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Biomedical subjects

M E Carroll

Publications and source records attributed to M E Carroll.

At least 55 records · Page 3Linked to original sources
PubMed1995

Concurrent self-administration of ethanol and an alternative nondrug reinforcer in monkeys: effects of income (session length) on demand for drug.

Eight rhesus monkeys (Macaca mulata) were trained to self-administer orally delivered ethanol (8%) and saccharin (0.03 or 0.3% wt/vol) or water under concurrent fixed-ratio (FR) schedules. The FR requirement for saccharin was fixed at 32, while the FR for ethanol was varied (4, 8, 16, 32, 64 and 128) in a non-systematic order to assess demand for drug. Demand was defined as consumption plotted as a function of price (FR). Income was defined as the duration of access to available resources. Income was varied by allowing access to the concurrently available liquids 20, 60 or 180 min per day. Order of testing was counter-balanced across monkeys. Saccharin deliveries were much higher than ethanol deliveries under the 180-min income condition; however, they were lower than ethanol deliveries when income was reduced to 20 min and the ethanol FR was 4, 8 or 16. Thus, when the price of drug was relatively low, consumption of drug exceeded that of the nondrug reinforcer, and that relationship was reversed as income decreased. Saccharin deliveries sustained a proportionally greater reduction due to decreased income compared to ethanol deliveries. As income decreased from 180 to 20 min, saccharin deliveries were reduced by an average of 79.1% (across ethanol FR conditions) while ethanol deliveries were reduced by an average of 41.2 and 40.8% when concurrent saccharin or water were available, respectively; thus, drug self-administration was more resistant to income changes than saccharin. The demand for ethanol was shifted downward in a parallel fashion as income decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Effects of food deprivation on cocaine base smoking in rhesus monkeys.

Studies have shown that both food deprivation and response cost have important influences on the magnitude of self-administration of a wide variety of psychoactive drugs. In an attempt to extend these findings to the smoked route of drug self-administration, the effects of food allotment and fixed-ratio (FR) value were evaluated in four male rhesus monkeys trained to smoke cocaine base. In the first phase of the experiment, monkeys were trained to self-administer experiment, monkeys were trained to self-administer smoked cocaine base under a chained progressive-ratio (PR), fixed-ratio (FR) schedule during daily experimental sessions. Monkeys were required to make 20 lever-press responses and then five inhalations on a smoking spout to obtain the first smoke delivery. The lever ratio than increased to 60, 140, 300, 620, 1260, 2540, and 4940 for each successive smoke delivery. The initial lever ratio value was reset to 20 at the beginning of each daily session. The body weights of three monkeys were determined under free-feeding conditions. Monkeys were then restricted to 100 g food and, when body weights had stabilized, the daily food allotment was increased to 150 g, approximately 210 g, or greater than 400 g (satiation). As the daily food allotment and body weight increased, the mean number of smoke deliveries decreased in two of three monkeys. In the second phase of the experiment, three monkeys were maintained under either food-satiated or food-restricted conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

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.

Animals↗
PubMed1994

Effects of concurrent saccharin availability and buprenorphine pretreatment on demand for smoked cocaine base in rhesus monkeys.

The effects of saccharin and the opioid partial agonist buprenorphine on cocaine base smoking were evaluated in five male rhesus monkeys. Monkeys completed a sequence of responding consisting of lever-press responses maintained under a fixed-ratio (FR) schedule followed by inhalation responses (FR5) on a smoking spout to gain access to a single delivery of volatilized cocaine base (1.0 mg/kg per delivery). Monkeys could receive a maximum of ten smoke deliveries per session. In the first experiment, either saccharin (0.03% wt/vol) or water was concurrently available under an FR1 schedule through a lip-operated drinking device. As lever FR values increased from 128 to 256, 512, 1024 and 2048, the number of cocaine smoke deliveries decreased. Cocaine intake was not statistically different when water versus saccharin was concurrently available. However, as cocaine consumption decreased, saccharin intake increased demonstrating that under these conditions, saccharin was substituting for cocaine as a reinforcer. On the first day that lidocaine replaced cocaine, all of the monkeys received the maximum number of smoke deliveries (ten) and saccharin intake increased. Lever-press responding gradually extinguished over days when lidocaine (1.0 mg/kg per delivery) was available with concurrent saccharin. In the second experiment, water was concurrently available with cocaine and buprenorphine (0.01 or 0.1 mg/kg) was administered intramuscularly (IM) 30 min before the start of the session. Although pretreatment with the lower dose of buprenorphine (0.01 mg/kg) had little effect on cocaine intake overall, individual differences in cocaine intake occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

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.

Aging↗
PubMed1994

Phencyclidine (PCP) self-administration and withdrawal in rhesus monkeys: effects of buprenorphine and dizocilpine (MK-801) pretreatment.

The effects of dizocilpine and buprenorphine pretreatment on behavior reinforced by orally delivered phencyclidine (PCP) and saccharin, and on PCP withdrawal-induced disruptions in food-maintained responding were examined. Sixteen male rhesus monkeys were used in six different experimental protocols. Two groups of monkeys (N = 4-5) self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 schedules, and were pretreated with IM injections of saline, and dizocilpine (0.001-0.1 mg/kg), or buprenorphine (0.003-0.8 mg/kg) 30 min before the 3-h sessions for 5 days. Two other groups (N = 5) were treated similarly except they had access to saccharin (0.03% or 0.3% w/v) and water under concurrent FR 16 schedules. In two other groups (N = 3), the effects of saline, dizocilpine (0.005-0.1 mg/kg), or buprenorphine (0.2 and 0.8 mg/kg) pretreatment were studied on PCP (0.25 mg/ml) withdrawal-induced disruptions in food-maintained responding. Dizocilpine and buprenorphine reduced both PCP (0.25 mg/ml) and saccharin (0.03% or 0.3% w/v) self-administration, especially at the 0.1-mg/kg dizocilpine dose and 0.2-mg/kg buprenorphine dose. Dizocilpine attenuated the PCP withdrawal effect, but buprenorphine had no effect on behavioral disruptions induced by PCP withdrawal. When dizocilpine was administered 2 days after PCP withdrawal began, the withdrawal effects were almost completely reversed. These results suggest that although drugs from the same and different pharmacological classes can suppress self-administration of drug and nondrug reinforcers, the same doses may produce an opposite effect or no effect on food-maintained behavior during PCP withdrawal.

Animals↗
PubMed1994

Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration.

We examined the influence of chronic cocaine exposure, in an unlimited access self-administration paradigm, on density of the dopamine transporter (3H-WIN 35,428 and 3H-GBR 12,935 binding) and concentration of monoamine (dopamine, serotonin, noradrenaline and metabolites) neurotransmitters in rat brain. In normal rodent striatum 3H-WIN 35,428 and 3H-GBR 12,935 binding to the dopamine transporter, although generally similar, showed different subregional rostrocaudal and mediolateral gradients, suggesting that the two ligands might bind to different subtypes or states of the dopamine transporter. Following chronic, unlimited access cocaine self-administration, binding of 3H-WIN 35,428 was significantly elevated in whole nucleus accumbens (+69%, p < 0.001) and striatum (+65%, p < 0.001) on the last day of cocaine exposure ("on-cocaine group"); whereas in the 3 week withdrawn animals ("cocaine-withdrawn group"), levels were either normal (striatum) or reduced (-30%, p < 0.05, nucleus accumbens). Although similar changes in 3H-GBR 12,935 binding were observed, this dopamine transporter ligand showed a smaller and highly subregionally dependent increase in binding in striatal subdivision of the on-cocaine group, but a more marked binding reduction in the cocaine-withdrawn animals. As compared with the controls, mean dopamine levels were reduced in striatum (-15%, p < 0.05) of the on-cocaine group and in nucleus accumbens (-40%, p < 0.05) of the cocaine-withdrawn group. These data provide additional support to the hypothesis that some of the long-term effects of cocaine exposure (drug craving, depression) could be consequent to reduced nucleus accumbens dopamine function. Our data also suggest that dopamine transporter concentration, and perhaps function, might undergo up- or downregulation, either as a direct effect of cocaine, or indirectly as part of a homeostatic response to altered synaptic dopamine levels, and therefore might participate in the neuronal events underlying cocaine-induced behavioral changes.

Animals↗
PubMed1993

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)

Animals↗
PubMed1993

The economic context of drug and non-drug reinforcers affects acquisition and maintenance of drug-reinforced behavior and withdrawal effects.

The focus of this review is to examine the effect of non-drug alternative reinforcers on drug-reinforced behavior. An increasing number of animal laboratory as well as human clinical studies have demonstrated the effectiveness of non-drug reinforcers in reducing steady-state levels of drug self-administration. One goal of this review was to determine what behavioral economic conditions are optimal for reducing drug-reinforced behavior. Variables such as price of the drug and non-drug reinforcer have been manipulated by changing fixed-ratio (FR) value of these commodities. Income has been changed by limiting the amount of access to the commodities or by changing session length. Substitution was evaluated by determining whether decreased demand for a drug (due to increased price) was related to increased demand for a non-drug reinforcer. A second goal of this review was to investigate transition states in the drug addiction process with respect to the role of alternative non-drug reinforcers. Animal models of acquisition and withdrawal were examined to identify behavioral economic conditions under which acquisition may be prevented or withdrawal effects (and potential for relapse) may be alleviated.

Animals↗
PubMed1993

Effects of buprenorphine and naltrexone on reinstatement of cocaine-reinforced responding in rats.

Reinstatement of responding previously maintained by cocaine was measured after noncontingent "priming" injections of cocaine, the opioid partial agonist buprenorphine, the opioid antagonist naltrexone and the opioid agonist etonitazene. The effects of pretreatment with buprenorphine, naltrexone or etonitazene on the reinstatement of responding produced by a priming injection of cocaine were also evaluated. The rats were trained to respond on a lever under a fixed-ratio 1 schedule to receive i.v. infusions of cocaine (1.0 mg kg-1 infusion-1) for the initial 2 hr during daily 7-hr sessions. Saline replaced cocaine at the beginning of hour 3, which resulted in an extinction of responding during the third hour and low levels of responding during the subsequent 4 hr of the session. Priming i.v. injections of cocaine (0.4-3.2 mg/kg), but not buprenorphine (0.025-0.4 mg/kg), naltrexone (1.6 and 3.2 mg/kg) or etonitazene (2.5 and 5.0 micrograms/kg), administered at the beginning of hour 4 of the session (i.e., during the extinction period), produced a dose-related reinstatement of responding. Pretreatment with either buprenorphine (0.025-0.4 mg/kg) or etonitazene (2.5 and 5.0 micrograms/kg), but not naltrexone (1.6 and 3.2 mg/kg), produced a dose-related suppression of the reinstatement of responding produced by 3.2 mg/kg of cocaine. These results indicate that 1) buprenorphine and naltrexone have little potential for producing reinstatement of responding in cocaine-maintained rats and 2) buprenorphine's effectiveness in preventing a reinstatement of responding produced by a cocaine priming injection may be related to its opioid agonist actions.

Animals↗
PubMed1992

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)

Animals↗
PubMed1992

Buprenorphine's effects on self-administration of smoked cocaine base and orally delivered phencyclidine, ethanol and saccharin in rhesus monkeys.

The effects of buprenorphine on behavior reinforced by smoked cocaine base and orally delivered phencyclidine (PCP), ethanol and saccharin were compared. There were six groups of four to five rhesus monkeys. Group 1 contained four monkeys that had been trained to smoke cocaine base under progressive ratio (PR) or fixed ratio (FR) schedules. Up to eight smoke deliveries (2 mg/kg) were available during daily 3-hr sessions. Each delivery was separated by a 15-min timeout. The remaining groups received concurrent access to different combinations of orally delivered liquids as follows: group 2, PCP (0.25 mg/ml) and water; group 3, saccharin (0.03% w/v) and water; group 4, PCP and saccharin; group 5, ethanol (8% w/v) and water; and group 6, ethanol and PCP. Saline or buprenorphine (0.003, 0.012, 0.05, 0.2 and 0.8 mg/kg) injections were given i.m. 30 min before each session for 5 consecutive days. Buprenorphine produced a dose-dependent reduction in behavior maintained by PCP, ethanol or saccharin in all of the six groups. In group 1, the suppressant effects of buprenorphine on cocaine base smoking were greater in the two monkeys that responded under FR 5 schedules than in the two that responded under PR schedules. When PCP and saccharin were concurrently available (group 4), buprenorphine had a greater suppressant effect on PCP than when water was concurrently present (group 2). Buprenorphine produced nearly a complete suppression in saccharin-maintained responding at doses of 0.012 mg/kg and higher in groups 3 and 4. Buprenorphine reduced ethanol deliveries to about 50% at doses of 0.012 mg/kg and higher in group 5. When PCP and ethanol were concurrently available (group 6), buprenorphine had an effect on PCP and ethanol that was similar to that found when the drugs were available concurrently with water. These results suggest that buprenorphine suppresses behavior maintained by several drug and nondrug substances, and it further suppresses PCP-maintained behavior that is already reduced by a nondrug alternative reinforcer.

Administration, Oral↗
PubMed1991

Effects of food FR and food deprivation on disruptions in food-maintained performance of monkeys during phencyclidine withdrawal.

Six rhesus monkeys self-administered orally-delivered phencyclidine (PCP) and water under concurrent fixed-ratio (FR) 8 schedules. Liquids were available during three 6.5-h periods daily preceded by 1-h components when food was available under an FR 64 (lever press) schedule. After 10 days of stable behavior, water was substituted for PCP for 8 days. PCP was subsequently reinstated, and this PCP withdrawal sequence was repeated using different food FR values (64, 128, 256, 512 and 1024). Each time the food FR was changed behavior was allowed to stabilize for at least 10 days. Under all FR values food-maintained responding decreased markedly during PCP withdrawal, with a gradual recovery over the next 8 days. As the FR value increased from 64 to 1024 there was a parallel shift downward in food-maintained performance. When PCP was reinstated, food-reinforced responding generally returned to baseline rates during the first few days. In a second experiment monkeys were tested for PCP withdrawal effects under relatively food deprived or food satiated conditions under both an FR 512 and 1024 schedule of food delivery. The results showed that the decrease in food-maintained responding during withdrawal was inversely related to the total amount of food consumed during the control period. The results of these experiments indicate that manipulation of both the response requirements for food (FR) and the total amount of food available (food deprivation/satiation) alters the magnitude of response disruptions during PCP withdrawal.

Animals↗
PubMed1991

Modifying drug-reinforced behavior by altering the economic conditions of the drug and a nondrug reinforcer.

Six rhesus monkeys were trained to self-administer orally delivered phencyclidine (0.25 mg/mL) and saccharin (0.03% wt/vol) under concurrent fixed-ratio 16 schedules. In Condition 1 the fixed-ratio requirement for phencyclidine was changed from 16 to 4, 8, 16, 32, 64, 128 and 16 while the fixed-ratio requirement for saccharin deliveries remained constant at 16. In Condition 2 the fixed-ratio value for saccharin was systematically altered while the fixed-ratio requirement for phencyclidine remained at 16, and in Condition 3 the fixed-ratio requirements for both phencyclidine and saccharin were altered simultaneously. Water was then substituted for saccharin, and the series of fixed-ratio manipulations was replicated. The phencyclidine concentration was reduced to 0.125 mg/mL and Conditions 1 and 3 were repeated. When the fixed-ratio requirement for phencyclidine was increased and the fixed-ratio requirement for saccharin or water remained fixed at 16, phencyclidine deliveries decreased when saccharin (vs. water) was concurrently available. The magnitude of the decrease ranged from 20% to 90% (of the concurrent water condition) as the fixed-ratio requirement for phencyclidine increased from 4 to 128. When the fixed-ratio requirement for phencyclidine remained at 16 and the fixed-ratio requirements for concurrent saccharin or water varied between 4 and 128, phencyclidine deliveries decreased by 30% to 40% due to the concurrent availability of saccharin (vs. water). This decrease occurred only at the three lowest fixed-ratio values when saccharin intake was relatively high. When the fixed-ratio requirements for both phencyclidine and concurrent saccharin or water were varied simultaneously, phencyclidine deliveries were reduced from 20% to 45% when saccharin (vs. water) was concurrently present. There was little effect of reducing the phencyclidine concentration when the data were analyzed in terms of unit price (responses per milligram). Thus, changes in the fixed-ratio requirement or drug concentration were functionally similar, and unit price of phencyclidine was the variable that was influenced by the presence of concurrent saccharin. These data indicate that drug-reinforced behavior is substantially reduced when the environment is enriched with an alternative nondrug reinforcer. The economic context in which these substances are presented is an important determinant of drug-reinforced behavior.

Animals↗
PubMed1990

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.

Animals↗
PubMed1990

Cocaine-base smoking in rhesus monkeys: reinforcing and physiological effects.

Four rhesus monkeys were trained to smoke cocaine-base under a progressive ratio (PR) schedule, with ten smoking trials available each day. Unit dose was varied from 0.25 to 3 mg/kg, and lidocaine (2 mg/kg) was substituted for cocaine. Number of responses and break-point on the PR schedule increased with dose while the number of smoke deliveries increased only slightly. Maximum daily smoke deliveries ranged from six to nine across monkeys. When lidocaine (2 mg/kg) was substituted for cocaine-base, responding decreased to approximately half of that maintained by cocaine, and when cocaine was reinstated, higher response rates returned. Cardiovascular changes associated with cocaine smoking were monitored with an indwelling radio transmitter. There was an initial decrease in heart rate (30 s) followed by a rapid rise and decline by the end of the 15-min trials. Blood pressure increased rapidly after trial onset and returned to pretrial baseline by 15 min. Over the eight trials completed during a session, heart rate and blood pressure steadily increased over presession base-lines during the first four trials, but there was then a decline suggesting acute tolerance development. Observations of the monkeys after each trial revealed dilated pupils and slightly agitated, hyperactive behavior. These findings indicated that smoked cocaine-base was rapidly established as a reinforcer for monkeys, and the physiological effects were similar to those reported in studies of human subjects.

Animals↗