects and to control for more accurate doses, the current experiment hypothesized that PT150 (20/40/60 mg/kg) given by subcutaneous (SC) injection to male quail would reduce sign tracking to a keylight conditional stimulus that predicts a grain unconditioned stimulus dose dependently. Results showed that SC injection of 20 mg/kg PT150 reduced sign tracking, but 40 or 60 mg/kg did not. The main findings from the current study are that the glucocorticoid receptor antagonist PT150 reduces sign tracking behavior dose dependently, and SC administration may provide better bioavailability compared with our previous study that used an oral route of administration. The current findings support previous literature by suggesting that the glucocorticoid receptor may be a potential pharmacological target for reducing relapse-like behaviors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Novel flexibility of social learning in dog puppies.

Social learning has a large impact on fitness by reducing the costs and dangers associated with independent learning but little research has been conducted to investigate the ontogeny or individual development of this type of learning. Recent research indicated that puppies demonstrate social learning to both conspecific and human demonstrators, but were also more likely to learn better from an unfamiliar conspecific compared to their mother.

A glucocorticoid receptor antagonist reduces sign-tracking behavior in male Japanese quail.

Addiction is characterized as a chronic debilitating disease. One devastating feature of addiction is the susceptibility of relapse (40-60%) after stretches of abstinence. One theory that may account for relapse suggests that drug cues (e.g., paraphernalia) may increase stress hormones, and this may prompt relapse. Repeatedly pairing a neutral cue with a reward is commonly utilized to measure what subjects learn about a cue that is predictive of reward. Research has shown that animals that attend to a cue more than to the reward (sign trackers) may be more vulnerable to drug addiction. Additionally, research has shown that sign tracking is associated with an increase in corticosterone, a primary stress hormone. PT150 is a novel glucocorticoid receptor antagonist that moderates the release of corticosterone. In the current experiment, it was hypothesized that subjects given repeated administration of PT150 would reduce sign tracking compared to subjects given placebo. Time spent (in seconds) near a cue that predicts reward (conditional stimulus) served as a measure of sign tracking, and PT150 or placebo was administered following sign tracking. An independent-samples t test revealed that subjects that received PT150 had reduced time spent near the conditioned stimulus compared to controls. Given the devastating effects of drug addiction, identification of a potential pharmacological intervention in the reduction of relapse would be of great value. Therefore, future research is needed to validate the use of PT150 in reducing behaviors associated with drug addiction. (PsycINFO Database Record

Intramuscular Route of Administration Increases Potency in Eliciting Cocaine-Induced Behavioral Sensitization.

BACKGROUND: Cocaine is the number one abused psychostimulant drug that reaches addiction criterion in the US. In animals, repeated administration of cocaine results in behavioral sensitization which is thought to represent adaptations in the mesolimbic dopamine neural circuitry, the reward pathway. Cocaine-induced behavioral sensitization is evident in rodents and quail when cocaine is administered intraperitoneally (IP). OBJECTIVES: The purpose of the current study was to investigate dose-dependent and temporal effects of acute and chronic intramuscular (IM) administration of cocaine in male quail. METHODS: After habituation to the test chambers, male quail received an IM injection of saline, 3 or 10 mg/kg cocaine and were immediately placed in the chambers. Distance traveled (in meters) was recorded in 5 min time bins for 30 min. Testing was conducted once per day for ten days with each subject receiving the same treatment throughout the experiment. Other behaviors including pecking, preening, and feather fluffing were measured. RESULTS: Cocaine-induced behavioral sensitization and tolerance were evident at relatively low doses of IM cocaine. Dose-dependent effects were evident. IM cocaine also reduced feather fluffing, a behavior that typically occurs during hypothermia. CONCLUSIONS: The findings replicated and extended previous research with pigeons and suggested that IM administration of cocaine may be a relatively potent route of administration. Potency of drugs of abuse may be related to the bioavailability of a drug and its addictive properties. Thus, studying drugs of abuse using an IM route of administration may be useful in drug addiction research.

Cocaine preexposure enhances sexual conditioning and increases resistance to extinction in male Japanese quail.

The incentive-sensitization theory posits that drug addiction results from altered learning and motivational processes that stem from drug-induced changes in the brain's reward circuitry. Although it is generally accepted that problematic drug use results from these neuroadaptations, less research has focused on how these neural changes affect the incentive-motivational properties of naturally rewarding stimuli such as sex. The present set of experiments was conducted to investigate (1) dose-dependent effects of preexposure to chronic cocaine on sexual conditioning and (2) how prior cocaine exposure affects the extinction of sexually conditioned behavior in male Japanese quail. In Experiment 1, male quail were exposed to saline or to cocaine (5, 10, or 20 mg/kg ip) for 10 days, and their locomotor activity was measured. After a washout period, ten sexual-conditioning trials were conducted in which a light (CS) was presented prior to the presentation of a female quail (US) and approach to the light was measured. The results showed that cocaine dose-dependently enhanced sexually conditioned approach behavior and copulation. Experiment 2 was procedurally similar to Experiment 1, except that the quail received either saline or 10 mg/kg cocaine (ip) and 24 extinction trials were conducted. During extinction, no female was presented after the CS. The results showed that preexposure to cocaine delayed extinction. Therefore, cocaine may dose-dependently increase the strength of sexual conditioning, and this may subsequently increase resistance to extinction. These findings and their possible mechanisms are explored.

Female Japanese quail with high levels of estradiol demonstrate cocaine-induced conditioned place preference.

Preclinical research has indicated that females may be more sensitive to the rewarding properties of cocaine. However, the majority of this research has been done in rodent species. Environmental cues associated with human drug-taking behavior tend to be visual. Because rodents do not rely on the visual system as their primary sense modality, the use of a visually oriented species may add to our understanding of cue-elicited drug cravings and relapse. The present study examined the potential role of the steroid hormone, estradiol, in the rewarding properties of cocaine in female Japanese quail using a conditioned place preference (CPP) procedure. In the current experiment, female quail were housed on either an 8L:16D (light:dark) or 16L:8D (light:dark) cycle for 21 days to induce photoregression or photostimulation, respectively. They then received 10, 20, or 30 mg/kg cocaine, or saline during conditioning. Conditioning trials were carried out for 8 days, once per day for 30 min, for a total of 4 cocaine and 4 saline alternating conditioning trials. Results indicated that female quail housed in long-light conditions (16L:8D) had significantly higher levels of estradiol than short-cycle females. Additionally, photostimulated female quail developed a CPP to 10 and 20 mg/kg cocaine. Short-cycle females did not show cocaine-induced CPP to any dose tested. Results indicate that cocaine is dose-dependently rewarding to photostimulated female Japanese quail. Furthermore, the current findings suggest that estradiol may enhance the rewarding properties of cocaine in female quail. (PsycINFO Database Record

Cocaine-induced sensitization correlates with testosterone in male Japanese quail but not with estradiol in female Japanese quail.

Research has indicated that gonadal hormones may mediate behavioral and biological responses to cocaine. Estrogen, in particular, has been shown to increase behavioral responding to cocaine in female rats relative to male rats. The current study investigated the effect of cocaine on locomotor activity and hormonal correlates in male and female Japanese quail (Coturnix japonica). In Japanese quail, circulating hormone levels can be manipulated without surgical alterations via modifying the photoperiod. Male and female quail were housed on either 8L:16D (light:dark) or 16L:8D (light:dark) cycle for 21days. Blood samples were taken prior to the beginning of the experiment and assays were performed to determine the levels of testosterone (T) and estradiol (E2). Quail were given injections of saline or cocaine (10 or 20mg/kg) once a day for 10days. Immediately after each injection, birds were placed in open field arenas and distance traveled was measured for 30min. Results showed that male quail housed under long-light conditions exhibited cocaine-induced sensitization to 10mg/kg cocaine which was correlated with the high levels of plasma T. Female quail housed under short-light conditions demonstrated sensitization to 10mg/kg cocaine, but this was not correlated with the levels of plasma E2. The current findings suggest that cocaine-induced locomotor activity was associated with T in males but not with E2 in females.

Cocaine induces state-dependent learning of sexual conditioning in male Japanese quail.

State dependent learning effects have been widely studied in a variety of drugs of abuse. However, they have yet to be studied in relation to sexual motivation. The current study investigated state-dependent learning effects of cocaine in male Japanese quail (Coturnix japonica) using a sexual conditioning paradigm. Cocaine-induced state-dependent learning effects were investigated using a 2×2 factorial design with training state as one factor and test state as the other factor. During a 14-day training phase, male quail were injected once daily with 10mg/kg cocaine or saline and then placed in a test chamber after 15min. In the test chamber, sexual conditioning trials consisted of presentation of a light conditioned stimulus (CS) followed by sexual reinforcement. During the state dependent test, half of the birds received a shift in drug state from training to testing (Coc→Sal or Sal→Coc) while the other half remained in the same drug state (Coc→Coc or Sal→Sal). Results showed that male quail that were trained and tested in the same state (Coc→Coc or Sal→Sal) showed greater sexual conditioning than male quail that were trained and tested in different states (Sal→Coc) except when cocaine was administered chronically prior to the test (Coc→Sal). For the latter condition, sexual conditioning persisted from cocaine training to the saline test. The findings suggest that state dependent effects may alter sexual motivation and that repeated exposure to cocaine during sexual activity may increase sexual motivation which, in turn, may lead to high risk sexual activities. An alternative explanation for the findings is also discussed.

Pavlovian discriminative stimulus effects of methamphetamine in male Japanese quail (Coturnix japonica).

Pavlovian drug discrimination (DD) procedures demonstrate that interoceptive drug stimuli may come to control behavior by informing the status of conditional relationships between stimuli and outcomes. This technique may provide insight into processes that contribute to drug-seeking, relapse, and other maladaptive behaviors associated with drug abuse. The purpose of the current research was to establish a model of Pavlovian DD in male Japanese quail. A Pavlovian conditioning procedure was used such that 3.0 mg/kg methamphetamine served as a feature positive stimulus for brief periods of visual access to a female quail and approach behavior was measured. After acquisition training, generalization tests were conducted with cocaine, nicotine, and haloperidol under extinction conditions. SCH 23390 was used to investigate the involvement of the dopamine D1 receptor subtype in the methamphetamine discriminative stimulus. Results showed that cocaine fully substituted for methamphetamine but nicotine only partially substituted for methamphetamine in quail. Haloperidol dose-dependently decreased approach behavior. Pretreatment with SCH 23390 modestly attenuated the methamphetamine discrimination suggesting that the D1 receptor subtype may be involved in the discriminative stimulus effects of methamphetamine. The findings are discussed in relation to drug abuse and associated negative health consequences.

Nicotine induces a conditioned place preference in male Japanese quail (Coturnix japonica).

Visual stimuli may play an important role in the development and maintenance of addiction in humans. Research with a visually-oriented animal model such as Japanese quail (Coturnix japonica) may provide insight into how visual cues contribute to the addiction process. The aim of the current study was to investigate the rewarding properties of nicotine in male Japanese quail using a biased conditioned place preference (CPP) procedure. Adult male quail (N=30) were allowed to freely explore the entire CPP apparatus during a place preference pre-test and time spent in each chamber was measured. During nicotine conditioning sessions, quail were administered nicotine (0.5, 1.0, or 2.0mg/kg) or saline and were then confined to their initially least preferred chamber. On alternating days, all quail received saline and were confined to their initially preferred chamber. Locomotor activity was assessed in both chambers. The conditioning chambers had yellow or green walls to enhance the visual salience of each context. Following 8 conditioning sessions (4 nicotine; 4 saline), quail were allowed to explore the entire apparatus during a CPP post-test and time spent in each chamber was measured. The results indicated that quail treated with 0.5 and 1.0mg/kg nicotine significantly increased the amount of time they spent in the nicotine-paired chamber compared to saline controls, suggesting that nicotine produced a CPP. Furthermore, quail treated with 0.5mg/kg nicotine showed a significant increase in locomotor activity with repeated treatments. The current findings suggest that nicotine may have a rewarding effect in quail and may tentatively suggest that the neuropharmacological mechanisms that mediate CPP for nicotine are conserved in birds.

Chronic pre-exposure to methamphetamine following 31 days of withdrawal impairs sexual performance but not sexual conditioning in male Japanese quail.

In the current study, male quail were administered methamphetamine (3.0 or 5.6 mg/kg IP) or saline once daily for 10 days and locomotor activity was assessed. Following a 31-day withdrawal period, sexual conditioning trials were conducted such that a conditioned stimulus (CS) was presented prior to a copulatory opportunity with a female quail. Male quail treated with methamphetamine (5.6 mg/kg) showed a decrease in locomotor activity from Trial 1 to Trial 10 suggesting a potential tolerance effect. Following the 31-day withdrawal period, all male quail that received the CS paired with a copulatory opportunity showed enhanced approach to the CS, regardless of treatment history. Thus, chronic pre-exposure to methamphetamine did not alter sexual conditioning. In contrast, chronic pre-exposure to methamphetamine (3.0 mg/kg) decreased the frequency of successful copulations suggesting that it impaired sexual performance. The findings suggest that methamphetamine may differentially affect the neural circuitry involved in motivational systems compared with those involved in consummatory aspects of sexual behavior. These effects may last long after drug cessation.

Chronic preexposure to methylphenidate cross-sensitizes methamphetamine in male Japanese quail.

An increasing debate exists about the potential of exposure to methylphenidate increasing later risk of drug abuse. The objective of this study was to investigate whether chronic preexposure to methylphenidate would induce cross-sensitization to a subsequent methamphetamine challenge in male Japanese quail. Male quail were treated intraperitoneally with either 5, 10, or 20 mg/kg methylphenidate or saline for 14 days. After a 14-day washout period, birds were challenged with 5.6 mg/kg of methamphetamine. Methylphenidate-induced behavioral sensitization was not evident after 14 days of preexposure. However, locomotor activity was greater during the methamphetamine challenge in birds that were preexposed to a high dose of methylphenidate. The findings suggest that chronic preexposure to methylphenidate may be sufficient to alter later responding to methamphetamine, regardless of whether preexposure resulted in behavioral sensitization.

Methamphetamine impairs sexual motivation but not sexual performance in male Japanese quail.

The present study investigated the effects of chronic pre-exposure to methamphetamine on sexual motivation and performance in male Japanese quail. Quail were pre-exposed to methamphetamine (1.0 or 3.0 mg/kg ip) or saline (ip) once daily for 10 days and locomotor activity was measured. After a 10 day washout period, sexual motivation was measured in a straight-arm runway with visual access to a female at one end. Three to 5 hr after sexual motivation tests, males were allowed to copulate with a receptive female quail and copulatory behavior was assessed. Tests were conducted once per day for 10 days. Results showed that males pre-exposed to methamphetamine had decreased locomotor activity compared to saline controls. Males pre-exposed to METH later ran slower toward a female in the runway and spent less time near her. In contrast, methamphetamine pre-exposed males showed similar copulatory behavior as saline pre-exposed males. The findings suggest that chronic pre-exposure to methamphetamine may impair sexual motivation but not sexual performance. The findings are discussed from a comparative perspective and with regard to their clinical relevance.

Cocaine-induced behavioral sensitization and conditioning in male Japanese quail.

Repeated intermittent cocaine treatment often results in behavioral sensitization or an augmented response to cocaine. Cocaine-induced behavioral sensitization may be an important contributor to cocaine addiction and abuse. Some studies have also shown that conditioned drug effects may play a role in behavioral sensitization. The current experiment utilized a simplified discrimination paradigm to investigate behavioral sensitization and the role of conditioning in an avian species. Male Japanese quail received alternating injections of cocaine (10 mg/kg i.p.) paired with a context and saline injections paired with a different context. They were later given a cocaine challenge followed by and a saline challenge in the drug-paired context. Results showed that birds that received cocaine paired with one context also demonstrated behavioral sensitization to a cocaine challenge given after a withdrawal period and they developed conditioning to the drug-paired context. A saline control and a control group that received cocaine that was not paired with the test context failed to demonstrate sensitization or conditioning. The findings demonstrate visual discrimination learning and implicate the role of Pavlovian conditioning in behavioral sensitization.

Cocaine sensitization in male quail: temporal, conditioning, and dose-dependent characteristics.

Chronic cocaine administration typically results in increased locomotor activity, known as behavioral sensitization. Investigating the time course of locomotor activity across trials may provide a more detailed analysis of the temporal changes that might occur within sensitization. Prior research with rodents shows that the peak of locomotor activity shifts from acute to chronic drug administration. The purpose of the current experiment was to investigate acute versus chronic cocaine effects on locomotor activity in an avian species, Japanese quail, and to investigate whether this phenomenon is dose-dependent. Subjects received daily i.p. injections of saline or 5, 10, or 20 mg/kg cocaine for 20 days. Following each injection, birds were placed in standard locomotor activity chambers, and activity was recorded for 150 min. A cocaine challenge was given after a ten-day withdrawal period. Two retraining trials were given to re-establish cocaine responding prior to a saline challenge in the drug-paired environment. Results showed that repeated administration of the 10 mg/kg dose of cocaine enhanced activity across 120 min compared with acute administration. In contrast, repeated administration of the 20 mg/kg dose resulted in greater cocaine-induced activity for 60 min compared with acute administration. In addition, behavioral sensitization was shown to be dose-dependent and appeared to be due, at least in part, to conditioning.

Ionotropic glutamate receptors in the ventral tegmental area regulate cocaine-seeking behavior in rats.

Drug addiction is characterized by compulsive drug-seeking and drug-taking behavior and by a high rate of relapse even after long periods of abstinence. Although the mesocorticolimbic dopamine (DA) pathway is thought to play a critical role in drug craving and relapse, recent evidence also implicates glutamate, an amino acid known to activate DA neurons in the ventral tegmental area (VTA) via ionotropic receptors. To assess whether increased glutamate transmission in the VTA is involved in cocaine-primed drug-seeking behavior, we tested rats in a between-session reinstatement model. They were trained to press a lever for cocaine infusions (0.25 mg/infusion) accompanied by compound stimuli (light and tone) under a modified fixed-ratio 5 reinforcement schedule. Cocaine-primed reinstatement was conducted after lever pressing was extinguished in the absence of the conditioned stimuli. Blockade of ionotropic glutamate receptors in the VTA by local application of kynurenate (0.0, 1.0, 3.2, and 5.6 microg/side) dose-dependently decreased cocaine-primed reinstatement, whereas sucrose-primed reinstatement of sucrose-seeking behavior was unaffected. In addition, the minimum effective dose for decreasing cocaine-primed reinstatement was ineffective in the substantia nigra. Together, these data indicate that glutamatergic activation of the VTA is critical for cocaine-primed reinstatement. Because such activation can increase impulse flow in DA neurons and thus DA release in mesocorticolimbic targets, this glutamate-DA interaction in the VTA may underlie cocaine-primed relapse to cocaine-seeking behavior.