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Biomedical subjects

C R Schuster

Publications and source records attributed to C R Schuster.

At least 55 records · Page 3Linked to original sources
PubMed1988

Discriminative stimulus and subjective effects of smoked marijuana in humans.

The discriminative stimulus (DS) effects of smoked marijuana were studied by training marijuana smokers to discriminate between the effects of marijuana containing 2.7% delta 9-THC (M) and marijuana containing 0.0% delta 9-THC (P). In addition to measures of discrimination responding, subjective effects were assessed with standardized mood questionnaires. The post-smoking increase in expired air carbon monoxide (CO) level was used as an index of smoke inhalation. Relative to P cigarettes, M cigarettes increased heart rate and produced changes on eight mood scales. M cigarettes were rated as harsher and more potent than P cigarettes, and produced lower levels of CO than P cigarettes. The P--M discrimination was readily acquired by most subjects. The DS effects of marijuana showed a rapid onset, appearing within 90 s from the beginning of smoking. The DS effects were dose dependent, with 0.9% delta 9-THC marijuana producing primarily placebo-appropriate discrimination responding, and 1.4% delta 9-THC marijuana producing 100% drug-appropriate responding. This experimental paradigm could be used to determine whether the DS effects of smoked marijuana would generalize to those of other psychoactive drugs.

Adolescent↗
PubMed1988

Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine.

Fenfluramine is an anorectic agent in clinical use that is believed to act by enhancing 5-hydroxytryptamine (5-HT) neurotransmission. Tolerance to the anorectic properties of fenfluramine develops rapidly and long-lasting depletions of brain 5-HT have been reported to occur after repeated administration. It is possible that tolerance to fenfluramine may be related to the 5-HT depletions. Rats (n = 96), previously allowed to drink sweetened condensed milk during daily 15-min sessions, were treated with fenfluramine (6.25 mg/kg/12 hr x 4 days) or saline. Two or 8 weeks later rats were administered fenfluramine acutely (0, 1.25, 6.25 or 12.5 mg/kg; n = 6/group), tested for milk intake and sacrificed 2 hr later. Brains were removed and regions assayed for dopamine, 5-HT and metabolites. Acute administration of fenfluramine produced a dose-dependent decrease in milk intake and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in cortex, hypothalamus and hippocampus. Tolerance to the effects of acute fenfluramine on milk intake was observed in rats at 2 weeks (ED50 = 3.24 vs. 6.37 mg/kg; saline vs. fenfluramine pretreatment, respectively) and, to a lesser extent, at 8 weeks (ED50 = 2.99 vs. 4.04 mg/kg; saline vs. fenfluramine pretreatment) after the 4-day regimen of fenfluramine. Levels of 5-HT and 5-HIAA in somatosensory cortex, hypothalamus, striatum and hippocampus were depleted significantly 2 weeks after the last daily fenfluramine injection. The acute 5-HT depleting effect of fenfluramine was markedly attenuated in these regions 2 weeks after the 4-day regimen of fenfluramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Sensitization to kappa opioid mechanisms associated with tolerance to the anorectic effects of cathinone.

To evaluate the possibility that tolerance to the anorectic effects of cathinone (CATH), an amphetamine-like compound, involves the sensitization of endogenous kappa opioid mechanisms, the influence of chronic treatment with CATH on the effects of the selective kappa opioid agonist U50488H (U50) on food and water intake was evaluated in rats. Since kappa agonists specifically increase urine output, the interaction between CATH and U50 on this physiological function was also evaluated. Acutely, CATH produced anorexia and diuresis, whereas water intake was not affected. U50 resulted in an increase in both food and water intake as well as urine output. After 9 days of daily CATH, tolerance to its anorectic effects had developed. In addition, water intake, which was not affected acutely by CATH, was significantly enhanced with respect to controls treated daily with water. In a group treated chronically with U50, its diuretic effect was unchanged, but water intake was no longer increased after 9 days of treatment. Food intake in this group remained higher than control intake for at least 19 days, but this hyperphagic effect was not detectable on day 34. On days 10 and 20 of the chronic regimen, the administration of U50 to the chronic CATH group resulted in a doubling of the hyperphagic response to U50, and this effect was naloxone-reversible. Water intake was also increased but to a lesser extent. The diuretic effect of U50 did not appear to be influenced by chronic CATH administration.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

The effects of ethanol on eye tracking in rhesus monkeys and humans.

The effects of ethanol on eye tracking function were compared in rhesus monkeys and humans using a similar experimental procedure. In Experiment 1, 3 rhesus monkeys were trained to visually track a projected image of a disk that oscillated sinusoidally along a horizontal plane on a screen. This training was accomplished using a procedure in which responses on a lever resulted in the delivery of water when the central area of the projected disk image was dimmed for a brief period. Intragastric administrations of ethanol at doses of 0.25 to 2 g/kg were tested during one-day test sessions using a cumulative dose procedure. Pursuit eye movements were disrupted at doses of 0.5 g/kg while lever pressing behavior was not disrupted until a dose of 2 g/kg was reached. In Experiment 2, pursuit eye movements of 6 humans were not disrupted when ethanol was given orally at cumulative doses of 0.25 to 1 g/kg, while microswitch pressing behavior was disrupted in some of the subjects at a dose of 0.5 g/kg. Blood ethanol levels increased in a dose-dependent manner in both species with higher levels in humans than in monkeys. The dose dependent effects observed in both species and qualitative similarities in some of the effects such as saccadic pursuit eye movements suggest that the eye tracking method employing monkeys is useful for predicting drug effects on sensory motor function in humans.

Adult↗
PubMed1987

Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.

(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions examined. The highest dose also reduced norepinephrine and/or dopamine in some regions. The 20-mg/kg dose of MDMA depleted 5-HT in all regions of the guinea pig brain assayed. In both species, repeated administration of 20 mg/kg of MDMA reduced the Vmax but not the Km of 5-HT uptake 2 weeks after administration. A single 40-mg/kg injection of MDMA depleted 5-HT 2 and 8 weeks after administration to rats in all regions of the brain examined except the hypothalamus. Administration of 80 mg/kg of MDMA twice a day for 2 days to rats depleted striatal 5-HT and dopamine. Brain sections from rats injected with MDMA according to this dosage regimen were stained by the Fink-Heimer method. Degenerating axon terminals and cell bodies were observed in the striatum and somatosensory cortex, respectively. These findings suggest that MDMA is toxic to serotonergic and, to a lesser extent, catecholaminergic neurons. Some neurons that do not contain these transmitters (neocortical neurons) are also affected.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Anorectics: effects on food intake and self-administration in rhesus monkeys.

The effects of the anorectics benzphetamine, chlorphentermine, clortermine, mazindol, phendimetrazine, and phenmetrazine on food intake were compared to the effects of d-amphetamine in rhesus monkeys given daily access to food pellets. The ability of these compounds to maintain intravenous self-administration under a fixed-ratio 10 schedule was also determined in rhesus monkeys. All drugs reduced food intake in a dose-related manner. d-Amphetamine was the most potent. Mazindol, chlorphentermine, phenmetrazine, and phendimetrazine were approximately 1/5 to 1/9 as potent as d-amphetamine while benzphetamine and clortermine were 1/14 and 1/20 as potent, respectively. Benzphetamine, mazindol, and phenmetrazine were self-administered above saline levels and were approximately equipotent. Chlorphentermine and clortermine were not self-administered and phendimetrazine was self-administered by only one of four monkeys at one dose. Thus, although all of the compounds were effective anorectics, chlorphentermine, clortermine, and phendimetrazine did not function as positive reinforcers. Since the ability of a drug to function as a positive reinforcer is related to its dependence potential, these three compounds might be less subject to abuse when used therapeutically. Within the group of 3 compounds that was self-administered, benzphetamine was relatively more potent as a positive reinforcer than as an anorectic. Therefore, this drug might be a less desirable compound for therapeutic use.

Animals↗
PubMed1986

The effects of Ro 15-1788 on anxiolytic self-administration in the rhesus monkey.

The ability of a benzodiazepine antagonist, Ro 15-1788, to modify the self-administration of anxiolytics was determined in rhesus monkeys. Lever-press responding was maintained in four monkeys under a fixed-ratio 10 schedule of drug delivery in daily sessions of 2 hr duration. Responding was maintained either by flurazepam, lorazepam or pentobarbital. When responding was stable for each of these drugs, a range of doses of a benzodiazepine antagonist, Ro 15-1788 (0.0001-10 mg/kg, IM), was given 5 min prior to a session. At some doses the antagonist increased responding for lorazepam and flurazepam whereas pentobarbital self-administration was largely unaffected or reduced. These results suggest that Ro 15-1788 was able to specifically modify the effects of benzodiazepines responsible for drug-maintained performance.

Animals↗
PubMed1986

Effects of dopaminergic agents on eye tracking before and after repeated methamphetamine.

The effects of methamphetamine (MA), apomorphine (AP) and haloperidol (HAL) on eye tracking function were tested in rhesus monkeys. Three rhesus monkeys were trained to track with their eyes a disk-shaped projected image that oscillated along a horizontal plane on a screen, using a training procedure in which responses on a lever were reinforced with water only when the center of the disk dimmed for a brief period. Eye movements were recorded by electrooculography (EOG). The effects of intramusuclar administration of MA, APO and HAL on responding were compared before and after a 8-14 day period of repeated MA administration. During this regimen, MA was given in 4 divided doses starting at a total daily dose of 4 mg/kg/day and increasing to 16-40 mg/kg/day. All three drugs disrupted performance during both the initial dose-response determination as well as during the redetermination following the regimen. However, tolerance to MA in 3 monkeys and to APO in 2 monkeys was observed after the regimen, while no marked sensitivity change was observed to haloperidol. Since other data reported elsewhere have shown that dopamine is depleted in the caudate after similar repeated administration regimens, long lasting brain dopaminergic changes are likely present in these monkeys. Therefore, these results suggest that the changes in sensitivity to the drugs that were observed in terms of eye tracking function are related to dopamine depletion in the brain.

Animals↗
PubMed1986

The effects of (+/-)-methylenedioxymethamphetamine and (+/-)-methylenedioxyamphetamine in monkeys trained to discriminate (+)-amphetamine from saline.

Recently, attention has been focused on (+/-)-methylenedioxymethamphetamine (MDMA), a psychotomimetic agent chemically closely related to the psychomotor stimulant methamphetamine, and also to the hallucinogen mescaline. In the present experiment, the effects of MDMA and (+/-)-3,4-methylenedioxyamphetamine (MDA) were determined in rhesus monkeys that were trained to discriminate intravenously administered (+)-amphetamine (AMPH) from saline in a two-lever, food-maintained paradigm or to discriminate intragastrically administered AMPH from saline in a signalled electric shock avoidance paradigm. MDMA produced 100% drug-appropriate responding in all six monkeys, regardless of the procedure and route of administration while MDA substituted completely for AMPH in only two of three monkeys in each paradigm. The results suggest that MDMA has subjective effects that are similar to those of AMPH while MDA is somewhat less like AMPH.

3,4-Methylenedioxyamphetamine↗
PubMed1986

Behavioral and neurochemical evaluation of phenylpropanolamine.

(+/-)-Phenylpropanolamine (PPA), a widely available anorectic and decongestant, was evaluated in several behavioral paradigms in rhesus monkeys and for central nervous system neurotoxicity in rats. PPA (1-30 mg/kg intragastric) reduced food intake in rhesus monkeys but was not self-administered i.v. (0.3-10 mg/kg/injection) by monkeys experienced in drug self-administration. PPA (30-100 mg/kg intragastric) resulted in amphetamine-like responding in two of four monkeys trained in a drug discrimination paradigm to discriminate d-amphetamine from saline. In rats, a 4-day injection regimen of high doses of PPA (200 and 400 mg/kg/day) resulted in approximately a 20% depletion of dopamine in the frontal cortex but failed to deplete dopamine, norepinephrine or serotonin in any other brain region studied. Thus, PPA is an effective anorectic in rhesus monkeys that, based upon drug discrimination results, would be expected to have limited amphetamine-like subjective effects and only at doses well in excess of effective anorectic doses. However, based upon self-administration results, PPA would not be predicted to have amphetamine-like dependence potential. Moreover, repeated administration of PPA did not produce the severe central nervous system neurotoxicity associated with many other amphetamine congeners.

Animals↗
PubMed1985

Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain.

Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.

Animals↗
PubMed1985

Behavioral effects of naloxone and nalorphine preceding and following morphine maintenance in the rhesus monkey.

The effects of morphine, naloxone, and nalorphine on responding maintained under a variable-interval schedule of food presentation were assessed in rhesus monkeys before and after successive periods of daily morphine maintenance (15.0 mg/kg/day SC). Withdrawal from morphine dependence was accomplished gradually following the first two maintenance periods and abruptly following the third period. Schedule-controlled responding was disrupted when morphine maintenance was abruptly discontinued but not when the maintenance dosage was gradually reduced to zero. Tolerance to the acute effects of IV morphine on responding developed during morphine maintenance and dissipated after daily injections were discontinued. The effects of IV naloxone and IV nalorphine following each period of morphine maintenance were generally similar to their effects in initial determinations. These data indicate that tolerance-producing regimens of repeated daily injections with morphine do not necessarily produce enduring changes in the effects of opiate antagonists on schedule-controlled behavior. Additionally, gradual withdrawal from morphine maintenance can minimize the behavioral disruptions that attend abrupt abstinence.

Animals↗
PubMed1985

Methamphetamine, physostigmine, atropine and mecamylamine: effects on force lever performance.

Dose response functions for d-methamphetamine (MA), physostigmine, atropine, and mecamylamine on force lever performance (a measure of motor control) were determined in three rhesus monkeys. The rhesus monkeys were then treated with a repeated high dose regimen of MA, and the effects of the four drugs were redetermined. Following the completion of the behavioral studies, the monkeys were killed and brain monoamine concentrations were measured. It was found that each of the four drugs produced differential effects on force lever performance indices. Following the MA regimen, the MA-treated monkeys were less sensitive to the effects of MA on force lever performance but showed no change in sensitivity to any of the cholinergic agents. The monkeys were subsequently shown to have decreased brain dopamine and serotonin levels.

Animals↗
PubMed1985

Sensitivity changes to dopaminergic agents in fine motor control of rhesus monkeys after repeated methamphetamine administration.

Long-term behavioral and neurochemical effects of repeated methamphetamine (MA) administration were investigated in rhesus monkeys trained to perform a fine motor task requiring control of exerted force for a specified time. Rhesus monkeys were trained to extend their arms into a tube to press a lever with a force between 25 and 40 g for 5 sec in order to receive 1.5 ml of water. The effects of intramuscular administration of MA, apomorphine (APO) and haloperidol (HAL) on responding were compared before and after a 2-week period of repeated MA administration. During this period, MA was given in 4 divided doses starting at a total daily dose of 4 mg/kg/day and increasing to 40 mg/kg/day. Tolerance to MA, increased sensitivity to HAL and no consistent sensitivity change to APO were observed when dose-response functions were redetermined starting 1 month after the repeated MA administration. One month after these determinations were completed, the brains of the monkeys were analyzed for changes in monoamines. Significant depletions of dopamine in the caudate nucleus and serotonin in the frontal cortex were seen. It is hypothesized that the sensitivity changes to the drugs on performance were related to the dopamine depletion.

Animals↗