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A M Young

Publications and source records attributed to A M Young.

At least 19 recordsLinked to original sources
PubMed1992

Increased dopamine release in vivo in nucleus accumbens and caudate nucleus of the rat during drinking: a microdialysis study.

Changes in dopamine release and metabolism during drinking in thirsty rats were studied using in vivo microdialysis. Animals were maintained on controlled water (1 h per day) and trained to lick for water in a behavioural box. Microdialysis probes were then inserted into the left nucleus accumbens and right caudate nucleus through previously implanted guide cannulae, and the following day animals were connected for dialysis perfusion, during which they were allowed 1 h free access to water. Dopamine, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased in both nucleus accumbens and caudate nucleus in association with drinking, but the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid, only increased in the caudate nucleus. There was a direct correlation between the maximum dopamine release in nucleus accumbens and the maximum licking rate per 10-min period, but the maximum increase in dopamine did not occur until after the period of maximum licking. Increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid were further delayed (by 20 and 30 min, respectively). In the caudate, changes in 5-hydroxyindoleacetic acid showed a very similar time-course to those of 3,4-dihydroxyphenylacetic acid. These data show that dopamine systems in both nucleus accumbens and caudate nucleus are activated in relation to drinking in thirsty rats. In addition, they indicate that 5-hydroxytryptamine systems in the caudate nucleus, but not in nucleus accumbens, may also be involved. The support that the results provide for the hypothesized connection between reward and limbic dopamine is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Discriminative stimulus effects of morphine: effects of training dose on agonist and antagonist effects of mu opioids.

Experiments examined how training dose of morphine modulates the agonist and antagonist effects of selected mu opioids. Saline and either 3.2 or 5.6 mg/kg morphine were established as discriminative stimuli for food-reinforced responses in two groups of rats. Etorphine and morphine evoked full morphine lever responding in both groups, but were more potent in subjects trained with 3.2 mg/kg morphine. Methadone, dezocine and dl-pentazocine were equieffective and equipotent in evoking full morphine-like stimulus effects in both groups. Nalbuphine evoked full morphine-like stimulus effects and decreased the dose of morphine required for stimulus effects in rats trained with 3.2 mg/kg morphine. In contrast, nalbuphine antagonized stimulus effects of morphine in rats trained with 5.6 mg/kg morphine, and antagonized rate-altering effects of morphine in both groups, with an apparent pA2 of 5.4 mol/kg. Nalorphine and naltrexone antagonized stimulus and rate-altering effects of morphine in both groups, with an apparent pA2 of 6.0 mol/kg for nalorphine and 7.8 mol/kg for naltrexone. For both compounds, apparent pA2 values did not discriminate between stimulus or rate-altering effects of morphine, or between training conditions. d-Amphetamine and ketamine enhanced the rate-suppressing effects of morphine. However, whereas d-amphetamine prevented stimulus effects of 3.2 mg/kg, but not 5.6 mg/kg morphine, ketamine increased sensitivity to stimulus effects of morphine in rats trained with 3.2 mg/kg morphine without altering sensitivity in rats trained with 5.6 mg/kg. These results demonstrate that training dose of morphine can modulate the likelihood that certain opioids will reproduce or antagonize discriminative stimulus effects of morphine. Furthermore, for nalbuphine and nalorphine, diminished morphine-like stimulus effects in subjects trained with the higher dose of morphine appeared to result from low efficacy mu agonist actions.

Animals↗
PubMed1991

Increased sensitivity to rate-altering and discriminative stimulus effects of morphine following continuous exposure to naltrexone.

Two experiments evaluated whether termination of a continuous infusion of naltrexone altered sensitivity to the rate-suppressing or discriminative stimulus effects of morphine in rats. An 8-day infusion of saline or doses of 3, 10, or 18 mg/kg/day naltrexone did not alter rates of lever pressing maintained under fixed-ratio 30 schedules of food delivery. A dose of 10 mg/kg day naltrexone produced insurmountable antagonism of the rate-suppressing and analgesic effects of morphine. The ED50 of morphine for rate suppression decreased by 2-fold 1 day after termination of the 8-day infusion of 10 or 18 mg/kg/day naltrexone. The ED50 of morphine returned to initial values within 8 days. Termination of infusion of either saline or 3 mg/kg/day naltrexone did not alter the ED50 of morphine. Changes in morphine stimulus control were evaluated in rats trained to discriminate saline and 3.2 mg/kg morphine under fixed-ratio 15 schedules of food delivery. The ED50 of morphine for stimulus control or rate suppression decreased by 2-fold 1 day after termination of an 8-day infusion of 18 mg/kg/day naltrexone. The ED50 of morphine for rate suppression returned to initial values within 3 days; that for stimulus control, within 5 days. Thus, termination of exposure to high doses of naltrexone produced brief changes in sensitivity to the rate-altering and discriminative stimulus effects of morphine that parallel reported changes in sensitivity to the analgesic and lethal effects of morphine.

Animals↗
PubMed1991

Onset of tolerance to discriminative stimulus effects of morphine.

Experiments assessed the onset of tolerance to discriminative stimulus effects of morphine in rats treated repeatedly with twice daily doses of 10 mg/kg morphine. Saline and 3.2 mg/kg morphine were established as discriminative stimuli for food-reinforced fixed-ratio performances in several groups of rats, and initial ED50 values were determined for stimulus and rate-altering effects of morphine. To assess onset of tolerance, training was halted and 10 mg/kg doses of morphine were administered repeatedly at 12-h intervals. In separate experiments, ED50 values were redetermined after various treatment periods. One treatment with 10 mg/kg morphine did not alter the ED50 for stimulus effects of morphine, whereas treatment for one or three days increased the ED50 by approximately 2-fold. Comparisons with published data showed even greater tolerance when treatment lasted one or two weeks. Tolerance to stimulus effects of morphine generally was accompanied by tolerance to its rate-decreasing effects. Repeated treatment with morphine also produced cross-tolerance to morphine-like stimulus effects of methadone and buprenorphine. As with morphine itself, greater tolerance developed with longer treatment. These results suggest that tolerance to discriminative stimulus effects of morphine develops gradually, with magnitude of tolerance increasing as a function of treatment duration.

Animals↗
PubMed1991

Pharmacological evidence, using in vivo dialysis, that substances additional to ascorbic acid, uric acid and homovanillic acid contribute to the voltammetric signals obtained in unrestrained rats from chronically implanted carbon paste electrodes.

In vivo voltammetry at chronically implanted carbon paste electrodes in unrestrained rats is a particularly useful technique for evaluating neurochemical changes during spontaneous behaviour, or behaviour under experimental control. A 3 peak signal is observed in the striatum; most recently the consensus view has attributed these peaks to ascorbic acid (AA), uric acid (UA) and homovanillic acid (HVA) in ascending order of oxidation potential. We have used a pharmacological approach, combined with in vivo dialysis, to further elucidate the nature of the contributing species. Allopurinol, an inhibitor of xanthine oxidase, and thus of uric acid production, has previously been reported to abolish peak 2. We now report, using dialysis, that it selectively depletes UA in the extracellular fluid (ECF). Pargyline, a monoamine oxidase inhibitor, reduces peak 3 transiently (max. 60%) as expected, however it results in a more sustained reduction in ECF HVA (max. 100%). It also increases peak 1 (max. 75%) and decreases peak 2 (max. 40%), although changes in ECF AA and UA measured by dialysis and HPLC are minimal. Pargyline does however reduce ECF 5-hydroxyindoleacetic acid by 65%. We conclude that, using linear sweep voltammetry at chronically implanted paste electrodes: (a) one or more substances in addition to AA can contribute to peak 1; dopamine can do so in some situations; (b) 5-hydroxyindoleacetic acid, as well as UA, contributes to peak 2; its contribution is about one third that of the latter; and (c) one or more substances in addition to HVA can contribute to peak 3. 3-Methoxytyramine can do so. Since this is another methylated metabolite of dopamine, this does not prevent the use of peak 3 as an index of dopamine metabolism, and may extend its usefulness to situations where monoamine oxidase is inhibited.

Allopurinol↗
PubMed1991

N-methyl-D-aspartate releases excitatory amino acids in rat corpus striatum in vivo.

There is a considerable amount of conflicting evidence from several studies as to the action of applied N-methyl-D-aspartate (NMDA) on the release of glutamate and aspartate in the brain. In the present study the effect of NMDA on extracellular levels of endogenous amino acids was investigated in conscious, unrestrained rats using intracerebral microdialysis. NMDA caused dose-related increases in extracellular levels of glutamate and aspartate; threonine and glutamine were unaffected. The NMDA-evoked release of glutamate and aspartate was significantly decreased by the specific NMDA receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-l-phosphonic acid. In addition, increasing the perfusate concentration (and therefore the extracellular concentration) of Ca2+ significantly enhanced the NMDA-evoked release of glutamate and aspartate, whereas removal of Ca2+ and addition of a high Mg2+ concentration to the perfusate caused a significant reduction in their NMDA-evoked release. Moreover, the NMDA-evoked release of glutamate and aspartate was reduced in decorticate animals. These results demonstrate that, in the striatum in vivo, NMDA causes selective release of endogenous glutamate and aspartate from neurone terminals and that this action occurs through an NMDA receptor-mediated mechanism. The ability of NMDA receptor activation to induce release of glutamate and aspartate, perhaps by a positive feedback mechanism, may be relevant to the pathologies underlying epilepsy and ischaemic and hypoglycaemic brain damage.

Amino Acids↗
PubMed1991

Tolerance to drugs acting as discriminative stimuli.

The experiments described above highlight the ways behavioral and pharmacodynamic processes interact to modulate the development of tolerance to the discriminative stimulus effects of drugs. These studies suggest that frequent drug exposure does not lead inevitably to the development of tolerance to a drug's discriminative effects. Rather, the interplay between a drug stimulus and reinforcement opportunities shapes the sensitivity of discriminative performances over successive episodes of drug exposure. Maintaining a discriminative relation between a drug and behavior strengthens the likelihood that an initially effective dose will maintain discriminative control. Development of tolerance requires exposure to both treatment regimens appropriate to the agent under study and behavioral contingencies that limit an individual's ability to learn a new discrimination. When both requirements are met, tolerance does develop to drugs acting as discriminative stimuli. When training is suspended during a period of chronic drug treatment, the dose of drug required to evoke stimulus control can be increased by treatment with appropriate maintenance doses of the training drug or a closely related drug. Tolerance is proportional to maintenance dose, develops relatively slowly, and disappears after termination of repeated drug treatment. Tolerance appears pharmacologically specific and can be accompanied by cross-tolerance to other drugs that evoke cross-generalization with the training drug. Finally, tolerance can be diminished markedly by continuing training with the original training dose. Taken together, these patterns suggest that development of tolerance to drugs acting as discriminative stimuli is the result of joint actions of conditioning and pharmacodynamic processes.

Animals↗
PubMed1991

Tolerance to morphine-like stimulus effects of mu opioid agonists.

Experiments assessed the ability of repeated treatment with morphine to produce tolerance to morphine-like discriminative stimulus effects of buprenorphine, etorphine, methadone, morphine, and nalbuphine. Before treatment, each compound evoked full morphine-like stimulus effects in rats trained to discriminate saline and 3.2 mg/kg morphine. During treatment, training was halted and a dose of 10 mg/kg morphine administered every 12 h for 14-18 days. Repeated treatment with morphine increased the ED50 for stimulus control by etorphine, methadone or buprenorphine 2- to 4-fold and that for morphine 4.5-fold. Repeated treatment produced an insurmountable tolerance to the morphine-like stimulus effects of nalbuphine, so that a dose 150-fold higher than the initial ED50 evoked only 40% generalization. Treatment with a lower dose of morphine (10 mg/kg every 24 h) produced a short-lived surmountable tolerance to stimulus effects of nalbuphine. For etorphine, methadone and morphine, tolerance to morphine-like stimulus effects was accompanied by tolerance to rate suppressing effects. After treatment ended, the ED50 for stimulus control by etorphine, methadone or nalbuphine returned to initial values within 3 days; that for morphine, within 5 days; that for buprenorphine, within 10 days. These results demonstrate that repeated treatment with morphine produces cross-tolerance to compounds that exert morphine-like stimulus effects. Additionally, the results suggest that differences among these compounds in agonist efficacy may be revealed as differences in the degree of tolerance produced by morphine treatment.

Animals↗
PubMed1990

Tolerance to morphine stimulus control: role of morphine maintenance dose.

Experiments assessed the development of tolerance to morphine stimulus control during treatment with selected maintenance doses of morphine. Separate groups of rats were trained to discriminate saline and either 3.2 mg/kg or 5.6 mg/kg morphine under fixed-ratio schedules of food delivery. Dose-response functions for generalization of morphine stimulus control were determined before, during, and after repeated treatment with selected doses of morphine. Similar experiments were performed with repeated pentobarbital treatment in order to assess the pharmacological selectivity of tolerance. Repeated treatment with saline, 3.2 mg/kg morphine, or twice daily injections of 17.8 mg/kg pentobarbital produced no tolerance to morphine stimulus control. In contrast, treatment with daily injections of 10 mg/kg or twice daily injections of 10 or 17.8 mg/kg morphine produced a dose-dependent increase in the dose of morphine required for stimulus control. The magnitude of tolerance to morphine stimulus control varied directly with the maintenance dose of morphine and was slightly greater for a lower than a higher morphine training dose. Termination of repeated treatment was followed by a return to initial sensitivity, without additional training. Tolerance to morphine stimulus control was not necessarily accompanied by tolerance to its rate-suppressing effects.

Animals↗
PubMed1990

Preloading in vivo: a rapid and reliable method for measuring gamma-aminobutyric acid and glutamate fluxes by microdialysis.

In vivo microdialysis was used in conjunction with a novel dual-label preloading method, to monitor changes in extracellular levels of gamma-aminobutyric acid (GABA) and glutamate in the striatum of conscious, unrestrained rats. [3H]GABA and [14C]glutamate were applied in the dialysis stream for a preloading period of 30 min, after which dialysis perfusion was continued for up to 6 h, and dialysate samples were collected for scintillation counting. Veratridine (Vtd: 100 microM in the dialysate) caused significant rises in both 3H and 14C content measured in the dialysates, the majority of which remained associated with the preload GABA and glutamate, respectively. The Vtd-stimulated release of GABA and glutamate measured in this way was blocked by tetrodotoxin and was Ca2+ dependent. Thus, by reproducing results obtained using other techniques, we have shown that the preloading method provides a quick and reliable method for measuring the effects of drugs on the release of neurotransmitter GABA and glutamate in vivo by dyalisis. It should enable sample times as low as 1 min to be used, thus allowing resolution of transient stimulated responses taking place over a time course of minutes.

Animals↗
PubMed1989

Evidence for perceptual masking of the discriminative morphine stimulus.

Morphine-amphetamine and morphine-naltrexone interactions were examined in three groups of White Carneaux pigeons (n = 3), which were trained in a two-choice drug discrimination procedure under a FR-30 schedule of food reinforcement using 3.2 mg/kg morphine and saline as discriminative stimuli. Once stimulus control was acquired by these initial training stimuli, the training doses of morphine were gradually changed to 1.0 mg/kg for group A and to 10 mg/kg for group C. The three groups differed in the minimum dose required for stimulus control and the drugs to which the training stimulus generalized. Stimulus generalization to amphetamine was inversely related to training dose. Amphetamine potentiated the discriminative stimulus properties of morphine. Naltrexone blocked the discriminative stimulus properties of morphine to varying degrees, which appeared to be limited by the training dose and the rate-suppressing effects of naltrexone when administered alone. Challenging the morphine stimulus with amphetamine resulted in a qualitatively similar blockade. This blockade was a direct function of the morphine training dose. It is argued that MS-AMP interactions result in perceptual masking of the MS stimulus, which can be differentiated from pharmacological antagonism by NTX. Two other challenge drugs, ketamine and sodium pentobarbital, did not alter stimulus control by morphine.

Animals↗
PubMed1989

Effects of prior saline-morphine discrimination by pigeons on three-way discrimination including two morphine doses.

The discriminative stimulus properties of morphine sulfate (MS) and their alteration by naltrexone (NTX) and d-amphetamine (AMP) challenges were examined in a quantitative dose 1, dose 2, and saline (SAL) drug discrimination task utilizing 1.8 mg/kg MS, 10 mg/kg MS, and SAL as discriminative stimuli under a fixed-ratio 30 schedule of food-maintained behavior in two groups of White Carneaux pigeons. Group A (Gp A) (n = 6) subjects (Ss) were initially experimentally- and drug-naive, whereas group B Ss (n = 4) were originally trained in a two-choice MS versus SAL discrimination task, and had a long behavioral and drug history. Significant differences were found in (1) number of sessions to criterion (STC) (group B greater than group A); (2) group A Ss generalized both NTX and AMP to SAL, whereas group B Ss generalized AMP to the low dose (1.8 mg/kg) MS stimulus; and (3) in drug interaction test sessions, the high dose MS stimulus (10 mg/kg) in group A was unmodified by a range of challenge AMP doses (0.32 to 3.2 mg/kg). In contrast, group B Ss exhibited a shift to the low dose or SAL-appropriate keys when the same high dose MS stimulus was challenged by moderate doses of AMP. Group A and group B were similar in their pattern and distribution of responses when tested with various doses of MS, and also when challenge tests of the high dose MS stimulus were made with NTX.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Receptor mechanisms of opioid drug discrimination.

Receptor theory of opioid action has provided an extremely useful interpretive framework for the discriminative stimulus effects of opioids. By and large, receptor theory has been applied to opioid actions as they are measured in in vitro and reflex systems. It is clear, however, that it can also assist in interpreting data from experiments addressing operantly conditioned behavior, and provide a link between these data and those obtained using other procedures. The current paper describes the criteria that can be used to determine whether a drug effect is receptor mediated and applies these criteria to the effects of mu and kappa opioids in drug-discrimination studies. Criteria for distinguishing between drug effects occurring through one, as opposed to two, receptor systems are described and again applied to the discriminative stimulus effects of mu and kappa opioids. The potential difficulties that can be caused by postreceptor variability and the presence of multiple receptor systems are noted, since they can modify the effects predicted from simple receptor theory, and are likely to play an important role when studies of opioid action are made in the whole animal. In discrimination studies, complicating variables include dose of the training drug, subject species, nature of the training drug, and context of the discrimination. Finally, the ability of receptor theory to guide future investigation of the phenomenon of partial generalization is explored.

Animals↗
PubMed1988

Potentiation by kainate of excitatory amino acid release in striatum: complementary in vivo and in vitro experiments.

The effect of kainate on extracellular levels of amino acids in corpus striatum was investigated in vitro and in vivo, to elucidate the mechanism underlying its neurotoxicity. Kainate increased extracellular glutamate and aspartate in both striatal slices in vitro and intact striatum in vivo, as previously reported. Both in vitro and in vivo, DL-threo-3-hydroxyaspartate increased extracellular glutamate and aspartate levels (to between 150 and 200% of basal), and also enhanced their kainate-evoked release. The action of kainate in vivo was reduced by prior frontal decortication, whereas in vitro the kainate-evoked responses were only slightly reduced by tetrodotoxin, and remained above control values. These results confirm that kainate increases extracellular glutamate and aspartate, and provide evidence that this is due to synaptic release evoked by an action on receptors on glutamatergic neurone terminals. These findings may be relevant to the understanding of epilepsy.

Amino Acids↗
PubMed1988

Production of colony-stimulating factors (CSFs) during infection: separate determinations of macrophage-, granulocyte-, granulocyte-macrophage-, and multi-CSFs.

After infection of mice with Listeria monocytogenes, elevated levels of colony-stimulating factors (CSFs) in the serum were quantitated by six different assays: ability to stimulate colony formation, the proliferation of 2 suspension of bone marrow cells (both measuring total colony-stimulating activity), a radioimmunoassay for macrophage-CSF (CSF-1), the WEHI-3B differentiation assay for granulocyte-CSF, and proliferation of 32D-c1-3 and FDC-P1 cell lines (specific for multi-CSF and either multi- or granulocyte-macrophage-CSFs, respectively). The great bulk of serum colony-stimulating activity represented macrophage- and granulocyte-CSFs, with small but measurable amounts of granulocyte-macrophage-CSF. The degree of elevation of serum CSF depended on the infecting dose used and the numbers of bacteria growing in the spleens and livers of the two mouse strains compared, i.e., L. monocytogenes-resistant C57BL/10 and susceptible BALB/cJ. The increase in serum CSFs occurred before the peak in bone marrow granulocyte-macrophage progenitors and before the reduction in bacterial numbers which follows the onset of specific cell-mediated immunity.

Animals↗
PubMed1987

Continuous glutamate leakage from brain cells is balanced by compensatory high-affinity reuptake transport.

The glutamate (and aspartate) uptake blocker threo-3-hydroxyaspartate (20 microM) was added to superfusion fluids employed for in vivo microdialysis of corpus striatum, and to incubation medium for striatal slices (5 microM). In vivo it caused an increase in glutamate and aspartate concentrations in the superfusion fluid. In vitro it caused increases in the levels of glutamate, aspartate, GABA, taurine and glutamine in the incubation fluid. Tetrodotoxin (1 microM) did not influence the rises in glutamate or aspartate. It is concluded from these results that there is a continuous outward leakage of glutamate, and aspartate, from neural cells which is normally balanced by an inward flux due to reuptake processes. This leakage is distinct from synaptic release of these substances due to spike activity, since tetrodotoxin added to striatal slices did not diminish the action of threo-3-hydroxyaspartate. The significance of the findings for mechanisms leading to ischaemic or hypoxic brain damage, and basic mechanisms in epilepsy is discussed.

Amino Acids↗
PubMed1987

Environmental modification of tolerance to morphine discriminative stimulus properties in rats.

The development of tolerance to the discriminative stimulus properties of morphine was examined in rats trained to discriminate saline and 3.2 mg/kg morphine under a multiple timeout 15 min, 5 min fixed-ratio 30 schedule of food delivery. Generalization gradients were generated by administering increasing doses of morphine before successive timeout periods within the experimental session. Over the course of the study, the minimal discriminable dose (MDD) of morphine under control conditions fluctuated but did not systematically increase or decrease. Acute pretreatments of 3.2-17.8 mg/kg morphine 4-24 h before a generalization test resulted in minor changes in the MDD. To examine development of tolerance, supplemental doses of morphine (17.8 mg/kg) or saline were administered twice daily while discrimination training was either suspended or continued. Tolerance was assessed by weekly generalization tests. Greater tolerance developed to the morphine stimulus when training was suspended than when training was continued. For both training conditions, response rates during generalization tests were markedly suppressed during supplemental morphine administration, and original generalization gradients were recaptured within 2 weeks after termination of supplemental morphine administration. Supplemental saline administration did not alter the discriminative or rate-altering effects of morphine under either training condition. Thus, the magnitude of tolerance to a morphine discriminative stimulus reflected an interaction of supplemental drug treatment with the training conditions imposed during that treatment.

Animals↗