Aminoglutethimide

The uptake of ¹⁴C-labeled aminoglutethimide into the brain was investigated in the rat after intracarotid injection according to the method of Oldendorf, as well as in cisternal cerebrospinal fluid obtained by suboccipital puncture after i.v. injection of the drug. The brain uptake index of aminoglutethimide after intracarotid injection was 30.7 + 2.4%. Cerebrospinal fluid/blood quotients after i.v. drug injection were 0.53 at 10 min and 0.26 at 60 min. The results of both methods clearly show that aminoglutethimide easily penetrates the blood brain barrier.     

Effects of methadone on activity and on brain monoamines in two strains of mice

Two strains of mice (C57BL/6J and DBA/2J) were used to determine the effects of single and multiple injections of methadone on open field activity and on brain monoamines. For the DBA strain, the initial injection of methadone produced an attenuation of locomotor activity. After 7 daily injections, activity increased to that of controls. For the C57 strain, the initial injection produced a slight increase in activity which become more pronounced after further daily injections. Norepinephrine concentration was elevated in brains of DBA mice chronically exposed to methadone. This effect was not observed in C57 mice nor in either strain injected only once with the drug. Serotonin concentration was not altered in animals of either strain whether or chronically exposed to methadone. The results of this study suggest: 1) that activity change following methadone injections is dependent upon genetic factors and previous experience with the drug; 2) that the tolerance develops to the drug produced decreases but not increases in activity; and 3) that chronic exposure to the drug can elevate noropinephrine concentration in brains of DBA mice.     

Safety assessment of encapsulated morphine delivered epidurally in a sustained-release multivesicular liposome preparation in dogs

We have shown that the epidural (EPI) delivery of morphine encapsulated in multivesicular liposomes (DepoFoam drug delivery system) produces a sustained clearance of morphine and a prolonged analgesia. We have sought to subsequently determine the likelihood of deleterious effects on local tissue of repetitive epidural injections of this encapsulated morphine preparation (C0401). Beagle dogs were prepared according to protocol approved by the Institutional Animal Care and Use Committee under volatile general anesthesia with chronic lumbar EPI catheters and subcutaneous injection ports. Male and female dogs (three groups) received a total of 4 EPI injections at 8-day intervals of 3 mL of C0401 (10 mg/mL morphine) (N = 6), DepoFoam vehicle (N = 6), or 0.9% sodium chloride (N = 6). Following EPI-C0401, but not saline or DepoFoam vehicle, there were transient (< 72 hr) decreases in food consumption, arousal, hindlimb muscle tone, and body temperature. Heart rate was unaltered, but there were modest decreases in blood pressure and respiratory rate, which persisted for 24-72 hr after C0401. No persistent changes in sensory/motor function, body weight, or stool/urine production were observed. Cerebrospinal fluid, blood chemistry, and urinalysis performed at surgery and on the day of sacrifice (24 hr after the last dose) were within normal ranges. Gross pathology at necropsy was unremarkable. Spinal histopathology findings were judged to be minimal (e.g., modest pericatheter inflammation and fibrosis) and present in all dogs. However, a statistical trend in the rank order of pathology scores was noted (Saline < DepoFoam vehicle < C0401). Repeated EPI injection of C0401 at the maximum dose that could be administered (30 mg) resulted in moderate, transient behavioral and physiological effects after each injection, consistent with morphine administration, and a modest effect on cord histopathology. This level of pathology is reflected in the lack of change observed in cerebrospinal fluid and lack of neurological findings. These results suggest that C0401 is without significant pathological effects at this dose after repeated epidural delivery in dogs.     

Topical delivery system of ophthalmic drugs by periocular injection with viscous solution.

The purpose of this study is to evaluate periocular injections with viscous solution as a topical delivery system of ophthalmic drugs. Tilisolol and carboxymethylcellulose (CMC) were used as a model beta-blocker and a viscous polymer, respectively. After intracapsular, retrobulbar and palpebral conjunctival injections (50 microl) of tilisolol with 3% CMC into rabbits, drug concentrations in the tear fluid, blood, aqueous humor and vitreous body were determined by HPLC. Periocular injection (50 microl) of tilisolol with 3% CMC showed slight leakage of the drug in the tear fluid from the injection site. The viscous vehicle decreased the absorption rate constant of the drug from the injection site to systemic circulation compared with the buffer solution. It suggests that the viscous solution improved the retention of drug at both the injection site and in periocular tissues. Although the periocular injections with viscous vehicle (3% CMC) showed lower AUC in the aqueous humor than that observed in instillation, they showed comparable AUC in the vitreous humor. Compared to the results after the periocular injections with buffer solution, CMC increased the AUCs in the vitreous body 3.1-fold with retrobulbar injection and 1.4-fold with palpebral conjunctival injection, respectively. As a result, periocular injections with 3% CMC showed higher delivery of tilisolol to the vitreous body against the aqueous humor than the instillation and periocular injections with buffer solution.     

Central effects of monosodium glutamate on feeding behavior in adult Long-Evans rats.

Monosodium glutamate (MSG) is known as a neurotoxic molecule when injected neonatally in rats, where it produces a marked decrease in food intake and an increase in adipose tissue mass. But, in adult rats subcutaneous injections of MSG produce a small, dose-dependent increase in food intake. It is not known if this action is centrally or systemically mediated. Therefore, the feeding pattern of adult rats injected intracerebroventricularly with MSG was measured. Seven days after installation of a cannula in the right lateral ventricle, rats were injected either with artificial cerebrospinal fluid or twice with 3 mg/brain MSG within a 3-day interval. The feeding pattern was recorded via a complete computerized system during 24 h. Feeding behavior was significantly modified by MSG treatments. These effects were observed immediately after drug injections, that is, upon the first meal, as well as during the 24 h that followed. For the first meal, modifications in meal size (+285%; p = 0.0001), meal duration (x10; p = 0.0005), postmeal interval (x4; p = 0.0005), and the satiety ratio (-50%; p = 0.01) were observed. During the 24-h postinjection period, modifications in meal number (-3; p = 0.0007), total amount of food eaten (+21%,; p = 0.007), time spent eating (+40%; p = 0.007), meal duration (+53%; p = 0.005), and meal size (+44%; p = 0.01) were noted. When the two MSG injections were compared, differences were also noted. For the first meal, postmeal interval (-50%; p < 0.005) and satiety ratio (-50%; p < 0.005) were decreased after the second injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

We assessed the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), and sodium valproate (VPA) on convulsions elicited by amygdala stimulation in kindled rats in three similar experiments. In each experiment, amygdala-kindled rats were assigned to a drug group or to a corresponding vehicle control group. The rats in the three drug groups received a total of 10 bidaily (one every 48 h) IP injections of CBZ (70 mg/kg), DZP (2 mg/kg) or VPA (250 mg/kg) at a dose that initially blocked the forelimb clonus elicited by an amygdala stimulation (400 microA, 60 Hz, 1 s) administered 1 h after the injection. The rats in the three vehicle control groups were similarly treated except that they received injections of the saline vehicle. The drug tolerance test occurred 48 h after the final tolerance-development trial; the rats from each drug group and the corresponding vehicle control group received an injection of the appropriate drug followed 1 h later by the administration of a convulsive stimulation. The drug tolerance test revealed almost total tolerance in each of the three drug groups but no tolerance in any of the three vehicle control groups. Such large tolerance effects are inconsistent with the less dramatic effects reported in previous studies; possible reasons for this inconsistency were considered.     

Modulation of brain delivery and copulation by intranasal apomorphine hydrochloride

Clinical studies showed apomorphine (APO) nasal spray was well tolerated, with lower dose and less side effect in treatment of erectile dysfunction compared with its sublingual formulation. The aim of this paper was to find out whether there exists any direct drug transport from nasal cavity to brain following intranasal administration to rats. Pharmacokinetic results illustrated there were no significant differences of AUC0-->120 values in most brain regions and cerebrospinal fluid (CSF) through intranasal delivery route compared with subcutaneous injection, while its plasma AUC0-->120 was only one-half. APO brain and CSF profiles after intranasal administration displayed faster onset compared with subcutaneous delivery. About 35-50% of APO content at 2h, by calculating brain drug direct transport percentage, were transported to different brain regions via the olfactory pathway. In addition, the similar brain drug concentration-time profiles through intranasal delivery compared with subcutaneous route had good correlation with its equivalent sexual stimulant activity on copulatory behaviour in rats. Therefore, we could conclude a nose-to-brain pathway for APO intranasal delivery, which significantly increased brain accumulation of APO. Current experiments also explained the reason why the intranasal application of APO could be an effective alternative to subcutaneous and oral formulations.     

Safety Assessment of Encapsulated Morphine Delivered Epidurally in a Sustained-Release Multivesicular Liposome Preparation in Dogs

We have shown that the epidural (EPI) delivery of morphine encapsulated in multivesicular liposomes (DepoFoam? drug delivery system) produces a sustained clearance of morphine and a prolonged analgesia. We have sought to subsequently determine the likelihood of deleterious effects on local tissue of repetitive epidural injections of this encapsulated morphine preparation (C0401). Beagle dogs were prepared according to protocol approved by the Institutional Animal Care and Use Committee under volatile general anesthesia with chronic lumbar EPI catheters and subcutaneous injection ports. Male and female dogs (three groups) received a total of 4 EPI injections at 8-day intervals of 3 mL of C0401 (10 mg/mL morphine) (N = 6), DepoFoam vehicle (N = 6), or 0.9% sodium chloride (N = 6). Following EPI-C0401, but not saline or DepoFoam vehicle, there were transient (&lt; 72 hr) decreases in food consumption, arousal, hindlimb muscle tone, and body temperature. Heart rate was unaltered, but there were modest decreases in blood pressure and respiratory rate, which persisted for 24-72 hr after C0401. No persistent changes in sensory/motor function, body weight, or stool/urine production were observed. Cerebrospinal fluid, blood chemistry, and urinalysis performed at surgery and on the day of sacrifice (24 hr after the last dose) were within normal ranges. Gross pathology at necropsy was unremarkable. Spinal histopathology findings were judged to be minimal (e.g., modest pericatheter inflammation and fibrosis) and present in all dogs. However, a statistical trend in the rank order of pathology scores was noted (Saline &lt; DepoFoam vehicle &lt; C0401). Repeated EPI injection of C0401 at the maximum dose that could be administered (30 mg) resulted in moderate, transient behavioral and physiological effects after each injection, consistent with morphine administration, and a modest effect on cord histopathology. This level of pathology is reflected in the lack of change observed in cerebrospinal fluid and lack of neurological findings. These results suggest that C0401 is without significant pathological effects at this dose after repeated epidural delivery in dogs.     

Capsaicin in adult frogs: Effects on nociceptive responses to cutaneous stimuli and on nervous tissue concentrations of immunoreactive substance P,somatostatin and cholecystokinin

Summary Adult frogs (Rana esculenta) were given subcutaneous injections of 10, 20, 30, 50 and 100 mg/kg capsaicin in sequential order over 5 days, or the vehicle only. The nociceptive thresholds to electrical, thermal and chemical stimuli were measured before, and 1, 5 and 24 h after each injection. Capsaicin was followed by a dose-related reduction of nociceptive responses to all stimuli, but these effects lasted for only 1–5 h after the given injection. Water/acetic extracts of undivided brains and spinal cords were prepared at the corresponding time periods for the radioimmunoassay of peptides. Spinal cord concentrations of immunoreactive substance P were essentially unaffected by capsaicin, while those of immunoreactive somatostatin were significantly increased after the second for fourth injections (20, 30 and 50 mg/kg) of capsaicin. Brain extracts showed an increase of somatostatin and substance P concentrations after the dose of 50 mg/kg. In an additional experiment, immunoreactive substance P, somatostatin and cholecystokinin were measured in tissue samples taken at 2 and 10 min, and 1, 5 and 24 h after a single dose of either 50 mg/kg capsaicin or the vehicle. The only signficant effect of capsaicin was an increase of immunoreactive somatostatin concentration in brain homogenates at 5 h, while the vehicle in itself elicited major variations of all three peptides in spinal cord and/or brain. These results indicate that capsaicin reduces the nociceptive responses to cutaneous stimuli in adult frogs. This effect is transient, and bears no clear relationship to the variations of spinal cord nor of brain concentrations of immunoreactive substance P, somatostatin and cholecystokinin. In the present experimental conditions, the effects of the vehicle injection to neuropeptides far exceeded those of capsaicin itself.     

Clinical evaluation of flomoxef in pediatrics and a study on the penetration into cerebrospinal fluid

The transfer to cerebrospinal fluid of a new oxacephem antibiotic flomoxef (FMOX, 6315-S) and its clinical efficacy against bacterial infections were investigated. 1. In 3 cases of purulent meningitis, cerebrospinal fluid concentrations of FMOX after one shot intravenous injection of 100 mg/kg during the acute stage of infections were 5.12-6.32 micrograms/ml and ratios of FMOX in cerebrospinal fluid in serum were about 5%. During the recovery stage, cerebrospinal fluid concentrations were about 3.8 micrograms/ml and cerebrospinal fluid/serum ratios were about 3.5%. 2. In 1 case of purulent meningitis, the treatment with FMOX was clinically effective but this case was classified as "unevaluable" because other drug was used concomitantly. FMOX was rated effective in other 2 cases of purulent meningitis. Of 9 cases of pneumonia, FMOX was rated very effective in 8 cases and it was rated only effective in the other. Of 4 cases of bronchitis, the drug was rated very effective in 3 cases and only effective in the other. FMOX was rated very effective against 2 cases of tonsillitis, also. 3. As side effects, thrombocytosis was observed in 3 of 20 cases examined. All cases, however, were deemed unrelated to the FMOX treatment and the side effect was only transient as are often found in courses of recovery from infections.     

Temporal and spatial control of neural effects following intracerebral microinfusion

Spatial and temporal control of neural drug delivery is critical for many therapeutic applications and analyses of brain patterns and behavior. Specifically, for localized injections that serve to deliver drug or inactivate an isolated tissue region in order to observe changes in neural activity at that site, excess distribution into surrounding regions may confound analysis or adversely affect healthy tissue. Here, we develop a mass transport model that simulates a short period of initial infusion of inactivating drug, followed by a successive convective wash with artificial cerebrospinal fluid (aCSF), while tracking the regions of tissue that are above a certain threshold concentration of inactivating agent. We analyze the effect of parameters such as effective diffusion coefficient, extracellular volume fraction, and injectate concentration upon spatiotemporal distribution profiles. Further, we observe the effects of following the initial injection with a wash-out period with aCSF upon the breadth of the volume affected by the injectate. These simulations indicate that, by injecting small volumes of drug at low concentrations and following them with an aCSF flush, a well-delineated region of tissue can be altered for a controlled duration.     

Temporal and spatial control of neural effects following intracerebral microinfusion

Spatial and temporal control of neural drug delivery is critical for many therapeutic applications and analyses of brain patterns and behavior. Specifically, for localized injections that serve to deliver drug or inactivate an isolated tissue region in order to observe changes in neural activity at that site, excess distribution into surrounding regions may confound analysis or adversely affect healthy tissue. Here, we develop a mass transport model that simulates a short period of initial infusion of inactivating drug, followed by a successive convective wash with artificial cerebrospinal fluid (aCSF), while tracking the regions of tissue that are above a certain threshold concentration of inactivating agent. We analyze the effect of parameters such as effective diffusion coefficient, extracellular volume fraction, and injectate concentration upon spatiotemporal distribution profiles. Further, we observe the effects of following the initial injection with a wash-out period with aCSF upon the breadth of the volume affected by the injectate. These simulations indicate that, by injecting small volumes of drug at low concentrations and following them with an aCSF flush, a well-delineated region of tissue can be altered for a controlled duration.     

A vehicle injection into the right core of the nucleus accumbens both reverses the region-specificity and alters the type of contralateral turning elicited by unilateral stimulation of dopamine D2/D3 and D1 receptors in the left core of the nucleus accumbens

The goal of the present study was to analyse to what extent variables such as (1) injected volume, (2) nature of the solvent of drugs (saline versus distilled water) and (3) placement of an additional cannula to inject the solvent of the drugs at the opposite side of the brain, influenced the behavioural effects of the combined administration of the dopamine D(1) receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine-7,8-diol (SKF 38393, 5.0 microg) and the dopamine D(2)/D(3) receptor agonist quinpirole (10.0 microg) into the shell or core of the nucleus accumbens of freely moving rats. First, we found that increasing the injected volume from 0.2 microl to 0.5 microl significantly increased the amount of contralateral turning after injection of the drugs into the shell and, especially, the core of rats equipped with one cannula. More importantly, the type of turning behaviour changed: instead of a predominance of pivoting, both pivoting and circling appeared. Second, replacing the solvent saline by distilled water resulted in a minor, but significant, decrease of the amount of contralateral turning elicited from either the shell or the core of the nucleus accumbens of rats equipped with one cannula. The type of turning was not changed by this new solvent. Third, and most importantly, this study showed that the vehicle injection into the right core exerted a potentiating effect on the number of contralateral rotations elicited by injections of SKF 38393+quinpirole into the left core, whereas such a vehicle injection into the right shell did not affect the number of contralateral rotations elicited by injections of SKF 38393+quinpirole into the left shell. The type of turning in these rats was not changed when compared to rats equipped with one cannula. It is hypothesized that the fluid injected into the core, directly or indirectly, enhanced the dopaminergic asymmetry between the left and the right brain, implying that this manipulation anyhow reduced the dopaminergic activity in the region under discussion. In conclusion, subtle changes in the methodology used to study both the behaviour-specificity and the region-specificity of drug injections into the brain significantly directs the outcome of such studies.     

Antinociceptive action of intraventricular bradykinin

The effects of the administration of bradykinin into the cerebrospinal fluid on the threshold of electric stimuli applied to the tooth pulp of the rabbit were studied, to further explore the resemblance between some of the central actions of morphine and those of bradykinin. Intraventricular injections of bradykinin produced a dose-dependent increase in threshold which was abolished by pretreatment with reserpine and potentiated by the brain kininase inhibitors aprotinin and bradykinin potentiating factor. Aprotinin and bradykinin potentiating factor by themselves also caused threshold increases. Intracisternal injection of bradykinin was ineffective. Intraventrieular morphine, like bradykinin, caused enhancement of the voltage threshold. The sites and mechanisms of action of bradykinin are discussed.     

The effects of chlorpromazine on one-trial passive avoidance learning in mice: Further examination of pre- and post-learning administration

Chlorpromazine in doses of 0.5 mg/kg was administered to mice 0.5, 2, or 10 min after a one-trial passive avoidance learning experience. The drug produced effects on the magnitude and rate of extinction of the learned response dependent upon the injection, time, confirming results contained in an earlier report. In a second experiment with doses of 2.0 mg/kg, the effects of further injecion times were investigated. The drug had no effect when given 240 min before learning, but produced maximal blocking of response acquisition when given 120 and 8 min before learning. Drug injections 6 and 3 min before learning were suggested as having actions on post-learning memory traces. A distinction was noted between the effects of drug injections 1 and 1.5 min after learning and this was related to an effect on a rapidly decaying short-term memory trace. Chlorpromazine had no effect when given 20 min after learning.     

Changes in body temperature and oxygen consumption rate of conscious mice produced by intrahypothalamic and intracerebroventricular injections of delta 9-tetrahydrocannabinol.

delta 9-Tetrahydrocannabinol (delta 9-THC) was injected into the preoptic area of the anterior hypothalamus or into the third or fourth cerebral ventricle of the conscious mouse through a chronically implanted cannula and the effects on body temperature and oxygen consumption rate were measured. At an ambient temperature of 22 degrees C, injections of delta 9-THC into the fourth ventricle (5 and 10 microgram) produced dose-dependent falls in rectal temperature. Hypothermia was also observed after injections of the drug into the hypothalamus (5 and 10 microgram) or into the third ventricle (10 microgram). The hypothermia produced by delta 9-THC was associated with a fall in oxygen consumption rate. Falls in rectal temperature and in oxygen consumption rate were significantly greater after injection of delta 9-THC than after injection of the drug vehicle, Tween 80. The falls in rectal temperature and oxygen consumption rate produced by injection of delta 9-THC into the fourth ventricle were abolished by elevation of the ambient temperature from 22 to 32 degrees C. A pretreatment that consisted of subcutaneous injections of delta 9-THC (20 mg/kg) given once daily for three days produced tolerance to the hypothermic effect of the drug when injected on day 4 either into the fourth ventricle (10 microgram) or into a lateral tail vein (2.0 mg/kg). The results suggest that delta 9-THC acts centrally to alter thermoregulation in mice not only when it is injected directly into the hypothalamus or cerebral ventricles but also when it is given intravenously.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain uptake and CNS levels of 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU)

The uptake of ¹⁴C-labeled 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea (HECNU) into the brain was investigated in the rat after intracarotid injection according to the method of OLDENDORF, as well as in cisternal cerebrospinal fluid obtained by suboccipital puncture after i.v. injection of the drug.The brain uptake index was 31.9 ± 2.9%. Cerebrospinal fluid/blood quotients after i.v. injection were 0.82 at 10 min and 1.10 at 60 min. The results of both methods clearly show that HECNU, in spite of its hydrophilic property, easily penetrates the blood-brain barrier.     

Reinforcing effects of contingently administered subcutaneous injections of etonitazene in rats

RATIONALE: Response-contingent injections of opioids have been shown to control behavior in various species. OBJECTIVE: To determine whether s.c. injections of etonitazene (ETZ) could maintain behavior in rats when administered under a single fixed-interval schedule. METHODS: Rats were trained to lever press for eight 45-mg food pellets under a single fixed-interval (FI) 10-min schedule of reinforcement: following passage of the 10-min interval, each lever press resulted in a pellet delivery until eight pellets were obtained. Delivery of the reinforcer was signaled by a change in visual stimulus conditions. Once stable responding for the food pellets under the FI 10-min schedule was established, a s.c. injection of 3.2 micrograms/kg ETZ was administered to the rat by the investigator following schedule completion and delivery of the food pellets. After receiving the drug injection, rats were returned to the experimental chamber for 30 min and exposed to the same stimulus conditions that accompanied food reinforcement. Across sessions, the number of food pellets was decreased until rats were responding solely for the drug. RESULTS: Responding for the s.c. administered drug stabilized and persisted across sessions. When saline vehicle injections were substituted for the drug injections, responses diminished across sessions to levels below that of the drug baseline. Subsequent alternating blocks of ETZ and vehicle injections produced respective increases and decreases in responding. CONCLUSION: This study demonstrates that response-contingent s.c. injections of a drug can control behavior in rats, systematically replicating a previous experiment that used the i.p. route. Since all pertinent operant behavior is emitted prior to the administration of drug, this procedure can be used for testing the reinforcing effects of a drug without interference from any direct (rate-altering) drug effects. The present findings also extend the conditions under which drugs of abuse may reinforce behavior.     

Comparison of two methods of administration of amphetamine on the dynamics of dopaminergic neurons in the rat

Dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in brain were examined in the striatum and nucleus accumbens septi after the administration of amphetamine by two different methods. A computer-controlled device was constructed to deliver intravenous injections of amphetamine in patterns mimicking those of animals in a self-administration paradigm, i.e. a total of 65 injections of 0.125 mg/kg/injection over 8 hr [total; 8.13 mg/kg (22.05 mumoles/kg)]. The second method was the intraperitoneal injection of 8.13 mg/kg as a single bolus. Control animals were intravenously or intraperitoneally administered saline. The effects of the two injection methods on the concentrations of DA and DOPAC were quite distinct at early times. This may in part be due to differences in the peak concentrations of amphetamine in brain achieved by the two regimens. Differences still persisted 48 hr after injection, particularly in the striatum. Increased levels of DA and DOPAC were observed at this time after the computer-controlled injections, while significantly decreased DA in the striatum is found after intraperitoneal bolus injections. These data strongly suggest that the method of administration of amphetamine can substantially alter the effects and possible toxicity of the drug on dopaminergic systems.     

Ovarian hormone replacement affects cocaine-induced behaviors in ovariectomized female rats

To determine whether cocaine-induced behavioral alterations are modulated by ovarian hormones, ovariectomized rats were randomly assigned to one of two drug treatment conditions: "binge" cocaine (three 15-mg/kg intraperitoneal (ip) injections, 1 h apart) or saline administration; and four hormone pretreatment sub-groups: vehicle control, estrogen, progesterone, or estrogen+progesterone. Cocaine-treated animals displayed more locomotor activity than saline-treated animals and locomotor activity was higher after the third injection than after the first two injections. When analyzed according to hormone group, the administration of estrogen+progestrone suppressed cocaine-induced locomotion after the first injection; this effect was significant when compared to estrogen-pretreated animals. While in each condition cocaine-treated animals displayed significantly higher stereotypic activity than saline-treated animals, in the estrogen+progesterone replacement group, there was more activity after the second injection of cocaine than after the first. Interestingly, animals in the estrogen+progesterone group had significantly lower plasma levels of the cocaine metabolite, benzoylecgonine, than animals in the progesterone or estrogen groups. These results extend our earlier findings in the intact female rat, which suggest an interaction between the endocrine environment, cocaine metabolism, and cocaine-induced behaviors. These effects may underlie reported sex and estrous cycle differences in cocaine-induced behavioral activity.