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. The higher dose of buprenorphine (0.1 mg/kg) decreased the amount of cocaine consumed at all lever FR values tested.     

Time-dependent exacerbation of amphetamine-induced taste aversions following exposure to footshock

Previous studies have shown that stressors attenuate LiCl-induced conditioned taste aversions (CTA) but not morphine-induced CTA. The current studies examined the effects of footshock on the acquisition and extinction of amphetamine-induced CTA. Experiment 1 demonstrated that exposure to 30 footshocks between saccharin consumption and amphetamine injections did not alter either the acquisition or the extinction of amphetamine-CTA. Experiment 2 demonstrated that exposure to the same shock parameters 2 and 4 days before saccharin-amphetamine pairing increased the magnitude of amphetamine-CTA after one saccharin-amphetamine pairing and delayed the recovery from the CTA. Experiment 2 also demonstrated that footshock increased the initial neophobic response to novel saccharin but did not alter subsequent saccharin consumption among saline-injected animals. These results indicate that stress-induced facilitation of amphetamine CTA are time-dependent and contrast with reports that stressors attenuate LiCl CTA. They also add support to the contention that CTAs induced by self-administered drugs like amphetamine are qualitatively different from CTAs induced by toxic substances like LiCL.     

Bidirectional changes in the consumption of food produced by β-carbolines

β-Carboline derivatives provide examples of benzodiazepine receptor ligands which span the range: full agonist-partial agonist-antagonist-partial inverse agonist-full inverse agonist. Taken together, the effects of these compounds illustrate two important principles: firstly, the bidirectionality of effects which can be achieved using benzodiazepine receptor ligands; secondly, the selectivity of effects which are produced by partial agonists. Applied to the study of feecling processes, these principles imply that both hyperphagic and anorectic effects can be generated by actions of selected ligands at benzodiazepine receptors. Furthermore, they suggest that a hyperphagic effect may occur in the absence of side-effects (e.g., sedation, muscle-relaxation), which are characteristic of classical benzodiazepines. Experimental data in support of these predictions are presented. A microstructural approach to feecling behaviour indicated that a benzodiazepine receptor agonist and an inverse agonist extend and abbreviate, respectively, the duration of individual bouts of eating. Preference for a saccharin solution was attenuated by the β-carboline inverse agonist, FG 7142, but rejection of a quinine solution was not increased. Adrenalectomy had no effect on the anorectic effect of inverse agonists.     

Effects of amperozide, 8-OH-DPAT, and FG 5974 on operant responding for ethanol

 Both 5-HT_1A and 5-HT_2A receptors have been implicated in modulating ethanol self-administration. A novel serotonergic compound, FG 5974, with combined 5-HT_1A agonist/5-HT_2A antagonist activities, has shown effects in decreasing ethanol consumption in two-bottle choice paradigms. In the present study, the effect of this compound on operant responding for ethanol (as well as water and a saccharin solution) was compared to compounds possessing the separate neuropharmacological effects of this drug (the 5-HT_1A agonist, 8- OH-DPAT, and the 5-HT_2A antagonist, amperozide). While all three serotonergic compounds decreased operant responding for ethanol, only FG 5974 had no effect on water and saccharin responding. These results suggest that combined 5HT_1A agonist/5-HT_2A antagonist activity provides a more selective effect on ethanol reinforcement than either neuropharmacological action alone. Therefore, further analysis of mixed serotonergic compounds in general, and FG 5974 in particular, is warranted as they offer potential treatments for alcoholism. Received: 14 May 1997 / Final version: 6 November 1997     

Effects of the imidazobenzodiazepine Ro 15-4513 on saccharin choice and acceptance, and on food intake, in the rat

The general aim of the present series of experiments was to investigate the effects of the imidazobenzodiazepine, Ro 15-4513, on ingestional behavior in the rat. The more specific aims were to test its effects on preference for sweet taste, to determine if it acts as a benzodiazepine-receptor inverse agonist, and if it selectively reduces sweetness preference. The results indicated that Ro 15-4513 (1.0-10 mg/kg, i.p.) abolished the preference for a 0.05% sodium saccharin solution in a two-choice test. Water intake in the same test was unaffected. Second, at 10 mg/kg, it suppressed saccharin ingestion in an acceptance test; this effect was completely reversed by the selective benzodiazepine antagonist, Ro 15-1788 (20 mg/kg). Third, Ro 15-4513 (1.0-10 mg/kg) reduced palatable food consumption in non-deprived rats, an effect which was also antagonized by Ro 15-1788. The results are consistent the bidirectional modulation of ingestional responses to palatable taste stimuli as a consequence of drug actions at benzodiazepine receptors. Furthermore, they emphasize that any reduction in consummatory responses produced by Ro 15-4513 is likely to reflect inverse agonist characteristics, as distinct from any putative ethanol antagonist property.     

Intravenous morphine self-administration by rats with low versus high saccharin preferences

An experiment was performed to determine the relationship between saccharin preference and the self-administration of morphine via the oral and intravenous routes. On the basis of voluntary intake of a saccharin solution by male rats, low and high preference groups were formed. Rats selected for high saccharin preference self-administered more morphine intravenously than rats selected for low preference. The two groups did not differ in oral morphine intake. The positive relationship between the intake of saccharin and intravenous morphine self-administration may be due to their mediation by a common mechanism. Measures of taste sensitivity or preference may be useful in identifying individuals at risk for drug abuse.     

Prenatal psychological stress effects on taste neophobia

Pregnant mothers were subjects to a novel environment, a treatment which is known to induce an 11-hydroxycorticosterone (stress) response, for 30 min daily for five successive days while control mothers were control handled. The novelty and control treatments were given to the pregnant mothers either during terms 1, 2 or 3 of pregnancy. After parturition, all offspring were fostered to neutral foster mothers. Testing for the neophobic taste response was carried out after the offspring were 90 days old. It was found that prenatally stressed animals responded with increased neophobia to a novel saccharin solution. Female offspring drank significantly more of the test solution than male offspring. The neophobic response appears to be an index of exploration. The neophobic response of prenatally treated rats was found to be in the opposite direction of postnatally treated rats. However, both findings follow similar response patterns of pre- and postnatal stressed rats tested in an open field.     

Short-term satiety signals generated by saccharin and glucose solutions

Four groups of rats were deprived of water for 24 hr and first allowed to drink 6 ml either of water, 0.25% saccharin solution, 3% glucose solution, or a mixture of 0.25% saccharin 3% glucose solution, subsequently they were given a 3% glucose solution for 20 min. The glucose solution was given either immediately or 30 min after the intake of 6 ml of the 4 experimental liquids. With immediate presentation the glucose intake was lowest following ingestion of the saccharin-glucose solution, next lowest, following ingestion of the saccharin solution and third lowest, following the glucose solution. The glucose intake was highest following water ingestion. However, with the 30-min delay period the differences dissipated. Saccharin and glucose solutions appear to generate a short-term satiety effect which inhibits subsequent intake of glucose solution.     

Nicotine-induced taste aversion: characterization and preexposure effects in rats

Rats were trained to drink their 24 hr water intake during a single daily 30 min period. After stabilization, rats were presented with 0.1% (w/v) of sodium saccharin for 30 min. Immediately after removal of the saccharin solution, the animals were injected with saline, mecamylamine hydrochloride or hexamethonium hydrobromide; thirty minutes later, saline or nicotine, 0.05, 0.16, or 0.50 mg/kg were administered. Twenty-four hr later, rats were allowed access to both water and saccharin. Nicotine caused a dose-related decrease in the proportion of fluid consumed as saccharin solution during the 30 min testing situation. Neither mecamylamine nor hexamethonium alone decreased saccharin preference; however, 3 mg/kg of mecamylamine blocked the decrease of saccharin preference induced by nicotine. Preexposure of drug-naive rats to 0.5 mg/kg of nicotine for 2 or 4 days abolished the nicotine-induced taste aversions to saccharin when tested one day, or one week, after conditioning.     

Schedule-induced ethanol polydipsia: enhancement by saccharin

The effect of adding sodium saccharin to a 5% ethanol solution on intake was examined. One set of animals were maintained at 80% of their free-feeding weight, in their home-cages with either 5% ethanol, or 5% ethanol-0.25% sodium saccharin as the only fluid available for three months (home-cage condition). A second set of animals were maintained in cages with automatic food dispensers that provided a 24 hr feeding regimen known to produce ethanol overdrinking (schedule-induced condition). These animals had 5% ethanol as their only available fluid for one month, followed by the 5% ethanol-0.25% sodium saccharin mixture for two months. No significant differences in ethanol intake were found between the 2 home-cage conditions (5% ethanol = 11.6 g ethanol/kg/day; 5% ethanol in 0.25% sodium saccharin = 11.7 g ethanol/kg/day. However, the addition of saccharin in the schedule-induced condition produced a marked increase in ethanol intake (5% ethanol = 13.1 g ethanol/kg/day; 5% ethanol in 0.25% sodium saccharin = 15.1 g ethanol/kg/day). The home-cage animals showed no sign of an abstinence syndrome upon substitution of water for ethanol. In the schedule-induced group, severe tonic-clonic seizures occured as a result of ethanol withdrawal.