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Biomedical subjects

D C Roberts

Publications and source records attributed to D C Roberts.

At least 55 records · Page 3Linked to original sources
PubMed1996

Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats.

The effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine.

Animals↗
PubMed1996

Initiation, maintenance and extinction of cocaine self-administration with and without conditioned reward.

Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS+ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n = 6) and a group responding on a second-order (SO) schedule (n = 5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n = 7) responses during extinction were counted with and without the CS+. Responding was greater in the presence of the CS+ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli.

Animals↗
PubMed1996

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement.

Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09-1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy.

Drug self-administration studies have recently employed progressive ratio (PR) schedules to examine psychostimulant and opiate reinforcement. This review addresses the technical, statistical, and theoretical issues related to the use of the PR schedule in self-administration studies in rats. Session parameters adopted for use in our laboratory and the considerations relevant to them are described. The strengths and weaknesses of the PR schedule are also discussed.

Animals↗
PubMed1996

Baclofen attenuates the reinforcing effects of cocaine in rats.

The effect of the GABAB agonist baclofen on cocaine self-administration in the rat was investigated. In the first experiment, rats trained to self-administer i.v. cocaine (1.5 mg/kg/inj) on a progressive ratio (PR) schedule were pretreated with various doses of baclofen (1.25, 2.5, or 5.0 mg/kg). Baclofen produced a dose-dependent decrease in the break points. In the second experiment, baclofen (2.5 mg/kg) was found to decrease significantly break points across a series of unit injection doses of cocaine (0.18, 0.37, 0.75, 1.5 mg/kg/inj). Baclofen produced only modest effects on food-reinforced responding even at the largest dose tested (5.0 mg/kg). These data suggest that baclofen may produce a specific attenuation of cocaine reinforcement. Baclofen produced no significant change in the rate of i.v. cocaine intake on a fixed ratio (FR 1) schedule. These data support a number of recent observations that rate of drug intake may be an insensitive measure of changes in the motivation to self-administer cocaine.

Animals↗
PubMed1996

Body protein in prepubertal children with phenylketonuria.

OBJECTIVE: To assess body protein and protein deposition in prepubertal children with phenylketonuria (PKU). DESIGN: Cross-sectional study with nested longitudinal cohort. SETTING: A tertiary referral paediatric hospital. SUBJECTS: 37 PKU patients (3.9-11.0 years) and 27 unselected healthy controls (4.0-11.5 years) of whom 29 PKU patients and 17 controls were followed longitudinally. INTERVENTIONS: All had measurements of height, weight, body fat and total body nitrogen (TBN) by neutron capture analysis; PKU patients and their unaffected siblings (n = 16) also had measurements of four day weighed food record and plasma amino acids by HPLC. RESULTS: The children with PKU compared with the controls were significantly shorter (height SD score -0.42 +/- 0.89 vs 0.17 +/- 0.94, respectively, P < 0.02) and had a lower TBN (575 +/- 200 vs 710 +/- 215g, respectively, P < 0.02). TBN in the controls was significantly correlated with lean body mass (LBM), weight, height and age (r = 0.97, 0.95, 0.95, 0.88, respectively, P < 0.001). The children with PKU had significantly lower TBN when predicted from LBM, weight and age (93%, 92%, 92% of predicted, respectively), but normal TBN predicted from height (102% of expected). The annual accretion of nitrogen was similar for the PKU and controls (86 +/- 45 and 77 +/- 58 g/y, respectively). There was no difference between the two groups in protein intake or plasma amino acids except for phenylalanine. CONCLUSION: The children with PKU had a deficit in height and body protein despite a normal to higher accretion of protein. If the deficit occurs early in life, amino acid supplementation and other nutritional practices used at this time need to be reviewed.

Amino Acids↗
PubMed1995

Periodic acid-Schiff (PAS)-positive deposits in brain following kainic acid-induced seizures: relationships to fos induction, neuronal necrosis, reactive gliosis, and blood-brain barrier breakdown.

Periodic acid-Schiff (PAS)-positive deposits have been demonstrated in the central nervous system (CNS) of patients suffering from a wide variety of neurodegenerative disorders including Alzheimer's disease, presenile dementia, Parkinson's disease, diabetes mellitus, myoclonic epilepsy, and cerebral palsy. The etiology of these deposits and their relationship to mechanisms of progressive neurodegeneration is unknown. In the present study, we demonstrate that the kainic acid model of limbic status epilepticus provides a useful system for the study of PAS-positive staining. The relationship between PAS-positive deposition, induction of fos-like immunoreactivity (FLI), neuronal necrosis, reactive gliosis, and blood-brain barrier breakdown following the kainic acid induction of status epilepticus was investigated. Epileptiform activity was elicited in rats by intraperitoneal administration of 10 mg/kg kainic acid and brains were examined 3, 5, 12, 24, 72, and 168 h after drug injection. Four distinct types of PAS-positive staining in rat brain were observed: type 1, extracellular matrix (ECM) or blood vessel associated-material; type 2, granular deposits; type 3, glial labelling; and type 4, neuronal labelling. Results demonstrated that the four types of PAS-positive staining were differentially associated with specific markers of neuropathology: (1) type 1 ECM staining and type 3 glia were preferentially localized to edematous tissue; (2) the majority of type 3 glia were identified as reactive astrocytes, while a minority of appeared to be proliferating microglia; (3) type 1 blood vessels labelled hemorrhaging vasculature; (4) early deposition of type 2 granules was predictive of subsequent cell loss; (5) chronic type 2 granular deposits and type 4 neuronal labelling not associated with cell death could be predicted by early changes in FLI; and (6) chronic deposition of all four forms of PAS-positive material was correlated with earlier, transient blood-brain barrier compromise. The results support the growing literature that local carbohydrate metabolism may be one of a constellation of parameters important to the development of progressive neurodegeneration.

Animals↗
PubMed1995

Effect of (-)-DS 121 and (+)-UH 232 on cocaine self-administration in rats.

The novel dopamine autoreceptor antagonists (-)-DS 121 and (+)-UH 232 were tested for their ability to alter cocaine self-administration behavior in rats reinforced on a progressive ratio (PR) schedule. (-)-DS 121 (15 mg/kg) and (+)-UH 232 (30 mg/kg) produced significant decreases in breaking point. (-)-DS 121 produced variable results on rate of cocaine intake on an FR1 schedule, indicating that rate may on occasion be insensitive to changes in cocaine reinforcement. In animals previously trained to self-administer cocaine, (-)-DS 121 failed to maintain responding when substituted for cocaine. This profile suggests that (-)-DS 121 is a promising new candidate for the treatment of cocaine abuse.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Oral self-administration of sweetened nicotine solutions by rats.

Oral self-administration of sweetened nicotine solutions in rats was studied in two ways. In the first experiment, one group had continuous access to a water bottle containing a sucrose solution and nicotine (10 micrograms/ml), while another group had access to an identical sucrose solution without nicotine. All rats had continuous access to water. While consumption of nicotine increased with increasing concentrations of sucrose, consumption of the sucrose+nicotine solution never exceeded the intake of sucrose alone. In subsequent experiments, the delivery of the solutions was made contingent upon an operant response. The sucrose+nicotine solution was found to maintain responding to higher response/reinforcer ratios than the sucrose only solution. These data demonstrate that rats will self-administer sweetened nicotine solutions and that sucrose+nicotine solutions are more reinforcing than sucrose solutions alone. Free access consumption is not a good predictor of the response maintaining properties of nicotine solutions.

Administration, Oral↗
PubMed1995

Transient torsion during and after saccades.

In five normal subjects, we analyzed uncalled for torsion (blips) during and after horizontal and vertical saccades. Torsion was defined as movement out of Listing's plane. During horizontal saccades in downward gaze the abducting eye extorted and the adducting eye intorted. The direction of the blips reversed in upward gaze. Peak torsional amplitudes (up to 1-2 deg) were always reached during saccades; drifts back to Listing's plane outlasted the saccades. Torsion of the extorting eye was larger than that of the intorting eye, producing a transient positive cyclovergence. Torsion and cyclovergence evoked by vertical saccades were also stereotyped in each eye, but showed idiosyncratic differences among subjects. We conclude that Listing's law is violated during saccades. Transient saccade-evoked torsion might reflect properties of the three-dimensional velocity-to-position integrator and/or the ocular plant.

Adult↗
PubMed1995

Effect of medial prefrontal cortex injections of SCH 23390 on intravenous cocaine self-administration under both a fixed and progressive ratio schedule of reinforcement.

Rats were trained to self-administer cocaine (1.5 mg/kg i.v.) under either a fixed ratio (FR) or progressive ratio (PR) schedule of reinforcement. Following acquisition, bilateral intracerebral cannulae were directed at the medial prefrontal cortex (mPFC) or striatum (STRM). Intracranial injections of the D1 receptor antagonist, SCH 23390 (0-2.0 micrograms/0.5 microliter/side), were made immediately prior to a self-administration session. Under the FR 1 schedule, SCH 23390 caused a dose-dependent increase in the rate of cocaine intake following injection into either the mPFC or the STRM. In contrast, under the PR schedule similar injections into the STRM had no effect on the breaking point, but large decreases were produced following injection into the mPFC. These results indicate that dopaminergic systems within the mPFC have a significant role to play in the reinforcing properties of cocaine. Moreover, the STRM does not appear to have a role in those reinforcing properties of cocaine measured under the PR schedule. The significant rate-increasing effects obtained from the STRM under the FR schedule, indicate that the two schedules must measure different aspects of cocaine's CNS action.

Animals↗
PubMed1995

Short-term cocaine self administration alters striatal gene expression.

Rats self-administered cocaine or received saline during 3 daily 5 h sessions and were euthanized 1 h after the final session. Quantitative in situ hybridization revealed that cocaine self-administration increased levels of preprodynorphin, but not preproenkephalin, c-fos, or zif/268 mRNAs in a patchy pattern in the dorsal striatum. These data demonstrate that the regulation of preprodynorphin gene expression is dissociable from that of c-fos and zif/268 in dorsal striatum following short-term cocaine self-administration.

Animals↗
PubMed1995

Resting energy expenditure in children with phenylketonuria.

Reports have suggested that children with phenylketonuria (PKU) weigh more compared with reference data. We found lower body protein and bone mineral density in children with PKU. These children may have a predisposition becoming overweight because of an alteration in body composition, which may lower resting energy expenditure (REE). REE was measured in 30 (15 males, 15 females) children with PKU (aged 9.6 +/- 2.9 y) and in 65 (23 males, 42 females) control children (aged 11.2 +/- 3.1 y). There was a comparable range in body fat within each group (control group: 11-34%; PKU group: 10-34%). The mean REE was similar between the male and female children with PKU (5300 +/- 757 and 4703 +/- 1024 kJ/24 h, respectively) and the control subjects (5306 +/- 969 and 5164 +/- 701 kJ/24 h, respectively). The children with PKU had an REE similar to that predicted from control data (males 102.1 +/- 7.8% of predicted and females 100.2 +/- 8.5% of predicted). This study found no evidence of a reduced REE or of increased weight in children with PKU.

Adolescent↗
PubMed1994

Effect of 6-hydroxydopamine lesions of the amygdala on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement.

Bilateral six-hydroxydopamine (6-OHDA) lesions were placed in the amygdala of rats self-administering cocaine (1.5 mg/kg per injection i.v.) under a progressive ratio schedule of reinforcement. Post-lesion access to three doses of cocaine (1.5, 0.75 and 0.37 mg/kg per injection i.v.) revealed a lesion effect only at the highest dose. At this dose, the lesion caused a significant increase in breaking point. No change in the breaking point was produced at the lower two doses. The biochemical results show a significant reduction in dopamine and DOPAC levels within the amygdala and an increase in dopamine within the NACC. In contrast, noradrenaline and serotonin (5-HT) levels were unaffected by the lesion in any of the dissected areas. These results demonstrate that no specific effect on cocaine reinforcement was produced by 6-OHDA lesions of the amygdala. The possibility that the lesion may have attenuated the anxiogenic qualities of the high dose of cocaine is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

A 31P nuclear magnetic resonance investigation of acyl group transfer from phosphatidylcholine to yield lysophosphatidylcholine in human plasma.

31P nuclear magnetic resonance (NMR) spectroscopy was used to measure the rate of acyl transfer from phosphatidylcholine (lecithin, PC) in whole plasma and in high density lipoprotein (HDL). Spectral deconvolution was used to resolve overlapping resonances in the 31P NMR spectra of the phospholipids. Mean values of the acyl group transfer rates from PC in plasma and HDL were 36 mumol L-1h-1 and 19 mumol L-1h-1, respectively. The reciprocal nature of the decrease in the spectral peak intensities of PC, compared to the increase in the intensities of the lysolecithin (lysoPC) peaks, suggested a substrate/product relationship consistent with the action of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for the esterification of free cholesterol in plasma. LCAT involvement was confirmed by measuring the cholesterol esterification rate based on the 13C NMR spectra obtained on lipid extracts from plasma that had been incubated at 37 degrees C. Within experimental error, the rate of lysoPC formation in plasma was shown to be equal to that of cholesteryl ester formation.

Carbon Isotopes↗
PubMed1994

Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food.

The effect of intraventricular infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), was examined in rats trained on a progressive ratio schedule for either IV cocaine or food reinforcement. Animals in the 5,7-DHT treatment group responded to significantly higher breaking points than vehicle-injected control animals, regardless of whether food or cocaine was used as the reinforcing stimulus. Analysis of the regional brain amines indicated that depletions of mesencephalic 5-HT correlated with postsurgical alterations in responding. These findings suggest that depletion of forebrain 5-HT produces a general effect on responding rather than a specific alteration in the reinforcing effects of psychomotor stimulant drugs.

5,7-Dihydroxytryptamine↗