Inhaled toluene produces pentobarbital-like discriminative stimulus effects in mice

The abuse of volatile solvents may be due to their ability to produce an intoxication similar to that produced by classical central nervous system depressants such as the barbiturates and ethanol. To evaluate this hypothesis, mice were trained to discriminate pentobarbital from saline injections in a two-lever operant task. Stimulus generalization was examined following 20-min inhalation exposures to toluene (300-5400 ppm). In 8 of 10 subjects, pentobarbital-lever responding occurred following toluene exposure indicating an overlap in the discriminative stimulus properties of toluene and pentobarbital.     

Anatomical substrates for the discriminative stimulus effects of methamphetamine in rats

Methamphetamine is a psychostimulant drug acting on central monoaminergic neurons to produce both acute psychomotor stimulation and long-lasting behavioral effects including addiction and psychosis. Drug discrimination procedures have been particularly useful in characterizing subjective effects of addictive drugs. In the present study, to identify potential anatomical substrates for the discriminative stimulus effects of methamphetamine, we investigated the drug discrimination-associated Fos expression in Sprague-Dawley rats trained to discriminate methamphetamine from saline under a two-lever fixed ratio 20 (FR-20) schedule of food reinforcement. The rats that fulfilled the criteria for learning the discrimination were anesthetized and perfused 2 h after the drug discrimination test, and Fos immunoreactivity was examined in 15 brain regions. Fos expression in the brains of rats that discriminate methamphetamine from saline was significantly increased in the nucleus accumbens (NAc) and the ventral tegmental area (VTA), but not in other areas including the cerebral cortex, caudate putamen, substantia nigra, hippocampus, amygdala and habenulla, as compared with the expression in control rats that were maintained under the FR-20 schedule. The present findings suggest a role for the VTA and NAc as possible neuronal substrates in the discriminative stimulus effects of methamphetamine.     

Comparison of the effects of central and peripheral aluminum administration on regional 2-deoxy-D-glucose incorporation in the rat brain

Intracerebroventricular (ICV) Injection of aluminum tartrate (ALT 205.7 mcg) in the rat induces a progressive encephalopathy characterized by neurobehavioral derangements, by the slowing of the background rhythm of the quantitative electroencephalogram and by learning and memory deficits. The condition, lethal within about 35 days, is associated with a reduced ability of cerebral synaptosomes to incorporate radiolabeled 2-Deoxy-D-glucose (2DG) in vitro. The present study surveyed and compared the in vivo regional cerebral glucose uptake (rCGlu) capacity of rats injected with ALT 7 or 14 days previously either by the ICV or intraperitoneal (120 mg/Kg) routes. ICV injection produces transient rCGlu depression in caudate-putamen, geniculate bodies and periaquaeductal gray, resolving by day 14. Thalamic nuclei exhibit depressed rCGlu by the 7th day undergoing further depression by day 14. The rCGlu of occipitoparietal cortices, normal at day 7, was increased by day 14. In contrast, peripheral aluminum administration produced transient rCGlu depression in olfactory bulbs, frontal and occipitoparietal cortices, nucleus accumbens and cerebellum, and transiently increased rCGlu in the geniculate nuclei. These effects, present by day 7, had resolved by day 14 when rCGlu had increased in the previously normal pontine nuclei and decreased in the previously normal hippocampus. Neither treatment changed rCGlu in the septal nuclei, globus pallidus, amygdala, olfactory cortex, substantia nigra, superior or inferior colliculi or the medullary nuclei. The pattern of anomalies in cerebral 2DG incorporation most probably indexes the deranged glucoregulatory and metabolic demands of these brain areas in the aluminum intoxicated state.     

Comparison of the effects of chronic central administration and chronic peripheral administration of islet amyloid polypeptide on food intake and meal pattern in the rat

Islet amyloid polypeptide (IAPP) is postulated to act as a hormonal signal from the pancreas to the brain to inhibit food intake and reduce adipose energy reserves. The present study compared the effects of chronic peripheral and chronic central administration of IAPP on food intake and meal pattern in rats. IAPP was administered subcutaneously (SC) for 7 days at doses of 0, 0.25, 2.5 and 25 pmol kg(-1) min(-1) using an osmotic minipump or administered centrally at doses of 0, 0.025, 0.25 and 2.5 pmol kg(-1) min(-1) using an osmotic minipump connected to an intracerebroventricular (ICV) catheter inserted into the third ventricle. Both SC and ICV infusion decreased total food intake dose-dependently. The minimal effective dose was 2.5 pmol IAPP kg(-1) min(-1) for SC administration and 0.25 pmol kg(-1) min(-1) for ICV infusion. The decrease in food intake produced by infusion of IAPP was mainly due to decreased meal size, although a significant decrease in meal number also occurred at the highest SC and ICV doses. SC administration produced a larger, more persistent decrease in food intake during the light period than in the dark period, while ICV infusion caused a larger, more persistent decrease during the dark period. The 10-fold difference in minimal effective doses indicates that ICV-administered IAPP acted primarily in the brain to inhibit food intake. The difference between the effects of IAPP on meal pattern with the two methods of administration suggests that IAPP does not act on the same target(s) when administered centrally as it does when it is administered peripherally.     

Comparative discriminative stimulus effects of 5-methoxy-N,Ndimethyltryptamine and LSD

Rats were trained to discriminate injections of either 5-OMe DMT (1.5 mg/kg) or LSD (0.096 mg/kg) from saline in a two-lever drug discrimination task. After stable discrimination performances were attained (> 85%) in each group, dose-response generalizations between the two groups of animals were examined. The results revealed that the 5-OMe DMT-stimulus response generalized to LSD and that the LSD-stimulus response generalized to 5-OMe DMT. Furthermore, both the 5-OMe DMT-stimulus and the LSD-stimulus could be significantly attenuated by the serotonin antagonist BC-105. However, the pattern of the doserelated antagonism by BC-105 was different between the drug stimuli. It was concluded that while the discriminative stimulus effects of 5-OMe DMT and LSD may be mediated via a common serotonergic system, the receptor interaction of these agents within that pharmacological system may be somewhat different.     

Differential properties between TRK-820 and U-50,488H on the discriminative stimulus effects in rats

It has been demonstrated that the newly synthesized kappa-opioid receptor agonist TRK-820, which has a unique structure that is different from those of other prototypical kappa-opioid receptor agonists such as U-50,488H, exert some behavioral effects that differ from those induced by U-50,488H. Therefore, the present study was designed to examine the possible difference between the discriminative stimulus effects of TRK-820 and U-50,488H in rats. Substitution tests with several kappa-opioid receptor agonists were initiated in rats trained to discriminate between TRK-820 (40 microg/kg) or U-50,488H (3.0 mg/kg) and saline. In the cross-substitution tests, U-50,488H substituted for the discriminative stimulus effects of TRK-820, whereas TRK-820 did not substitute completely for those of U-50,488H, indicating that the discriminative stimulus effects of TRK-820 and U-50,488H were somewhat different. In the substitution tests, E-2078, but not R-84760, substituted for the discriminative stimulus effects of both TRK-820 and U-50,488H. KT-90, CI-977 and ICI-199441 each substituted for the discriminative stimulus effects of U-50,488H, but not to those of TRK-820. These results imply that these kappa-opioid receptor agonists possess U-50,488H-like discriminative stimulus effects. Furthermore, that U-50,488H and the other kappa-opioid receptor agonists substituted for the discriminative stimulus effects of U-50,488H, produced aversive effects in rats. These findings suggest the possibility that unlike those of TRK-820, the cue of the discriminative stimulus effects of U-50,488H may be, at least in part, associated with its aversive effects.     

Central and peripheral monitoring of the cellular redox state after reduced glutathione administration in the rat

In this study we measured reduced glutathione as DTNB reactive material in different brain areas as well as in liver and kidney of rat, before and after exogenous administration of GSH. Treatment with GSH produced an increase in DTNB positive material as well as a decrease of lipoperoxidation, in central and peripheral organs of rat, suggesting the possibility of an exogenous modulation of redox balance in mammalian cells.     

Role of 5-hydroxytryptamine1B receptors and 5-hydroxytryptamine uptake inhibition in the cocaine-evoked discriminative stimulus effects in rats.

Mesolimbic dopamine pathways play a critical role in the behavioural effects of cocaine in rodents. Nonetheless, research has also demonstrated involvement of 5-hydroxytryptamine (5-HT; serotonin) transmission in these effects. The present study investigated the ability of selective 5-HT1B receptor ligands and a 5-HT reuptake inhibitor to substitute for or to alter (enhance or antagonise) the discriminative stimulus effects of cocaine. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i.p.) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, the selective 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253; 2.5-5 mg/kg, i.p.) and the 5-HT reuptake inhibitor fluoxetine (5-10 mg/kg, i.p.) elicited ca. 40 and 0% drug-lever responding, respectively. In combination experiments, CP 94253 (2.5-5 mg/kg) given with submaximal doses of cocaine (0.3-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve; pretreatment with CP 94253 (5 mg/kg) prior to a dose of cocaine (2.5 mg/kg) which elicited lower than 40% drug-lever responding, caused full substitution. Fluoxetine (5 and 10 mg/kg) given in combination with a submaximal dose of cocaine (2.5 mg/kg) produced a 100% drug-lever responding. Pretreatment with the 5-HT1B receptor antagonists N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,1'-biphenyl-4 carboxamide (GR 127935; 0.5-5 mg/kg, s.c.) and 3-(3-dimethylamino)-propyl)-4-hydroxy-N-[4-(4-pyridinyl)-phenyl]benzamide (GR 55562; 1 mg/kg, s.c.) failed to modulate the dose-effect curve for cocaine (0.6-5 mg/kg). On the other hand, GR 127935 (5 mg/kg) and GR 55562 (1 mg/kg) significantly attenuated the enhancement of cocaine discrimination evoked by a combination of CP 94253 (5 mg/kg) or fluoxetine (5 mg/kg) and cocaine (2.5 mg/kg). These results indicate that 5-HT1B receptors are not directly involved in the cocaine-induced discriminative stimuli in rats. On the other hand, they indicate that pharmacological stimulation of 5-HT receptors--that also seem to be a target for fluoxetine-mediated increase in 5-HT neurotransmission--can enhance the overall effects of cocaine.     

Ro 15-1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital

The benzodiazepine antagonist properties of Ro 15-1788 were evaluated in rats trained to discriminate between saline and either 1.0 mg/kg of diazepam or 10 mg/kg of pentobarbital in a two-choice discrete-trial shock avoidance procedure. When administered alone, 1.0 mg/kg of diazepam and 10 mg/kg of pentobarbital produced comparable amounts of drug-appropriate responding (> 84%), whether rats were trained to discriminate between diazepam or pentobarbital and saline. Ro 15-1788 (3–32 mg/kg, p.o.), administered 10 min before diazepam or pentobarbital, produced a dose-related blockade of the discriminative effects of diazepam in both groups of rats, but was completely ineffective in blocking the discriminative effects of pentobarbital. The dose-effect curve for the discriminative effects of diazepam was shifted to the right in a parallel fashion 3- and 13-fold by 10 and 32 mg/kg of Ro 15-1788, respectively, indicating that Ro 15-1788 acts as a surmountable, competitive antagonist of diazepam. When administered alone, Ro 15-1788 (32–100 mg/kg, p.o.) produced primarily saline-appropriate responding, although 100 mg/kg of Ro 15-1788 produced drug-appropriate responding in one out of eight rats. When administered orally 30 min after diazepam, Ro 15-1788 (32 mg/kg) completely reversed within 10 min the discriminative effects of diazepam. The blockade of diazepam's discriminative effects by 32 mg/kg of Ro 15-1788 appeared to last at least as long (approximately 2 hr) as the effects of diazepam alone.     

Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration

The mu agonist, morphine, and the prototype kappa agonists, ketocyclazocine and ethylketocyclazocine (EK), were studied for their effects on gastrointestinal transit. Following s.c. administration, both morphine (0.3-3 mg/kg) and ketocyclazocine (0.3-10 mg/kg) antagonized transit of an opaque marker through the small intestines of mice. Morphine (0.1-1 microgram) was also effective after intracerebroventricular (icv) administration in mice whereas ketocyclazocine (0.3-30 micrograms) was not. Similarly, while both morphine (0.3-5 mg/kg) and EK (0.6-10 mg/kg) slowed transit after s.c. injection to rats, only morphine (1-10 micrograms), but not EK (0.3-300 micrograms), was active following icv administration. Icv infusion of the mu benzomorphan, phenazocine (10-100 micrograms), slowed transit in a dose-related manner. These results indicate that there may be an anatomically distinct distribution of receptors for benzomorphan kappa agonists in both the mouse and rat, with these opiate receptors not being located near the lateral cerebral ventricles. The difference in efficacy between morphine and ketazocines in slowing gastrointestinal transit after icv administration to rodents suggests that (a) inactivity in this endpoint is a characteristic of benzomorphan kappa compounds and (b) the model may serve as a useful screen when establishing in vivo profiles of kappa agonists in mice and rats.     

Brain and blood indole metabolites after peripheral administration of14C-5-HT in rat

Radioactive techniques were used to reexamine the reports that pharmacological quantities of peripheral serotonin (5-hydroxytryptamine or 5-HT) gain access to brain parenchyma. Intravenous injection of 0.108–4.19 mg/kg of¹⁴C-5-HT (3.55 Ci/100 g weight) produced significant metabolic differences in brain but not blood as a function of dose at up to 10 min after injection. Neither of the metabolites, 5-hydroxyindoleacetic acid nor 5-hydroxytryptophol, were detectable in brain following their intravenous injection, suggesting that when such metabolites are found in brain they represent central metabolism. It has also been shown that peripheral compartments in general, and specifically blood in the cerebral vasculature and the adrenergic nerve endings in the cerebral blood vessels, contribute to the uptake and metabolism of 5-HT. We conclude that doses up to 0.435 mg/kg 5-HT do not cross the blood-brain barrier in the rat but are being totally metabolized in nonneuronal tissues that are invariably removed and assayed along with brain parenchyma. The level at which 5-HT actually passes the blood-brain barrier was found to be at least 0.863 mg/kg. This value is one-third lower than that previously reported.     

Comparison of the anticonvulsant effects of opioid peptides and etorphine in rats after icv administration

The effect of acute icv administration of β-endorphin (5–160 μg), D-ala²-D-leu⁵-enkephalin (DADL; 5–160 μg), D-ala²-met-enkephalinamide (DAME; 10–160 μg), and etorphine (0.05–1.6 μg) on brain excitability was studied by measuring flurothyl seizure thresholds in rats. Each test compound produced a behavioral stupor characterized by muscle rigidity, exophthalmos, and the absence of spontaneous movement. Wet-dog shakes occured only after injection of the opioid peptides. All four compounds produced a dose-related increase in seizure threshold. Naloxone antagonized the behavioral and anticonvulsant effects; the increase in seizure threshold induced by β-endorphin was the most resistant to naloxone. These results indicate that the opioid peptides, in addition to their known EEG epileptogenic potential, are also anticonvulsant in the rat, thus raising the possibility of a dual action for the opioid peptides on central nervous system excitability.     

Sedative and cardiovascular effects of midazolam in swine.

The ability to reliably produce sedation in swine is hampered by the paucity of agents available. This project examined the use of a new water soluble benzodiazepine, midazolam, as a sedative in swine. Echocardiographic studies were performed on thirty 23 to 30 kg Yorkshire swine before and 20 minutes after each animal received a single intramuscular dose of 100 micrograms/kg midazolam. Heart rate and respiratory rate decreased significantly compared to nonsedated values (93 +/- 7 versus 117 +/- 2 bpm and 10 +/- 1 versus 20 +/- 1 breaths/min, respectively [p less than 0.05]). However, there was no effect on left ventricular fractional shortening (29.9 greater than 0.05 versus 29.5 +/- 0.05% [p greater than 0.05]). An additional five pigs were instrumented for a dose response study in order to collect hemodynamic data and blood gas values at baseline, and 15 min after the intravenous administration of incremental doses of midazolam (100 to 1,000 micrograms/kg). Despite a significant decrease in heart rate and respiratory rate, cardiac output, blood gases, and pH remained within normal ranges at all dosage levels. Both routes of administration produced sedation for 20 min in all animals. Midazolam is an effective swine sedative that is associated with stable cardiac function.     

Comparison between the in vivo rate of metabolism of prostaglandin I2 and its blood-pressure-lowering response after intravenous administration in the rat.

Intravenous bolus injection of prostaglandin I2 in the Inactin-anaesthetised rat produces a slow dose-dependant vasodepression which reaches maximum approximately 15 s. after injection. Administration of 9 beta-[3H1]-prostaglandin I2 by the same route followed by serial arterial sampling and TLC analysis revealed a slow conversion into one less polar metabolite starting after 20 s and reaching 40% by two minutes in the circulation. These experiments indicate that prostaglandin I2 survives pulmonary transit for a sufficiently long time to elicit a biological action. Thus its continuous systemic vascular synthesis could play an important role in the control of hypertension.     

Comparison between multiple behavioral effects of peripheral ethanol administration in rats: sedation, ataxia, and bradykinesia

Although low doses of systemic ethanol stimulate locomotion in mice, in rats the typical response to peripheral ethanol administration is a dose-dependent suppression of motor activity. In the present study, male rats received acute doses of ethanol IP (0.0, 0.25, 0.5, 1.0 or 2.0 g/kg) and were tested on several behavioral tasks related to the motor suppressive or sedative effects of the drug. This research design allowed for comparisons between the effects of ethanol on different behavioral tasks in order to determine which tasks were most sensitive to the drug (i.e., which tasks would yield deficits that appear at lower doses). In the first two experiments, rats were evaluated on a sedation rating scale, and ataxia/motor incoordination was assessed using the rotarod apparatus. Administration of 2.0 g/kg ethanol produced sedation as measured by the sedation scale, and also impaired performance on the rotarod. In a third experiment, ethanol reduced locomotion in the stabilimeter at several doses and times after IP injection, with 0.25 g/kg being the lowest dose that produced a significant decrease in locomotion. Finally, experiment four studied the effects of ethanol on operant lever pressing reinforced on a fixed ratio 5 (FR5) schedule for food reinforcement. Data showed suppressive effects on lever pressing at doses of 1.0, and 2.0 g/kg ethanol. Analysis of the interresponse time distribution showed that ethanol produced a modest slowing of operant responding, as well as fragmentation of the temporal pattern of responding and increases in pausing. Taken together, these results indicate that rats can demonstrate reduced locomotion and slowing of operant responding at doses lower than those that result in sedation or ataxia as measured by the rotarod. The detection of subtle changes in different motor test across a broad range of ethanol doses is important for understanding ethanol effects in other cognitive, motivational or sensory processes.