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. However, responding during hour 4 did increase in all cocaine maintenance dose groups when rats were fed before versus after the session. The effects of food deprivation level (8–12 g, 20 g, unlimited food) and time of feeding (before versus after the session) were also assessed in rats maintained at 0.4 mg/kg cocaine. While the magnitude of reinstatement of responding during hour 4 did not vary as a function of food level, extinction responding during hour 3 was significantly increased in rats maintained at the lowest food level (8–12 g) when feeding occurred after the session. These results suggest that food deprivation level and time of feeding, but not cocaine maintenance dose, are important variables in altering extinction and reinstatement of responding.     

Increased intravenous drug self-administration during deprivation of other reinforcers

Previous research has shown that food deprivation markedly increased self-adminstration of a variety of drugs. The present study concerns an extension of the food deprivation effect to a range of doses and other forms of deprivation. In each experiment, etonitazene infusions were continously available to rats under the following sequence of satiation (S) or deprivation (D) sessions: S, S, D, S, S, D, S, S, D, S, S, S. Each infusion contingent upon a lever-press response, and session lenght was 4 hr. In the first experiment, five groups of rats, each receiving a different etonitaze dose: 0 (saline), 5, 10, 20 or 40 μg/kg, were tested under conditions of food satiation (free access) and deprivation (8 g food, sessions). Food deprivation produced no increases in responding maintained by saline, but it produced nearly parallel increases in respon3ing across all drug doses. In the second experiment, effects of water satiation (free access) and deprivation (no water) were tested at the 10 μg/kg etonitaze unit dose. Etonitazene-maintained responding was more than twice as high during water deprivation sessions as during satiation sessions. In the third experiment, rats receiving saline infusion (after brief exposure to 10 μg/kg etonitazene infusions to elevate response rates) did not show any systematic changes in saline-maintained behavior as a result of water deprivation or satiation. In the fourth experiment, rats were allowed continous access to food, water and etonitazene infusions (10 μg/kg). In addition, they were given a drinking solution containing 3% glucose and 0.125% saccharin (G + S). When the rats were deprived of the G + S solution, they showed small but reliable increases in etonitazene self-administration. The present results extend previous findings with food deprivation to a range of doses and other deprivation conditions, suggesting that drug-maintained behavior can be controlled by alterations in a variety of other reinforcing events in the environment.     

Effects of cocaine microinjections into the nucleus accumbens and medial prefrontal cortex on schedule-induced behaviour: comparison with systemic cocaine administration

The effects of cocaine HCl infusions into either the nucleus accumbens (NACC) or medial prefrontal cortex (PFC) were compared on the performance of schedule-induced polydipsia (SIP) and related behaviours. Food-deprived rats were exposed to a fixed-time 60-s schedule of food delivery in daily 30-min sessions until stable levels of behaviour were obtained (14 days). Rats were then bilaterally infused with cocaine into either the NACC or PFC via chronically indwelling guide cannulae. Each subject received a sequence of five cocaine infusions (0, 12.5, 25, 50, 100 µg) according to a Latin Square design. For comparison, following these intracranial infusions each rat received a sequence of five IP injections of cocaine (0, 2.5, 5, 10, 20 mg/kg) also in a counterbalanced order. NACC and PFC infusions of cocaine and IP cocaine dose-dependently reduced SIP. Cocaine infusions into the NACC, but not the PFC, increased locomotor activity but the characteristic temporal profile of locomotor activity during SIP was retained. IP cocaine also increased locomotor activity in a dose-dependent manner, but the temporal profile of activity was flattened following 20 mg/kg cocaine. NACC and PFC infusions of cocaine had little effect on the total number of panel presses to gain access to the food pellets, but did slightly decrease the high rates of responding immediately prior to the pellet delivery. IP cocaine increased the total number of panel presses at the higher doses, mainly by increasing the low rates of responding. The effects of cocaine infusions into the PFC were behaviourally the most selective, as they reduced SIP without having substantial effects either on locomotor activity or panel pressing. These data therefore implicate a role for the PFC in the performance of SIP.     

Alcohol-preferring (P) rats are more sensitive than Wistar rats to the reinforcing effects of cocaine self-administered directly into the nucleus accumbens shell

Wistar rats will self-administer cocaine directly into the nucleus accumbens shell (AcbSh), but not into the nucleus accumbens core. In human and animal literature, there is a genetic association between alcoholism and cocaine dependency. The current experiment examined whether selective breeding for high alcohol preference is also associated with greater sensitivity of the AcbSh to the reinforcing properties of cocaine. P and Wistar rats were given cocaine (0, 100, 200, 400, or 800 pmol/100 nl) to self-infuse into the AcbSh. Rats were given cocaine for the first 4 sessions (acquisition), artificial CSF for sessions 5 and 6 (extinction), and cocaine again in session 7 (reinstatement). During acquisition, P rats self-infused 200-800 pmol cocaine (59 infusions/session), whereas Wistar rats only reliably self-infused 800 pmol cocaine (38 infusions/session). Furthermore, P rats received a greater number of cocaine infusions in the 200, 400 and 800 pmol cocaine groups compared to respective Wistar groups during acquisition. Both P and Wistar rats reduced responding on the active lever when aCSF was substituted for cocaine, and reinstated responding in session 7 when cocaine was restored. However, P rats had significantly greater infusions during session 7 compared to session 4 at all concentrations of cocaine tested, whereas Wistar rats only displayed greater infusions during session 7 compared to session 4 at the 400 and 800 pmol cocaine concentrations. The present results suggest that, compared to Wistar rats, the AcbSh of P rats was more sensitive to the reinforcing effects of cocaine. The reinstatement data suggest that the AcbSh of P rats may have become sensitized to the reinforcing effects of cocaine. Overall, the findings from this study support a genetic association between high alcohol preference and greater sensitivity to the reinforcing effects of cocaine.     

Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats

RATIONALE: Ketoconazole, an inhibitor of corticosterone synthesis, has been reported to decrease the self-administration of low doses of cocaine and prevent stress-induced reinstatement of cocaine-reinforced behavior in rats. OBJECTIVES: The effects of ketoconazole were extended to the acquisition of i.v. cocaine self-administration during food restriction, a form of stress. Food restriction accelerates the acquisition of cocaine self-administration, and the purpose of this experiment was to determine whether ketoconazole would block the food-restriction effect. As control conditions, the effects of ketoconazole on the acquisition of cocaine self-administration in food-satiated rats and acquisition of food-reinforced responding were also evaluated. METHODS: Six groups of rats (groups 1-6) were trained to self-administer i.v. cocaine (0.2 mg/kg; groups 1-4) or food pellets (45 mg; groups 5 and 6) under a fixed-ratio 1 (FR 1) schedule. Food availability was restricted to 20 g per day in groups 1, 2, 5, and 6, while groups 3 and 4 were fed ad libitum. Daily sessions included a 6-h autoshaping component followed by a 6-h self-administration component. During autoshaping, 10 infusions or food pellets were delivered each h under a random interval 15-s schedule after extension and retraction of a lever. During self-administration, the lever remained extended and infusions or food pellets were available under an FR 1 schedule. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions or 150 food pellets was obtained during the self-administration component. Rats were given 30 days to reach this criterion. They were pretreated with ketoconazole (25 mg/kg, i.p.; groups 1, 3, and 5) or vehicle (i.p.; groups 2, 4, and 6) 30 min prior to the autoshaping and self-administration components. RESULTS: Pretreatment with ketoconazole decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion but only under food-restricted conditions. Ketoconazole had no effect on the acquisition of food-reinforced responding. CONCLUSIONS: These results extended previous findings of the suppressant effects of ketoconazole on cocaine-reinforced responding in rats to the acquisition of cocaine self-administration using food restriction as a stressor.     

Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period

 We have shown previously, using an animal model of relapse, that acute exposure to intermittent footshock stress induces reinstatement of heroin-taking behavior in rats. Here we report that in rats trained to self-administer cocaine, exposure to acute intermittent footshock stress induces reinstatement of cocaine-taking behavior after prolonged extinction sessions and after a 4- to 6-week drug-free period; an effect comparable to that induced by a priming injection of cocaine. Animals were initially allowed to self-administer cocaine HCl (1.0 mg/kg per infusion, IV) during one 3-h session/day for 12 days. Subsequently, extinction conditions were introduced by substituting saline for cocaine so that lever-pressing resulted in IV infusions of saline rather than of drug. Extinction conditions were maintained until animals made 15 responses or less in the 3 h, after which animals were given saline infusions at the start of each daily session to establish baseline responding of ten responses or less. Subsequently, animals were tested for reinstatement of responding for saline infusions following a non-contingent injection of cocaine (2.0 mg/kg, IV) and exposure to intermittent footshock (10 min, 0.5 mA, 0.5 s on, mean off period of 40 sec). After an additional 4- to 6-week drug-free period, tests for reinstatement were repeated. Reinstatement of cocaine-taking behavior was observed in both sets of tests in response to footshock and cocaine. These results extend previous reports from this laboratory that footshock stress is an effective stimulus for reinstatement of drug-taking behavior in the rat. Received: 21 March 1996 / Final version: 13 July 1996     

Effects of continuous infusions of SCH 23390 on cocaine- or food-maintained behavior in rhesus monkeys

Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025-0.10 mg/kg/injection, i.v.) was available under a FR 30 schedule. There was a brief time-out period after each reinforcer was delivered. When responding was stable, monkeys received continuous (24 h/day) i.v. infusions of several doses of SCH 23390 (0.8-6.4 mg/kg/day) for at least the same number of sessions as was required for responding to decline to low levels when saline was available for self-administration. In two of four monkeys, SCH 23390 produced larger decreases in responding maintained by cocaine than in responding maintained by food. The effects of SCH 23390 on drug- and/or food-maintained responding progressively diminished over several days of continuous infusion such that, at the end of the infusion period, responding approximated control rates. Termination of daily infusions of SCH 23390 caused minimal effects on food-maintained responding, whereas in three of four monkeys decreases in responding maintained by cocaine were observed. These latter effects were greater following exposure to the higher doses. Following recovery from these effects, consistently higher rates of responding were maintained by doses of cocaine on the ascending limb of the dose-response function. These results suggest that a D(1) antagonist may decrease the reinforcing effects of cocaine. However, these effects diminish over time and exposure to SCH 23390 may result in long-lasting enhancement of sensitization to the reinforcing effects of cocaine.     

Intravenous cocaine self-administration in rats is reduced by dietaryl-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 ofl-tryptophan (2, 4, and 8%) were tested in different groups of five rats each. Three other groups of five rats each received the samel-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 concentrationsl-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 thel-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 ofl-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 ofl-tryptophan. The results of this experiment indicate thatl-tryptophan reduces behavior reinforced by IV cocaine infusions.     

Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug

The drug self-administration paradigm is routinely used to assess the abuse liability of psychoactive compounds. Investigations of the behavioral effects of drug use, however, often involve the response-independent (experimenter-delivered) administration of the compound. It is frequently assumed that response-independent presentation of a compound has the same effects as response dependent deliveries. The present study examined directly the effects of response-dependent (self-administered) versus response-independent (experimenter- delivered) administration of cocaine on food intake and lethality. Littermate triads were exposed to either cocaine (0.33 mg/infusion) or saline using a yoked-box procedure. One member of the triad self-administered the drug under a fixed-ratio 2 schedule. The other two rats received response-independent infusions of either cocaine or saline. Groups of triads were exposed to two different cocaine access conditions. Daily sessions were terminated after 6 h for one group and after the delivery of 80 infusions for the other. The mean number of infusions delivered each session was 47 (±12) and 70 (±11), respectively, for the 6-h and 80-infusion condition. Under the 80-infusion condition, response-independent infusions of cocaine resulted in a significantly higher rate of mortality compared to littermates self-administering identical amounts of the drug. A fewer number of deaths occurred under 6-h condition; however, only rats exposed to response-independent infusions died under both access conditions. These data indicate that the presence or absence of response dependency can profoundly alter the lethal effects of cocaine.     

Impulsivity on a Go/No-go task for intravenous cocaine or food in male and female rats selectively bred for high and low saccharin intake

The purpose of this study was to examine a form of impulsive behavior (impaired inhibition) using cocaine or food reward in addiction-prone and addiction-resistant rats that were bred for high saccharin (HiS) or low saccharin (LoS) intake, respectively. A Go/No-go procedure was used to examine cocaine and food reinforcement (Go component) and the inhibition of responding during a subsequent period of nonreward (No-go component). Rats were initially trained to self-administer intravenous cocaine (0.4 mg/kg) under an FR 1 schedule during daily Go/No-go sessions consisting of three components of cocaine reinforcement (Go) alternating with two nonreward components (No-go), each signaled by different stimuli. Responding and drug intake were compared under three FR values (FR 1, FR 3, and FR 5) and three cocaine doses (0.2, 0.4, and 0.8 mg/kg). A similar Go/No-go procedure was used with food reinforcement and the same three FR conditions. During the Go components for intravenous cocaine, female rats self-administered more infusions at the 0.2 and 0.4 mg/kg doses than males, indicating a sex difference in cocaine intake. During the No-go periods under the cocaine condition, HiS rats and females responded significantly more than LoS rats and males, indicating phenotype and sex differences in impaired inhibition. During the Go components with food reward, males responded more and earned more pellets than females, but there were no phenotype or sex differences in No-go responding (impulsivity). The results indicate that HiS rats and females are more prone than LoS rats and males to impulsive drug-seeking behavior.     

Predictive validity of the extinction/reinstatement model of drug craving

 The effects of chronic desmethylimipramine (DMI) treatment on measures of incentive motivation for cocaine were assessed in order to investigate the predictive validity of the extinction/reinstatement model of drug craving. Rats were trained to respond for cocaine infusions (0.75 mg/kg per 0.1 ml IV) or received yoked-saline infusions during daily 3-h sessions. A light and tone were presented with the infusions. Following self-administration training, each group received daily injections of either saline or DMI (10 mg/kg, IP) for 21 days of withdrawal from the self-administration regimen. On days 12–21 of withdrawal, rats were allowed to respond in the absence of cocaine reinforcement (extinction phase). After reaching an extinction criterion of no responses for 1 h, the cocaine-paired stimuli were repeatedly presented to reinstate responding (reinstatement phase). In the control group, DMI treatment did not alter responding during either test phase, but increased the response latency during the extinction phase. In contrast, DMI treatment in the cocaine group decreased responding and increased the response latency during both test phases, and decreased the extinction latency during the extinction phase. Overall, the effects of DMI were consistent with a reduction of incentive motivation for cocaine, lending support for the predictive validity of the extinction/reinstatement model of drug craving. Received: 1 April 1997/Final version: 3 July 1997     

Potentiated reinstatement of cocaine-seeking behavior following D-amphetamine infusion into the basolateral amygdala.

Reinstatement of extinguished drug-seeking behavior following chronic drug self-administration has been demonstrated in rats in the presence of conditioned cues. This experimental model of cue-induced relapse can be used to assess the neural circuitry involved in relapse. We have previously shown that blockade of dopamine D1 receptors in the basolateral amygdala (BLA) abolishes conditioned cue-induced reinstatement of cocaine-seeking behavior. The present study tested the hypothesis that D-amphetamine-induced facilitation of monoamine neurotransmission in the BLA would potentiate conditioned cue-induced reinstatement of extinguished drug-seeking behavior. During daily self-administration sessions over 10 consecutive days, rats pressed a lever to receive cocaine infusions (0.2 mg/0.05 ml) paired with a light+tone compound stimulus. Following self-administration, rats underwent daily extinction sessions, during which no stimuli were presented. On the test days, rats received intra-BLA D-amphetamine (10 or 30 micro g/side) or vehicle infusions followed by extinction or conditioned cue-induced reinstatement testing. D-amphetamine infusions did not alter extinction responding relative to vehicle infusions. During reinstatement testing, conditioned cue presentation significantly increased responding over extinction levels, and intra-BLA D-amphetamine produced a dose-dependent increase in lever responding relative to vehicle infusions. These findings suggest that enhanced monoamine tone in the BLA potentiates the motivational effect and/or salience of cocaine-paired cues during reinstatement.     

Food deprivation and cocaine self-administration

The effects of food deprivation on the self-administration of cocaine were assessed in three rhesus monkeys under different schedules of reinforcement. In one subject, decreasing body weight to 80% of free-feeding weight (ffw) resulted in increased response rates and number of cocaine infusions taken. The same effects were observed in a second subject when restricted food intake resulted in 88% ffw. When schedule contingencies limited the number of infusions available, reduction to 90% ffw in the third subject resulted in increased response rates. These data suggest that food deprivation can be a potent variable in responding maintained by cocaine self-administration.     

Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys

This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8–6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8–12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.     

Acute sleep deprivation increases the rate and efficiency of cocaine self-administration, but not the perceived value of cocaine reward in rats

Relapse to drug seeking and drug taking is elicited by exposure to stress, drug-associated cues, or drugs of abuse themselves. According to the clinical literature, relapse also can be elicited in humans by sleep deprivation. Even so, the effect of sleep deprivation on drug-seeking and drug-taking behaviors has received relatively little attention in the laboratory (i.e., currently, no animal model exists) and the underlying circuitry remains unexplored. In the present study, 42 naïve male Sprague–Dawley rats were trained to self-administer cocaine and were then divided, on the basis of their behavior, into low (n = 20) and high (n = 22) drug-taking groups. Self-administration behavior was extinguished, and the effect of acute sleep deprivation (0, 4, or 8 h) on drug-induced reinstatement and on progressive ratio responding (i.e., on the motivation to work for drug) was investigated. The results showed that, relative to low drug-takers, high drug-takers took more drug in acquisition, made more infusion attempts during drug-induced reinstatement, worked harder for drug, and exhibited greater goal-directed behavior. Acute sleep deprivation had little impact on high drug-takers beyond increasing the rate of infusions self-administered during progressive ratio (PR) testing. Conversely, in low drug-takers, acute sleep deprivation completely abolished cocaine-induced reinstatement during extinction testing. During PR testing, however, sleep deprivation increased the speed with which low drug-taking rats initiated responding for drug, increased the rate of infusions, and increased goal-directed behavior. It did not, however, increase the perceived value of the cocaine reward (i.e., neither sleep-deprived low drug-takers nor high drug-takers exhibited a higher break point for cocaine than their non-deprived counterparts). These data are the first to demonstrate a direct link between sleep deprivation and responding for cocaine, particularly in subjects that would otherwise respond little for drug.     

Self-administration of minaprine in rhesus monkeys

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and minaprine [3-(2-morpholinoethylamino)-4-methyl-6-phenyl pyridazine dihydrochloride, 3-300 micrograms/kg per infusion] during daily 1-h sessions. From 4 to over 25 times more cocaine infusions were obtained than saline infusions during baseline sessions. When minaprine was substituted for cocaine, none of the tested doses maintained responding above saline levels in two of the monkeys. Some doses of minaprine did maintain responding slightly above those of saline in the other two monkeys; however, the average number of infusions and the within-session time course of minaprine infusions at these doses were markedly more similar to saline than to that of cocaine. It was concluded that minaprine did not serve as a positive reinforcer under the present experimental conditions for any of the monkeys and it was predicted that minaprine would have low liability for recreational use in humans.     

Neonatal isolation stress potentiates cocaine seeking behavior in adult male and female rats.

Little is known with regard to how sex and stress might interact as vulnerability factors in cocaine abuse. In this study, we compared the effects of neonatal isolation stress on cocaine self-administration under extended access conditions and on subsequent responding in a cue-induced reinstatement paradigm in adult male and female rats. Pups from each litter were subjected to either neonatal isolation (1 h/day) or brief daily handling from postnatal day 2 through 12. Adults rats were then trained to self-administer cocaine, and once they acquired lever responding for cocaine under a fixed ratio 1 schedule, they were given 24-h access to intravenous cocaine infusions (1.5 mg/kg) that were available in discrete trials (4, 10 min trials/h) for 7 consecutive days. At 10 days after the last discrete trial session, responding was assessed during six to eight 1-h extinction sessions that were followed by a 1-h cue-induced reinstatement session. Results revealed that females took more cocaine than did males over the 7-day discrete trial self-administration period and tended to respond at higher levels during the initial extinction sessions. Although intake did not differ between handled control rats and isolated rats under extended access conditions, stress effects were observed under subsequent extinction and cue-induced reinstatement testing conditions with isolated rats responding at higher levels during both phases. Notably, stress seemed to obscure sex differences in extinction responding such both isolated males and females responded at high levels. These findings demonstrate robust and enduring effects of neonatal isolation stress on cocaine seeking behavior in adult male and female rats.     

Reinstatement of conditioned reinforcing properties of cocaine-conditioned stimuli

The aim of the present experiment was to investigate the effects of cocaine primes and exposure to foot shock stress on reinstatement of operant responding maintained by a cocaine-conditioned stimulus in rats never trained to actively self-administer cocaine. Following a baseline session of responding for a light-buzzer compound stimulus, rats underwent classical conditioning whereby the compound stimulus was paired with passive intravenous infusions of cocaine (vehicle, 0.5 or 1.0 mg/kg/inf). On subsequent test sessions, operant responding for the compound stimulus was re-assessed in the absence of cocaine. Finally, rats received a cocaine prime (20 mg/kg, i.p.) and foot shock stress prior to two separate test sessions assessing lever pressing for the cocaine-conditioned stimulus. It was found that the animals conditioned with cocaine displayed sustained responding on the lever activating the cocaine-conditioned stimulus. In addition, priming injections of cocaine reinstated responding for the light-buzzer compound stimulus, and this effect was proportional to the dose of cocaine received during classical conditioning. Foot shock stress also reinstated responding, but its effect was smaller and observed only in animals conditioned with the highest dose of cocaine. These findings suggest that cocaine primes and stress can induce reinstatement by reactivating the motivational value of cocaine-conditioned cues.     

Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users.     

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) sacharin (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 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. The results suggest that behavior reinforced by IV-delivered cocaine can be substantially altered by the discontinuation or presentation of G+S, an orally self-administered nondrug reinforcer.