Cell recognition during neuronal development.

Insect embryos, with their relatively simple nervous systems, provide a model system with which to study the cellular and molecular mechanisms underlying cell recognition during neuronal development. Such an approach can take advantage of the accessible cells of the grasshopper embryo and the accessible genes of Drosophila. The growth cones of identified neurons express selective affinities for specific axonal surfaces; such specificities give rise to the stereotyped patterns of selective fasciculation common to both species. These and other results suggest that early in development cell lineage and cell interactions lead to the differential expression of cell recognition molecules on the surfaces of small subsets of embryonic neurons whose axons selectively fasciculate with one another. Monoclonal antibodies reveal surface molecules in the Drosophila embryo whose expression correlates with this prediction. It should now be possible to isolate the genes encoding these potential cell recognition molecules and to test their function through the use of molecular genetic approaches in Drosophila.

The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation.

Both clinical and experimental evidence have firmly established that chronic pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane protein 1 (VMP1), a pancreatitis-associated protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.

TAp73 loss favors Smad-independent TGF-ß signaling that drives EMT in pancreatic ductal adenocarcinoma.

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-ß (TGF-ß) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-ß pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-ß signaling through a SMAD-independent pathway, favoring oncogenic TGF-ß effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-ß signaling. By suggesting TAp73 as a predictive marker for response to TGF-ß inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-ß inhibitors.

Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

Acquisition of i.v. amphetamine and cocaine self-administration in rats as a function of dose.

The effect of dose on the acquisition of i.v. amphetamine and cocaine self-administration was examined. Three unit doses of amphetamine (0.03, 0.06 and 0.12 mg/kg) and three unit doses of cocaine (0.05, 0.2 and 0.8 mg/kg) were tested in separate groups of ten (amphetamine) or 13 (cocaine) rats. Autoshaping methods were used to train rats to press a lever that resulted in drug infusion under a fixed-ratio (FR) 1 schedule. A daily 6-h autoshaping component non-contingently delivered 60 infusions according to a 60-s random time schedule with ten infusions delivered during the first half of each h. Each day autoshaping sessions were followed by a 6-h self-administration session. The criterion for acquisition was a 5-day period during which a daily mean of 100, 50 or 25 infusions for the three amphetamine doses and 400, 100 or 25 infusions were earned during the 6-h self-administration period for the three cocaine doses, respectively. As dose increased, more rats per group acquired drug self-administration and the mean number of days to meet the acquisition criterion decreased. The percentage of rats acquiring amphetamine self-administration increased with dose and ranged from 80 to 100%. Only one rat at the lowest cocaine dose met the acquisition criterion, but 100 percent of the rats at the two higher doses acquired. During the last 2 days of acquisition, mean infusions decreased and mean drug intake (mg/kg) increased as dose increased. On the last day of acquisition, the time course of infusions during the 6-h self-administration component was characterized by a steady rate of infusions per hour, and number of infusions was inversely related to dose. These findings indicate that the initial available dose of a drug is an important determinant of the rate and probability that successful acquisition will occur.

Effects of buprenorphine on self-administration of cocaine and a nondrug reinforcer in rats.

Nine groups of rats self-administered intravenously-delivered cocaine (0.1, 0.2, or 0.4 mg/kg) during 24-h sessions contingent upon lever-press responses under a fixed-ratio (FR) 4 schedule. Three other groups of rats responded on tongue-operated drinking devices for deliveries (0.01 ml) of a solution of glucose and saccharin (G + S). There were an additional three groups that initially self-administered cocaine (0.2 mg/kg), and later saline replaced cocaine and extinction behavior was allowed to stabilize. All 15 groups of rats were injected twice daily for 5 days with one of three doses of buprenorphine (0.1, 0.2 or 0.4 mg/kg). Buprenorphine decreased cocaine self-administration, but the effect of the highest dose was only slightly greater than that of the lowest dose tested. Cocaine infusions were reduced on the first day of treatment, but they increased over the next 4 days of buprenorphine injections. Buprenorphine decreased G + S intake during the last 2 or 3 days of injections. When buprenorphine treatment was terminated, G + S intake decreased even further. These lower rates of intake persisted for at least 5 days, and they returned to baseline by 2 weeks. Saline self-administration was decreased by buprenorphine in all saline extinction groups. Food intake was not altered by buprenorphine in the groups self-administering IV cocaine or saline; however, food intake was reduced in the G + S groups. Water intake increased during buprenorphine treatment in some of the cocaine groups but not in the G + S groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary additives and the acquisition of cocaine self-administration in rats.

The effects of dietary caffeine and the amount and palatability of food on the acquisition of cocaine (0.2 mg/kg) self-administration were examined. Using an autoshaping procedure, seven groups of 13 rats each were trained to press a lever resulting in a cocaine (0.2 mg/kg infusion under a fixed-ratio 1 (FR 1) schedule. One group had ad libitum access to caffeine- (0.2% w/w) admixed food. Three groups had access to 10 g, 20 g or ad lib food each day. Another three groups had the same three amounts of ground food with powdered saccharin (0.2% w/w) added. During daily 6-h autoshaping sessions, ten infusions were delivered each hour under a random-time 90-s schedule after a brief (15 s) extension of a retractable lever. These were followed by 6-h self-administration sessions, when the lever remained extended and cocaine infusions were available under an FR 1 schedule. The acquisition criterion was self-administration of a mean of 100 infusions over 5 days. Cocaine self-administration was accelerated in the caffeine group compared to the regular chow group. However, by 30 days nearly the same percentage of rats in the caffeine and regular food groups met the acquisition criterion. In the other six groups, as the amount of food increased, the rate of acquisition and percentage of rats per group meeting the acquisition criterion decreased. In the ad lib group, acquisition was further reduced when saccharin was added to food. In summary, dietary caffeine accelerated acquisition and a greater amount and increased palatability of food independently interfered with acquisition of cocaine self-administration in rats.

Autoshaping i.v. cocaine self-administration in rats: effects of nondrug alternative reinforcers on acquisition.

The purpose of this experiment was to examine the effects of a nondrug alternative reinforcer and feeding conditions on the acquisition of cocaine self-administration. Rats were autoshaped to press a lever that resulted in a 0.2 mg/kg i.v. cocaine infusion. Responses on the lever were monitored during six consecutive autoshaping sessions that occurred each day. A retractable lever was inserted into the operant chamber on a random time 60 s schedule 10 times per session for six sessions that began each hour. Each day the six autoshaping sessions were followed by a 6-h cocaine self-administration session. During self-administration the lever remained extended, and each response on the lever resulted in a cocaine infusion (0.2 mg/kg). The criterion for acquisition of cocaine-reinforced behavior was met when there were 5 consecutive days during which the mean number of infusions during the 6-h self-administration session was at least 100. This procedure was repeated daily until the criterion was met or 30 days elapsed. The rats were also trained to respond on lick-operated automatic drinking devices that delivered 0.05 ml water or a glucose and saccharin solution (G + S) contingent upon each lick response. Five groups of 12-14 rats were compared. The first four groups constituted a 2 x 2 factorial design whereby either G + S or water was available in the home cage for 3 weeks before autoshaping began and G + S or water was available in the operant chamber during autoshaping. These groups were limited to 20 g food per day and all had free access to water.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous cocaine self-administration in rats is reduced by dietary L-tryptophan.

Rats were trained to self-administer intravenously-delivered cocaine. Four lever-press responses resulted in a cocaine infusion (0.2 mg/kg) during daily 24-h sessions. The rats were also trained to obtain water from tongue-operated solenoid-driven drinking spouts. Ground food and water from a standard drinking bottle were also available. When cocaine injections reached stable levels, L-tryptophan was mixed with the rats' food for 5 days. Three concentrations of L-tryptophan (2, 4, and 8%) were tested in different groups of five rats each. Three other groups of five rats each received the same L-tryptophan treatments; however, in these rats saline was substituted for cocaine and a sweet drinking solution consisting of glucose and saccharin (G + S) replaced water in the automatic drinking device. Two other groups consisting of five rats each self-administered a higher (0.4 mg/kg) or lower (0.1 mg/kg) unit dose of cocaine and food adulterated with 4% tryptophan. At the two higher concentrations L-tryptophan reduced cocaine infusions by at least 50% during the 5 days of treatment, and cocaine infusions returned to baseline levels within 48 h after the regular diet was restored. Responding reinforced by the G + S solution was not altered by any of the L-tryptophan concentrations. Food intake was substantially lowered by the 8% L-tryptophan concentration; however, water intake, responding on an inactive lever, and the number of saline infusions were not affected by addition of L-tryptophan to the food. L-Tryptophan had the same magnitude of effect on self-administration of the 0.1 and 0.2 mg/kg unit doses of cocaine, but behavior maintained by the highest cocaine dose (0.4 mg/kg) was resistant to the effect of L-tryptophan. The results of this experiment indicate that L-tryptophan reduces behavior reinforced by IV cocaine infusions.

A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior.

Lever-pressing responses of 55 rats were reinforced with IV-delivered cocaine (0.2 mg/kg) or saline under conditions of continuous access for 15 24-h sessions. The rats also responded on tongue-operated drinking devices for deliveries of a 3% (w/v) glucose + 0.125% (w/v) saccharin (G+S) solution or water. The effects of removing these substances on behavior maintained by G+S, water, cocaine, or saline were compared in 11 groups. Terminating cocaine access produced a decrease in G+S drinking and an increase in food and water intake. In contrast, a group of rats that did not initially self-administer G+S showed increases in G+S drinking when cocaine was removed, and G+S-maintained responding persisted when cocaine was reinstated. Substitution of water for G+S produced a nearly two-fold increase in cocaine-reinforced behavior but no change in IV-delivered saline self-administration in a control group. A group that did not initially self-administer cocaine increased its infusion rate to over 400 infusions per day as soon as G+S was replaced with water. The effect of presenting cocaine to a group that responded for G+S alone was to decrease G+S intake, but there was only a transient decrease in water intake in the control group. Likewise, presentation of G+S to a group of rats self-administering cocaine resulted in a decrease in infusions, but saline infusions did not change in a control group. Generally, there was an increase in food and water intake during cocaine removal, but food and water intake did not vary systematically with the removal or presentation of G+S.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats.

RATIONALE: Recent studies suggest that the GABA(B) receptor agonist, baclofen, may be a useful pharmacotherapy for cocaine abuse. OBJECTIVES: To investigate further the effects of baclofen on maintenance and reinstatement of cocaine-reinforced behavior in rats. METHODS: Two groups of rats were trained to self-administer IV cocaine (0.2 or 0.4 mg/kg per infusion) during daily 7-h sessions under a fixed-ratio 1 schedule. Rats were pretreated with baclofen (1.25, 2.5 or 5 mg/kg IP) or saline before the session for 5 consecutive days. An additional group of rats was trained to self-administer IV cocaine (0.4 mg/kg per infusion) during the first 2 h of daily 7-h sessions. Cocaine was replaced by saline for the remaining 5 h of the session. Once behavior had stabilized over the 7-h period, priming injections of saline (IV), cocaine (3.2 mg/kg IV) or baclofen (1.25 or 2.5 mg/kg IP) were administered prior to hour 4. Injections of baclofen (1.25 or 2.5 mg/kg IP) or saline were also given before priming injections of cocaine. RESULTS: Pretreatment with the two higher doses of baclofen (2.5 and 5 mg/kg) decreased the number of cocaine infusions in both maintenance groups (0.2 and 0.4 mg/kg) over the 5-day treatment period. Baclofen had a greater suppressant effect on responding maintained by the lower dose of cocaine. Priming injections of baclofen (1.25 and 2.5 mg/kg) or saline did not reinstate responding. However, these same doses of baclofen dose-dependently reduced the reinstatement of responding produced by priming injections of cocaine. CONCLUSIONS: 1) The magnitude of the suppressant effects of baclofen on maintenance of cocaine self-administration depends upon the maintenance dose, 2) baclofen may be useful in preventing reinstatement of cocaine-seeking behavior, and 3) compared to maintenance, reinstatement of responding is more sensitive to the suppressant effects of baclofen.

Combined effects of buprenorphine and a nondrug alternative reinforcer on i.v. cocaine self-administration in rats maintained under FR schedules.

Although previous studies have shown that pharmacological agents, such as buprenorphine, and alternative nondrug reinforcers, such as money or sweetened solutions, reduce cocaine self-administration, few studies have examined the combined effects of these two approaches. The purpose of the present study was to evaluate the effects of the opioid partial against buprenorphine (0.1 mg/kg) and concurrent access to either water or a glucose plus saccharin solution (G+S, 3% and 0.125% wt/vol) in rats self-administering intravenous (IV) cocaine (0.4 mg/kg per infusion) under fixed-ratio schedules (FR2, 8 or 32). One group had concurrent access to water and another group had concurrent access to G+S. After 3 consecutive days of stable cocaine self-administration, a single buprenorphine injection (0.1 mg/kg IV) was administered 30 min before the start of the experimental session for 3 consecutive days. To summarize the results, (1) the presence of an alternative non-drug reinforcer significantly reduced cocaine self-administration, (2) buprenorphine selectively decreased cocaine, but not water or G+S, self-administration; (3) the decrease in cocaine infusions by buprenorphine was greatest on the first day of buprenorphine administration; and (4) expressed as a percentage of baseline conditions, the combination of buprenorphine and G+S produced a greater decrease in cocaine self-administration than either buprenorphine or G+S alone. These results indicate that combined treatment with buprenorphine and concurrent access to a sweetened solution is a more effective strategy for reducing cocaine self-administration than either strategy alone.

Food deprivation affects extinction and reinstatement of responding in rats.

Food deprivation has been shown to increase the self-administration of a wide variety of drugs in a number of different species. However, the effects of food deprivation on other phases of drug taking have not been established. The purpose of the present study was to evaluate the effects of food deprivation on reinstatement of responding for cocaine. Rats trained to self-administer 0.2, 0.4, or 1.0 mg/kg cocaine intravenously (IV) under a fixed-ratio 1 schedule for the first 2 h during daily 7-h sessions were fed either before or after the experimental session. During hours 3-7, rats self-administered saline. Saline replaced cocaine in the infusion pumps at the beginning of hour 3 and a priming injection of either saline or cocaine (0.32, 1.0, or 3.2 mg/kg IV) was administered at the beginning of hour 4. The number of infusions that was self-administered was measured throughout the 7-h session. During hours 1 and 2 when cocaine was available, the number of infusions was inversely related to cocaine dose. During hour 3, rats typically self-administered several infusions of saline, which gradually decreased to near-zero levels by hours 4-7 (extinction responding). A priming injection of cocaine administered at the beginning of hour 4 reinstated responding in a dose-related manner. The magnitude of extinction responding during hour 3 and reinstatement of responding during hour 4 were similar regardless of cocaine maintenance dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Choline acetyltransferase activity is reduced in rat nucleus accumbens after unlimited access to self-administration of cocaine.

Choline acetyltransferase (ChAT) activity was measured in discrete areas of rat brain after chronic, unlimited access to self-administration of cocaine. Mean activity of ChAT was reduced by approximately 30% in the nucleus accumbens, both on the last day of cocaine access and after 3 weeks cocaine withdrawal. These data suggest that chronic cocaine exposure might inhibit nucleus accumbens cholinergic neurones which could underlie some of the behavioral effects of cocaine.

Absence of the abducens nerve in Duane syndrome verified by magnetic resonance imaging.

PURPOSE: To demonstrate that currently available magnetic resonance imaging techniques may verify the absence of the abducens nerve in Duane syndrome. METHODS: We performed magnetic resonance imaging in a 36-year-old woman with left Duane syndrome, type 1, using spoiled gradient recalled acquisition in the steady state to obtain high-resolution T1-weighted images through the abducens nerve in its subarachnoid segment. Scans were obtained in the axial plane from the medulla to the midbrain and then reformatted along the plane of the abducens nerve. RESULT: Unilateral absence of the left abducens nerve was verified using magnetic resonance imaging. CONCLUSION: The absence of the abducens nerve in Duane syndrome can be verified by modern magnetic resonance imaging techniques.

Cocaine withdrawal produces behavioral disruptions in rats.

There is currently no laboratory or clinical evidence from animal or human studies documenting a withdrawal syndrome associated with cocaine dependence, although many users report that withdrawal disturbances are responsible for their repeated use of the drug. In the present study rats self-administered i.v. cocaine and a sweetened drinking solution. When cocaine access was terminated there was a marked suppression in operant behavior reinforced by the sweetened solution, and this withdrawal disruption was immediately reversed when cocaine was reinstated. There were no physical signs of withdrawal, and food intake increased when cocaine was withdrawn. The results suggest that sensitive behavioral tests reveal aspects of drug dependence that may account for persistent abuse.

Nicotine dependence in rats.

Health hazards associated with nicotine and tobacco use are well known. A contributing factor, the dependence producing potential of this drug, has become widely accepted. However, there are only a few human and animal studies that provide objective measures of the behavioral consequences of nicotine abstinence. The purpose of the present experiment was to use sensitive measures to examine behavioral disruptions that resulted when nicotine administration was terminated. Six rats were administered 96 daily intravenous infusions of nicotine (0.125 mg/kg/infusion) for at least 10 days. They were trained to respond on a tongue-operated solenoid-driven drinking device that delivered 0.005 ml of a glucose and saccharin solution (G + S) per lick. When nicotine access was terminated for six days, there was a marked suppression in behavior reinforced by the sweetened solution, and this disruption was immediately reversed when nicotine was reinstated. In contrast, nicotine removal also resulted in a decrease in food intake on the first day, but on subsequent days food intake was significantly higher than when nicotine was administered. When cotinine (0.25 mg/kg/infusion), a metabolite of nicotine was substituted for nicotine for six days, similar disruptions resulted in responding maintained by G + S, but food intake was not significantly decreased on the first day of nicotine abstinence. These findings illustrate the utility of sensitive behavioral tests to reveal effects of nicotine abstinence.

Fluoxetine reduces intravenous cocaine self-administration in rats.

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized, the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G + S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G + S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G + S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Food deprivation history and cocaine self-administration: an animal model of binge eating.

In this two-part study, an animal model of binge eating was first produced, then the rate of acquisition of cocaine self-administration was assessed. Initially, 16 female weanling rats were food deprived (DEPR) at 25, 95, and 143 days of age. Another group of 16 age-matched controls was allowed ad lib access to food. Each time the DEPR group was food deprived, they were allowed to recover to normal weight. They were then injected with butorphanol tartrate (BUTR), an opioid that stimulates feeding, and food intake was measured for 4 h. All rats given BUTR consumed significantly more food than those given saline. Animals with DEPR history consumed food over a longer period of time, and at h 4 after BUTR injection, they consumed significantly more food than controls. In the second part of the experiment, an autoshaping procedure was used to quantitatively evaluate the rate of acquisition of cocaine self-administration. By day 30, 86% of the DEPR and 69% of the control groups had acquired cocaine self-administration.

Effects of carbamazepine on self-administration of intravenously delivered cocaine in rats.

Carbamazepine (Tegretol) is widely used therapeutically as an anticonvulsant. Based on an hypothesis that links electrical kindling in the limbic system (leading to seizures) to reverse tolerance or sensitivity to cocaine's effects, carbamazepine is being tested as a treatment for human cocaine users. The purpose of this experiment was to examine the effects of carbamazepine on intravenous cocaine self-administration in rats. Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio 4 schedule. When cocaine injections reached stable levels, carbamazepine was mixed with the rats' food for 8 days. Three doses of carbamazepine were tested (80, 120, and 160 mg/kg) in different groups of 5 rats each. The rats were later separated into groups with a high (greater than 750 infusions) and a low (500-750 infusions) cocaine baseline. Two control groups of 5 rats each received carbamazepine treatments (120 or 160 mg/kg) and self-administered an orally delivered solution of glucose and saccharin (G + S). At the highest carbamazepine dose in the high cocaine baseline group, carbamazepine reduced cocaine infusions by at least 50 percent and food intake by approximately 25 percent during the 8 days of treatment. Cocaine infusions returned to baseline within 24 hr after the regular diet was restored. Carbamazepine had a minimal effect in groups of rats with lower cocaine baselines. Responding reinforced by the G + S solution was reduced by both the 120 and 160 mg/kg carbamazepine doses. Water intake was not systematically affected by the addition of carbamazepine to the food; however, activity measures were significantly lower in some groups at the higher carbamazepine doses.(ABSTRACT TRUNCATED AT 250 WORDS)