Joshua S. Rodefer

Progressive ratio and behavioral economic evaluation of the reinforcing efficacy of orally delivered phencyclidine and ethanol in monkeys : effects of feeding conditions

Abstract The effect of feeding conditions on the reinforcing efficacy of orally-delivered drugs was evaluated using a progressive-ratio (PR) paradigm and a behavioral economic analysis of demand. Seven monkeys self-administered phencyclidine (PCP) (0.06, 0.12, 0.25, 0.5, and 1.0 mg/ml) or ethanol (2, 4, 8, 16, and 32% wt/vol) and concurrent water from two drinking spouts under concurrent PR schedules. The ratios increased from 8 to 4096, and 40 liquid deliveries were available after completion of each ratio schedule. The entire range of drug concentrations was presented in nonsystematic order under two feeding conditions, food restriction and food satiation. Drug maintained responses, deliveries and break points were significantly greater than those maintained by water. Food restriction significantly increased the rate of PCP-maintained responses, deliveries and PR break points over the food satiation baseline. There was also a significant interaction between feeding condition and drug concentration. Although ethanol-maintained responses, liquid deliveries and break points consistently increased in five of seven monkeys during food restriction, only drug concentration produced significant differences in these measures. Using break point as a measure of reinforcing efficacy, food restriction increased the reinforcing efficacy of PCP and had a more pronounced effect at higher drug unit prices.

Naltrexone pretreatment decreases the reinforcing effectiveness of ethanol and saccharin but not PCP or food under concurrent progressive-ratio schedules in rhesus monkeys.

Abstract The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1–1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8–4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability.

A comparison of progressive ratio schedules versus behavioral economic measures: effect of an alternative reinforcer on the reinforcing efficacy of phencyclidine

Abstract Alternative non-drug reinforcers have been demonstrated to decrease drug-reinforced behavior by both decreasing relative reinforcing efficacy and substituting for the drug reinforcer. The effect of saccharin on responding maintained by orally delivered phencyclidine (PCP) was examined in this study using concurrent progressive-ratio (PR) schedules of reinforcement and a behavioral economic analysis of demand. Seven adult male rhesus monkeys self-administered PCP (0.06, 0.12, 0.25, 0.50 and 1.0 mg/ml) and either concurrent water or saccharin (0.03% wt/vol) from two drinking spouts under concurrent independent PR schedules. During daily sessions the response requirements (lip contacts on automatic drinking spouts) increased across 15 levels, from 8 to 4096. Each successful ratio completion resulted in the availability of 40 liquid deliveries under an FR 1 schedule and a subsequent increment in the PR. Concentrations of PCP were presented in a non-systematic order and presentation of the concurrent liquid, saccharin or water, was counterbalanced across subjects. All behaviors maintained by PCP were significantly greater than those maintained by water. Replacement of water with saccharin served to significantly decrease PCP-maintained responding and break points (BP) across the range of PCP concentrations; however, saccharin did not significantly decrease deliveries of PCP. Saccharin maintained significantly greater responding, BPs and deliveries compared to either PCP or water, across all PCP concentrations. The use of BP as a measure of reinforcing efficacy suggests that saccharin decreased the relative reinforcing efficacy of PCP. Furthermore, behavioral economic analyses suggested that saccharin decreased maximal PCP-maintained responding (Pmax) in a similar fashion, suggesting that BP and Pmax may be analogous measures of reinforcing efficacy.

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 nonsystematic 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. As ethanol cost (FR) increased, there were proportionately greater decreases in ethanol intake when saccharin was concurrently available compared to when water was available. There was a 35–50% reduction in ethanol deliveries due to concurrent saccharin (versus water) at FR 4, compared to a 55–75% reduction at FR 128. Cost of ethanol (FR), income level and the availability of a nondrug reinforcer are all variables that modify ethanol-reinforced behavior, and income alters the relative preference for a drug versus nondrug reinforcer.

Effects of dopamine receptor antagonists (D1 and D2) on the demand for smoked cocaine base in rhesus monkeys

Abstract  Rationale: Previous studies suggest that dopamine antagonists may reduce the reinforcing effects of cocaine. However, the effects of these antagonists on the demand for smoked cocaine base have not been quantified. Objectives: To evaluate the effects of selective D1 (SCH 23390) and D2 (raclopride) dopamine receptor antagonists on the demand for smoked cocaine base in rhesus monkeys using a behavioral economic analysis. Methods: Six rhesus monkeys were trained to self-administer smoked cocaine base (1.0 mg/kg/delivery) under chained fixed-ratio (FR) schedules (FR64, 128, 256, 512, 1024 or 2048 for lever presses and FR5 for inhalations) during daily 4-h sessions. A maximum of ten smoke deliveries were available. After 5 days of stable behavior at each FR, SCH 23390 (0.01 and 0.056 mg/kg) or raclopride (0.03 and 0.056 mg/kg) were injected intramuscularly, before each session, for 3 consecutive days. Results: Pretreatment with both antagonists dose-dependently reduced cocaine intake across most FR values tested; however, the decrease in consumption was greater at the higher unit prices than at the lower unit prices. A statistical estimate of the price (FR) at which maximum responding occurred (Pmax) was decreased during drug pretreatment, indicating weakened reinforcing effectiveness of cocaine. Conclusions: These data suggest that both antagonists reduce the reinforcing effectiveness of smoked cocaine base, and they have a greater effect on cocaine consumption at higher FR values.

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.

Concurrent progressive-ratio schedules to compare reinforcing effectiveness of different phencyclidine (PCP) concentrations in rhesus monkeys.

Abstract  Rationale: Progressive ratio (PR) schedules have become well accepted for testing the reinforcing effectiveness of drugs. This study extends the methods to concurrent PR schedules with different concentrations of orally delivered phencyclidine (PCP). Objective: The sensitivity of the procedure is tested by presenting different PCP concentrations with independently-operating PR schedules. Method: PCP self-administration was investigated in seven rhesus monkeys. Six different PCP concentrations (0.03–1.0 mg/ml) and water were randomly paired (21 pairings). Liquid delivery (24 ml) was contingent upon lip-contact responses on solenoid-operated drinking spouts; whereby, the response requirement or fixed-ratio (FR) increased (from 8 to 16, 32, 64, 128... to 4096) after each successful completion of a previous FR and subsequent liquid delivery. Monkeys self administered PCP during daily 3-h sessions, and each pair of concentrations was held constant until behavior had stabilized for at least 4 days. Results: The higher of the two PCP concentrations always maintained greater responding, PR break point (BP), or the last ratio completed, and liquid deliveries than did the lower concentration. However, the monkeys did not exclusively respond on the drinking spout that yielded the higher drug concentration. When examined across all drug pairings, the percentage of total available deliveries of the higher concentration was significantly greater than those of the lower concentration. The monkeys maximized the amount (mg) consumed for the response output. Responding, BPs and liquid deliveries maintained by 0.12 and 0.25 mg/ml PCP were significantly greater than other PCP concentrations; however, drug intake (mg) increased directly with PCP concentration. Conclusion: These results indicate that concurrent PR schedules using oral drug self-administration and a concurrent choice paradigm reliably provide an estimation of relative reinforcing strength, and behavior maintained by these schedules is sensitive to small changes in PCP concentration.

The effect of a reduced energy diet and meal patterns on smoking and coffee drinking in women

OBJECTIVE We examined the effect of three feeding conditions on cigarette smoking and coffee drinking in four healthy women. We hypothesized that food deprivation and changes in meal patterns would increase rates of smoking and coffee drinking based on extensive animal literature documenting this effect. METHOD The conditions were: normal three meals per day containing usual energy intake, one meal per day (dinner time) containing 50% of usual energy intake, and three meals per day containing 50% of usual energy intake. Each condition lasted 3 days. RESULTS Neither reduction of energy intake nor alteration in the pattern of meals had any observable effect on number of cigarettes smoked, number of cups of coffee consumed, expired air carbon monoxide levels, or urges to smoke or drink coffee. DISCUSSION This study adds to the growing body of literature suggesting that the food deprivation effect observed in animals does not apply readily to humans. Reasons for the absence of this effect are discussed.