Biomedical subjects

S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 109 records · Page 6Linked to original sources

PubMed1988

Caffeine elevates reinforcement threshold for electrical brain stimulation: tolerance and withdrawal changes.

Caffeine dose-dependently increased the reinforcement threshold for electrical self-stimulation of the brain in rats, which is opposite to the effect of other behavioral stimulants. Tolerance to this effect of caffeine developed rapidly with daily drug administration. Abrupt cessation of daily drug treatment was followed by decreases in reinforcement threshold and response rate lasting 24-48 h, changes consistent with a drug withdrawal phenomenon. Because caffeine has the characteristics of a drug of abuse, these results question the generality of hypotheses relating the abuse potential of a drug to its ability to sensitize brain reward systems.

Animals↗

PubMed1988

Effects of beta-funaltrexamine on ingestive behaviors in the rat.

The effects of beta-funaltrexamine (beta-FNA), an irreversible mu-opioid receptor antagonist, were determined on water and food intake of non-deprived rats. Intracerebroventricular administration of 1.25 or 2.5 micrograms of beta-FNA did not affect drinking or eating. However, 5.0 micrograms first transiently increased food intake and then reduced both water and food intake for at least 72 h. Locomotor activity was unaffected by 5.0 micrograms of beta-FNA; thus, changes in ingestive behavior were not a secondary consequence of drug-induced behavioral stimulation or depression. The early increase in food intake may be due to the short lived and reversible kappa-agonist activity of beta-FNA. On the other hand, selective blockade of mu-opioid receptors appears sufficient to reduce the intake of water and food.

Animals↗

PubMed1988

Effects of d-amphetamine, morphine, naloxone, and drug combinations on visual discrimination in rats.

The effects of d-amphetamine, morphine, and naloxone on visual discrimination were investigated using a two-choice discrete-trial procedure in which rats were trained to discriminate the position of a lightflash. Morphine (0.3-5.6 mg/kg) but not amphetamine (0.1-1.0 mg/kg) caused a significant dose-dependent disruption in discriminative performance. Both amphetamine and morphine increased response latencies. Naloxone (1.0 mg/kg) prevented the disruption of any aspect of performance by up to 100 mg/kg morphine. Performance after naloxone/amphetamine co-administration was not significantly different from that observed after amphetamine alone. Naloxone alone (0.3-10 mg/kg) had no effect on discrimination, spatial bias or response latencies. These results suggest that morphine and amphetamine affect different components of discrimination performance.

Animals↗

PubMed1988

Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory role of D-Ala2-D-Leu5-enkephalin (DADL) and dynorphin A (1-13).

The role of the different opioid receptors was studied in rats trained to discriminate SC injections of 3.0 mg/kg morphine from saline by tests for generalization to graded doses of morphine and receptor-selective peptides administered into the lateral cerebral ventricle. Dose-dependent morphine-like stimulus effects were produced over a wide range of doses (0.001-30 micrograms), depending upon ligand and animal, by morphine, by the mu-selective peptides DAGO[D-Ala2-NMePhe4-Gly(ol)-enkephalin] and FK33824[D-Ala2,NMePhe4-Met(O)5-(ol)-enkephalin], and by the delta-selective peptide, DADL[D-Ala2,D-Leu5)enkephalin]. The order of relative potency of these substances was: FK33824 greater than DAGO greater than morphine greater than DADL. In contrast, DPLPE[D-Pen2,L-Pen5)enkephalin], which has much greater delta receptor selectivity than does DADL, and dynorphin A(1-13) (0.1-10 micrograms), a kappa-receptor agonist, engendered choice responding appropriate for saline. When 1.0 micrograms DADL, a dose lacking morphine-like discriminative effects, was administered concurrently with SC morphine, the stimulus effects of morphine were potentiated. Concurrent administration of 10 micrograms dynorphin A(1-13) and morphine attenuated the stimulus effects of morphine inconsistently. These results support previous findings that mu-opioid receptors are of primary importance in mediating the morphine-like discriminative effects of opioid peptides. They also suggest that morphine-like discriminative effects can be modulated by other types of opioid receptors.

Animals↗

PubMed1988

Tolerance and cross-tolerance to theophylline-induced stimulation of locomotor activity in rats.

Rats treated chronically with caffeine become tolerant to caffeine-induced stimulation of locomotor activity and cross-tolerant to theophylline. This study was performed to determine if the cross-tolerance between these two methylxanthine drugs is symmetrical. Symmetrical cross-tolerance produced by two different drugs implies a common underlying mechanism of action. Separate groups of rats were given scheduled access to drinking bottles containing either drug-free tap water or 1.0 mg/ml theophylline solution. Daily theophylline intake averaged 59 mg/kg. Dose-effect curves were determined in both control and theophylline-treated groups for 5 drugs: the methylxanthines theophylline and caffeine, a nonxanthine psychomotor stimulant, d-amphetamine, and the adenosine analogs R(-)-N6-2-(phenylisopropyl)adenosine and 5'-(N-ethyl)carboxamidoadenosine. All drugs were injected i.p. and locomotor activity was measured for 30 min beginning 35 min later. Rats that were maintained chronically on theophylline were completely tolerant to the locomotor activity stimulant effects of acutely administered theophylline and cross-tolerant to caffeine-induced stimulation of locomotor activity. In contrast, both control and treated groups were fully responsive to the stimulant effects of d-amphetamine. Low doses of the adenosine analogs produced stimulation of locomotor activity in both groups of rats. Higher doses produced a dose-dependent depression of locomotor activity in control rats; curves for the theophylline-treated rats were shifted to the right of the control curves. Thus, adenosine antagonist activity of theophylline remained evident at a time of complete tolerance to the stimulant effect of the drug on locomotor activity.

Adenosine↗

PubMed1988

Tolerance to behavioral effects of caffeine in rats.

Tolerance develops to three behavioral effects of caffeine in rats treated daily with the drug: stimulation of locomotor activity, rate-decreasing effect on food-reinforced operant responding, and discriminative stimulus effects. Tolerance induced by caffeine to stimulation of locomotor activity: (1) develops rapidly, being nearly maximal 24 hr after the start of daily treatment with 35-40 mg/kg in four divided oral doses; (2) is insurmountable (i.e., complete) so that rats are unresponsive, even to high doses of caffeine, and dose-response curves are displaced downward and flattened; (3) is pharmacologically specific, extending to other methylxanthines but not to nonxanthine psychomotor stimulants. Tolerance to the other two behavioral effects of caffeine: (1) appears to develop gradually; (2) is surmountable so that dose-response curves are displaced to the right; (3) extends to nonxanthine psychomotor stimulants, methylphenidate, in the case of discriminative effects. Thus, at least two distinct types of tolerance to behavioral effects of caffeine in the rat can be identified. The potency of an adenosine analog, R(-)-PIA, in depressing locomotor activity does not increase during or 24 hr after termination of chronic daily treatment with caffeine when rats are completely tolerant to caffeine-induced stimulation of locomotor activity. These results do not support the view that enhanced functional sensitivity of central adenosine systems (e.g., up-regulation of receptors) is the mechanism of tolerance to the stimulant effect of caffeine on locomotor activity.

Animals↗

PubMed1988

Restricted feeding does not modify discriminative stimulus effects of morphine in the rat.

An experiment was performed to determine if the discriminative stimulus effects of morphine are modified by mild food deprivation, a condition that increases drug-reinforced behavior. Rats were trained to discriminate between SC injections of saline and morphine (3.0 mg/kg) in a discrete-trial shock-avoidance procedure. Stimulus generalization curves for morphine were then determined on three occasions by a cumulative-dosing procedure: before, during and after the body weight of the rats had been reduced to 86-87% of normal by restricted feeding. Food deprivation had little or no effect on the morphine generalization curve. Despite a close relationship between the reinforcing and discriminative stimulus properties of opioid drugs, stimulus control of behavior by morphine was not modified by a condition that enhances opioid-reinforced behavior.

Animals↗

PubMed1988

Neural mechanisms of drug stimuli: experimental approaches.

Drug discrimination methodology affords a behavioral end point that reflects actions of a drug at the cellular level. The stimulus control of behavior by drugs of many pharmacological classes satisfies criteria for a receptor-mediated phenomenon. Within many classes of drugs, order of relative of potency for discriminative effects correlates highly with the order of potency of the drugs in other procedures that involve interactions with a defined population of receptors. Examples include the morphine-like opioids and the benzodiazepines. Specific competitive antagonists are of paramount importance for defining neuronal substrates that subserve the discriminative effects of a drug. Quantitative pharmacological approaches can be used not only to define the receptor mediating the discriminative effects of a drug but also to assess the intrinsic activity of the drug at the receptor. The primary site of stimulus control of behavior by most drugs can be shown by indirect and direct means to be of central rather than peripheral origin; however, neuronanatomical localization of specific sites of drug action remains elusive. Attention is starting to be focused on endogenous neuropeptides, their discriminative stimulus properties and potential role in modulating discriminative effects of drugs. Some of the most important contributions of drug discrimination methodology may arise in the rapidly emerging area of peptide neuropharmacology.

Animals↗

PubMed1987

Effects of stress and beta-funal trexamine pretreatment on morphine analgesia and opioid binding in rats.

This study was essentially an in vivo protection experiment designed to test further the hypothesis that stress induces release of endogenous opioids which then act at opioid receptors. Rats that were either subjected to restraint stress for 1 hr or unstressed were injected ICV with either saline or 2.5 micrograms of beta-funaltrexamine (beta-FNA), an irreversible opioid antagonist that alkylates the mu-opioid receptor. Twenty-four hours later, subjects were tested unstressed for morphine analgesia (tail-flick assay) or were sacrificed and opioid binding in brain was determined. [3H]D-Ala2NMePhe4-Gly5(ol)enkephalin (DAGO) served as a specific ligand for mu- opioid receptors, and [3H]-bremazocine as a general ligand for all opioid receptors. Rats injected with saline while stressed were significantly less sensitive to the analgesic action of morphine 24 hr later than were their unstressed counterparts. Beta-FNA pretreatment attenuated morphine analgesia in an insurmountable manner. Animals pretreated with beta-FNA while stressed were significantly more sensitive to the analgesic effect of morphine than were animals that received beta-FNA while unstressed, consistent with the hypothesis that stress induces release of endogenous opioids that would protect opioid receptors from alkylation by beta-FNA. beta-FNA caused small and similar decreases in [3H]-DAGO binding in brain of both stressed and unstressed animals. Stressed rats injected with saline tended to have increased levels of [3H]DAGO and [3H]-bremazocine binding compared to the other groups. This outcome may be relevant to the tolerance to morphine analgesia caused by stress.

Analgesia↗

PubMed1987

Discriminative stimulus effects of caffeine: tolerance and cross-tolerance with methylphenidate.

Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days shifted the caffeine stimulus generalization curve to the right by 3-fold in rats trained to discriminate saline from 30 mg/kg of caffeine, and by 4-fold in rats trained to discriminate saline from 10 mg/kg of caffeine. The latter group was also tested for cross-tolerance with methylphenidate, a drug that generalizes completely with caffeine. Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days increased the ED50 of methylphenidate for caffeine-appropriate responding from 1.5 to 5.5 mg/kg. Conversely, injections of methylphenidate (3.0 mg/kg) increased the ED50 of caffeine from 5.2 to 15 mg/kg. The development of symmetrical cross-tolerance to the discriminative effects of caffeine and to the caffeine-like discriminative effects of methylphenidate supports previous observations suggesting commonalities in the cellular bases of the stimulus properties of these drugs.

Animals↗

PubMed1987

Pharmacologic specificity of tolerance to caffeine-induced stimulation of locomotor activity.

The pharmacologic specificity of tolerance to caffeine-induced stimulation of locomotor activity was studied in adult male rats that were given access to either caffeine solution (0.5 or 1.0 mg/ml) or plain water for 10 min every 6 h on a chronic daily basis; daily caffeine intake averaged 41 and 62 mg/kg, respectively. Dose-effect curves were determined for behavioral stimulant and depressant drugs in control and caffeine-treated groups. Drugs were injected IP and locomotor activity was measured for 30 min beginning 35 min later. Rats tolerant to stimulation of locomotor activity by caffeine were also tolerant to theophylline and 7-(2-chloroethyl)theophylline, but not to any of six nonxanthine stimulants, including cocaine, methylphenidate, and d-amphetamine. The adenosine analogs, R(-)-N6-2-(phenylisopropyl)adenosine(R(-)-PIA) and 5'-(N-ethyl)carboxamidoadenosine (NECA), decreased locomotor activity of control and caffeine-treated (0.5 mg/ml) rats; dose-effect curves in rats consuming caffeine chronically were displaced to the right of the control curves by 10-fold for R(-)-PIA and 100-fold for NECA. Dose-effect curves for the nonadenosine behavioral depressants chlorpromazine and diazepam were unchanged by chronic treatment with caffeine, but the curve for pentobarbital, which is thought to inhibit adenosine receptor binding, was shifted to the right by a factor of 3. Rats withdrawn from chronic caffeine for 24 h were still completely tolerant to caffeine-induced stimulation of locomotor activity. Dose-effect curves for R(-)-PIA and d-amphetamine in rats withdrawn from chronic caffeine for 24 h were not different from curves in control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Suppression of deprivation-induced water intake in the rat by opioid antagonists: central sites of action.

The effects of naltrexone methobromide, a quaternary derivative of the opioid antagonist naltrexone, were investigated on deprivation (24 h)-induced water intake in the unilaterally cannulated rats. Naltrexone methobromide reduced post-deprivational water intake with an ED50 of 7.3 micrograms when tested at 30 min (peak effect) after intracerebroventricular administration. It also dose-dependently (0.3-10 micrograms) depressed water intake, with peak effects at 15 min, after microinjection into the paraventricular hypothalamic nucleus and into the supraoptic hypothalamic nucleus. The drug did not produce any other effects on behaviors. The ED50S were 1.4 micrograms when given into the paraventricular nucleus, and 3.3 micrograms when given into the supraoptic nucleus, respectively. Although injections of higher doses (1.0, 3.0 and/or 10 micrograms) of the drug into the preoptic area, zona incerta, and corpus callosum significantly suppressed water intake, other behavioral manifestations, such as rotational behaviors, convulsions, body shakes, head swaying, and/or backward locomotion were manifested simultaneously with the reduction in drinking. When injected into the lateral hypothalamic area, water intake was not significantly affected by the drug. These findings suggest that the paraventricular and supraoptic hypothalamic nuclei are important sites of action in the naltrexone-induced suppression of water intake.

Animals↗

PubMed1987

Effects of naloxone and diprenorphine on amphetamine-stimulated behavior in guinea pigs and rats.

Amphetamine (0.1-10 mg/kg), naloxone (0.1-10 mg/kg) and diprenorphine (0.03-10 mg/kg) were studied for their ability to modulate locomotor behavior in the guinea pig. Naloxone, administered alone, caused a non-significant decrease in locomotor activity and had a similar non-significant effect on amphetamine-stimulated activity. Diprenorphine induced a significant suppression of locomotor activity, the magnitude of which was inversely related to dose: smaller doses of diprenorphine caused a greater suppression of locomotor activity than larger doses. Two doses of diprenorphine (0.1 and 1.0 mg/kg) were tested in combination with amphetamine in the guinea pig. They significantly reduced amphetamine-stimulated behavior and were equipotent in this regard. In contrast, diprenorphine had no effect on amphetamine-stimulated activity in rats. However, in keeping with other reports, naloxone (10 mg/kg) significantly reduced amphetamine-stimulated behavior. The differences in the actions of diprenorphine and naloxone on the behavior of guinea pigs and rats may reflect a different underlying distribution of subtypes of opioid receptor in the two species.

Amphetamine↗

PubMed1987

The interaction of d-amphetamine and naloxone differs for rats trained on separate fixed-interval or fixed-ratio schedules of reinforcement.

The effects of d-amphetamine and naloxone were investigated using two groups of rats trained on either an FR30 or F12 schedule of reinforcement. Amphetamine (0.1-1.0 mg/kg), and naloxone (1.0 and 10 mg/kg) administered separately reduced responding on the FR procedure in a dose-dependent manner. The combined administration of naloxone with amphetamine had an additive suppressive effect on responding. The same doses of amphetamine and naloxone, when given separately, did not significantly depress responding in the FI procedures. However, naloxone/amphetamine combinations produced a marked inhibition of lever-pressing. Naloxone did not alter the characteristic pattern of responding engendered by amphetamine in this schedule, as measured by the quarter-life and Index of Curvature. It appears that the type of procedure used is a critical factor in demonstrating the effects of naloxone on behavior, and the nature of naloxone/amphetamine interactions.

Animals↗

PubMed1986

Stress-induced changes in the analgesic and thermic effects of opioid peptides in the rat.

Stress (e.g. restraint) potentiates analgesia and alters changes in body temperature induced by morphine administered either systemically or intracerebroventricularly (i.c.v.) in rats. In order to extend the generality of this phenomenon to opioid peptides, we determined whether the analgesic and thermic effects of i.c.v. D-Ala2-D-Leu5-enkephalin (DADLE) or D-Ala2-N-MePhe4-Gly5(ol)-enkephalin (DAGO), agonists selective for delta- and mu-opioid receptors, respectively, were affected by restraint stress. Analgesia was measured in the tail-flick test and core body temperature by rectal probe. The unstressed rats exhibited a dose-dependent increase in tail-flick latencies after administration of either DAGO or DADLE. Restrained rats treated with DAGO or DADLE had a greater analgesic response to each dose of peptide than did unstressed rats; both the magnitude and duration of the drug effect were increased. The unstressed group of rats responded to all doses of DAGO and DADLE with an increase of core temperature. In contrast, restrained rats showed a decrease of core temperature following injection with either DAGO or DADLE. Thus, restraint stress can significantly modify the effects of DAGO and DADLE on analgesia and body temperature in a manner that is qualitatively and quantitatively similar to that observed previously for morphine administered by the i.c.v. route.

Animals↗

PubMed1986

Discriminative stimulus properties of caffeine in the rat: noradrenergic mediation.

The stimulus properties of caffeine were studied in separate groups of rats trained to discriminate between i.p. injections of saline and either 10 or 30 mg/kg of caffeine in a discrete-trial avoidance paradigm. Stimulus control of behavior (i.e., reliable completion of at least 18 of 20 trials on the appropriate choice lever after injection of saline or caffeine) was established in an average of 50 to 52 sessions. Novel drugs were tested over a range of doses for generalization to one (10 mg/kg) or both doses of caffeine. The methylxanthine derivatives, theophylline, theobromine, 1,7-dimethylxanthine, 3-isobutyl-l-methylxanthine, 8-phenyltheophylline and 8-chlorotheophylline, were generalized to caffeine partially or not at all. Of the nonxanthine drugs, apomorphine, clonidine and picrotoxin occasioned responding only on the saline-appropriate choice lever, d-amphetamine and ephedrine generalized partially, and cocaine and methylphenidate generalized with caffeine completely, as did 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine an alpha-1 adrenergic receptor agonist. The discriminative effects of 10 mg/kg of caffeine were blocked dose-dependently and completely by alpha adrenergic receptor blocking drugs (phentolamine, prazosin and yohimbine) and were blocked partially by propranolol and by drugs having behavioral depressant properties (diazepam, pentobarbital and the adenosine analogs, R-(-)-N6-(2-phenylisopropyl)adenosine, cyclohexyladenosine, 2-chloroadenosine). The blockade by phentolamine could be surmounted by increasing the dose of caffeine, the partial blockade by diazepam and 2-chloroadenosine could not. Alpha adrenergic receptor blocking drugs also antagonized the caffeine-like discriminative effects of methylphenidate and 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine. The discriminative stimulus effects of caffeine in the rat appear to be mediated in part by alpha adrenergic mechanisms.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Discriminative stimulus effects of the opioid antagonist diprenorphine in the squirrel monkey.

Squirrel monkeys were trained in a discrete-trial avoidance paradigm to discriminate i.m. injections of the opioid antagonist diprenorphine (0.1 mg/kg) from vehicle. When the monkeys could complete reliably at least 22 trials of a 25-trial session on the choice level appropriate for the substance injected before the session (i.e., diprenorphine or vehicle), tests of stimulus generalization to novel drug conditions were conducted. Mu receptor agonists (morphine, etorphine and buprenorphine) and kappa receptor agonists (ethylketocyclazocine, nalorphine and I-N-allylnormetazocine) produced dose-dependent diprenorphine-like discriminative effects. The dextrorotatory isomer of N-allynormetazocine was almost two-orders of magnitude less potent than the levorotatory isomer in this respect and phenycyclidine generalized to diprenorphine only partially, suggesting that the phencyclidine/sigma site does not have a prominent role in the discriminative effects of diprenorphine. Other nonopioid drugs (d-amphetamine, mescaline and pentobarbital) also did not produce discriminative effects comparable to those of the training drug. The pure opioid antagonists, naloxone, naltrexone, and WIN 44,441-3 [(2-alpha-6 alpha, 11S)-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trim eth yl-2, 6-metheno-3-benzazocin-11-yl)-3-pentanone] occasioned responding primarily on the lever appropriate for vehicle. Naloxone (1.0 mg/kg) blocked surmountably the diprenorphine-like discriminative effects of the mu and kappa agonists, displacing generalization curves to the the right by 10- to 100-fold; however, naloxone failed to shift the curve for diprenorphine itself. Thus, in the squirrel monkey diprenorphine has discriminative stimulus effects in common with mu- and kappa-opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Behavioral effects of opioid peptides selective for mu or delta receptors. I. Morphine-like discriminative stimulus effects.

The morphine-like discriminative stimulus effects of opioid peptides with selectivity for the mu- or delta-opioid receptors were examined in rats trained to discriminate 3.0 mg/kg of morphine (s.c.) from saline in a two-choice discrete-trial avoidance paradigm. The mu-selective peptides D-Ala2-NMePhe4-Gly5(ol)enkephalin, FK 33,824 and morphiceptin, the delta-selective peptides D-Ala2-D-Leu5enkephalin and metkephamid and beta-endorphin (mu- and delta-selective) produced morphine-like stimulus effects after administration into the lateral ventricle. Generalization with the morphine cue was dose-dependent and occurred over a wide range of doses (0.01-30 micrograms), depending upon peptide. On a molar basis, the order of relative potency of the peptides as morphine-like discriminative stimuli was: D-Ala2-NMePhe4-Gly5(ol)enkephalin = FK 33,824 greater than beta-endorphin greater than D-Ala2-D-Leu5enkephalin = metkephamid greater than morphiceptin. The discriminative effects of D-Ala2-NMePhe4-Gly5(ol)enkephalin, D-Ala2-D-Leu5enkephalin and beta-endorphin were antagonized by low doses of s.c. naltrexone (0.01-1.0 mg/kg). Furthermore, the stimulus effects of s.c. morphine were antagonized by 24-hr pretreatment of rats with the irreversible mu-antagonist beta-funaltrexamine (5.0 micrograms i.c.v.). Based upon the order of relative potency of the peptides and the relative potency for antagonism of their discriminative effects by naltrexone and beta-funaltrexamine, mu-opioid receptors in the brain appear to be an important element in the genesis of morphine-like discriminative effects by opioid peptides.

Animals↗