Biomedical subjects

T E Robinson

Publications and source records attributed to T E Robinson.

At least 55 records · Page 3Linked to original sources

PubMed1996

Signalled versus unsignalled intravenous amphetamine: large differences in the acute psychomotor response and sensitization.

Both the acute psychomotor response and the development of sensitization to amphetamine are attenuated if i.p. injections are given in the cage where animals live (HOME), relative to when injections are given in a novel (NOVEL), but otherwise physically identical cage. It was suggested that this effect of environment on sensitization may be due to the relative availability of cues predictive of drug administration in the two conditions. It was hypothesized, therefore, that removal of all environmental cues predictive of drug administration would attenuate the development of sensitization even further. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated unsignalled intravenous (i.v.) infusions of 1.0 mg/kg amphetamine given in a HOME environment with those of signalled i.v. infusions given in a NOVEL environment. It was found that signalled i.v. amphetamine administration (NOVEL) produced a large acute psychomotor response, and repeated administrations resulted in a significant increase in psychomotor response (i.e., sensitization). In contrast, the same treatment in the HOME condition produced only a very small acute response and no sensitization. Indeed, the magnitude of the psychomotor response to an amphetamine challenge varied approximately 23-fold as a function of past drug history and environmental condition. It is suggested that this paradigm provides a powerful new model to study how environmental factors modulate responsiveness to psychoactive drugs.

Amphetamine↗

PubMed1996

Fimbria-fornix lesions do not block sensitization to the psychomotor activating effects of amphetamine.

The repeated, intermittent administration of amphetamine produces a long-lasting sensitization to its behavioral activating effects. Excitatory amino acid receptors in the striatum have been implicated in the development of amphetamine sensitization, and one source of excitatory amino acid input to the striatum is the hippocampus. The purpose of this experiment, therefore, was to determine if an intact hippocampal system is necessary for either the development or expression of sensitization to the psychomotor activating effects of amphetamine. Rats received either fimbria-fornix lesions or sham lesions and approximately 2 weeks later received 10 injections of 3.0 mg/kg d-amphetamine or saline (IP) every other day. Rotational behavior was quantified as an index of amphetamine's psychomotor stimulant effects. Animals with a fimbria-fornix lesion were hyperresponsive to an acute injection of amphetamine, but animals with a fimbria-fornix lesion and control animals did not differ in the development of sensitization (i.e., the rate of sensitization). Furthermore, both groups expressed comparable sensitization (relative to their respective saline-pretreated control groups) when given a challenge injection of amphetamine. These results suggest an intact hippocampal system is not necessary for the development or expression of amphetamine sensitization.

Animals↗

PubMed1996

Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum. Analysis of circadian patterns using automated on-line microdialysis.

The purpose of the study is to determine the relationship between behavioral symptoms of amphetamine withdrawal and the extracellular concentration of dopamine (DA) in the dorsolateral caudate nucleus and the nucleus accumbens across the entire light-dark cycle. This was accomplished using automated on-line microdialysis sampling in behaving rats. Animals were pretreated with escalating doses of d-amphetamine (or saline) over a 6-week period and then were withdrawn from amphetamine for 3, 7, or 28 days before testing. There were regional differences in the effects of amphetamine withdrawal on the concentrations of DA and DA metabolites in dialysate. Early during withdrawal (3 and 7 days), when animals showed postamphetamine withdrawal behavioral depression (nocturnal hypoactivity), there was a significant decrease in DA and DA metabolites in the dorsolateral caudate nucleus and a disruption in the normal circadian pattern of DA activity. In contrast, there was no effect of amphetamine withdrawal on DA dynamics in the nucleus accumbens. By 28 days after the discontinuation of amphetamine pretreatment, after basal DA in the caudate returned to normal, there was a significant increase in basal DA metabolism in both the caudate and the accumbens. This increase in DA metabolism may be related to the expression of sensitization, including a hypersensitivity to an amphetamine challenge. It is concluded that the role of the dorsal striatum in psychostimulant drug withdrawal syndromes deserves further consideration.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Sensitization to the psychomotor stimulant effects of amphetamine: modulation by associative learning.

The authors investigated the influence of associative pairing of contextual stimuli with amphetamine administration on the expression of psychomotor sensitization. Animals received d-amphetamine or saline in group-specific environments. Amphetamine produced robust behavioral sensitization in all environments, but when an amphetamine challenge was given in a test environment that was novel for some groups but not others, the expression of sensitization was completely context specific. An injection of saline in the amphetamine-paired environment produced a conditional response (CR), but this was quite small compared to the magnitude of the sensitized response, and sensitization remained completely context specific following extinction of the CR. Results are discussed in relation to 3 models of how context may modulate the expression of sensitization: an excitatory conditioning model, an inhibitory conditioning model, and an occasion-setting model.

Amphetamine↗

PubMed1995

Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine.

The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a 'novel' test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to those NOVEl test cages, for each test session. In Exp. 1, the acute psychomotor response to 3.0 mg/kg of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 mg/kg of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to the independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.

Amphetamine↗

PubMed1995

Circulating adrenal hormones are not necessary for the development of sensitization to the psychomotor activating effects of amphetamine.

We reported previously that when amphetamine is given in NOVEL test cages both its acute psychomotor activating effects (rotational behaviour and locomotor activity) and the degree of sensitization are greater than when amphetamine is given in HOME cages that are physically identical to the NOVEL test cages. Since exposure to the NOVEL environment increases plasma corticosterone levels (Experiment 1) it is possible that the enhancement in the effects of amphetamine in the NOVEL condition is mediated by corticosterone. If this hypothesis is correct adrenalectomy (ADX) should abolish the difference between the HOME and NOVEL groups. This was tested in three independent experiments, in which the response (rotational behavior in Experiments 2 and 3; locomotor activity and rearing behavior in Experiment 4) to repeated injections of amphetamine was assessed in rats that underwent adrenalectomy (ADX) or a sham operation (SHAM). ADX animals received either no corticosterone replacement or one of two corticosterone replacement treatments. Adrenalectomy, with or without corticosterone replacement treatment, had no significant effect on the development of amphetamine sensitization, either in the HOME or the NOVEL environment. By contrast, the effects of adrenalectomy on the acute response to amphetamine varied depending on the behavioral measure and possibly on the dose of amphetamine (2.0 mg/kg, 3.0 mg/kg and 1.5 mg/kg IP, in Experiments 2, 3 and 4, respectively). We conclude that: (i) a stress-induced secretion of adrenal hormones is not responsible for the enhancement in sensitization to amphetamine seen in animals tested in a NOVEL environment; (ii) circulating adrenal hormones are not necessary for development of sensitization to the psychomotor activating effects of amphetamine.

Adrenal Glands↗

PubMed1995

Amphetamine-induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats.

The purpose of this study was to compare the effects of amphetamine exposure on subsequent amphetamine-induced changes in behavior and dopamine (DA) release in the dorsal and ventral striatum, as a function of time following the discontinuation of repeated amphetamine treatment. Rats were pretreated with either saline or an escalating-dose amphetamine regimen, and then received a 0.5 mg/kg amphetamine "challenge" after either 3, 7, or 28 days of withdrawal. Animals tested after 28 days of withdrawal were hypersensitive (sensitized) to the locomotor-activating effects of amphetamine, and relative to control animals showed a significant enhancement in amphetamine-stimulated DA release in both the dorsal and ventral striatum, as revealed by in vivo microdialysis. Animals tested after only 3 or 7 days of withdrawal showed neither behavioral sensitization nor enhanced amphetamine-stimulated DA release. These results establish that time-dependent changes in behavioral sensitization to amphetamine are associated with time-dependent changes in amphetamine-stimulated DA release, and support the hypothesis that persistent sensitization-related changes in striatal DA neurotransmission contribute to the expression of behavioral sensitization.

Amphetamine↗

PubMed1995

The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment.

Two experiments were designed to assess the effect of a "novel" environment on the development of sensitization to the psychomotor activating effects of d-amphetamine. In the first experiment, rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system received ten daily injections of amphetamine (2 mg/kg), either in their home cages or in novel test cages. The home and novel cages were physically identical (cylindrical transparent buckets), but one group lived and were tested in these cages, whereas the other group was transported from the stainless steel hanging cages where they lived to these novel test cages, for each test session. The first injection of amphetamine produced significantly more rotational behavior in animals tested in a novel environment than in animals tested at home. In addition, animals tested in a novel environment showed greater sensitization than animals tested at home, so the difference between the two groups was even more pronounced following the last injection. In a second experiment, locomotor activity was quantified in rats that received ten injections of either saline or 1.5 mg/kg amphetamine, in their home cages or in a physically identical novel environment. Again, there was a significantly greater locomotor response to the first injection of amphetamine, and greater sensitization, in animals tested in a novel environment than in animals tested at home. These data indicate that environmental factors can exert a large effect on the susceptibility to sensitization, and mechanisms by which this may occur are discussed.

Amphetamine↗

PubMed1995

Dynamic measurements of cerebral pentose phosphate pathway activity in vivo using [1,6-13C2,6,6-2H2]glucose and microdialysis.

Cerebral pentose phosphate pathway (PPP) activity has been linked to NADPH-dependent anabolic pathways, turnover of neurotransmitters, and protection from oxidative stress. Research on this potentially important pathway has been hampered, however, because measurement of regional cerebral PPP activity in vivo has not been possible. Our efforts to address this need focused on the use of a novel isotopically substituted glucose molecule, [1,6-13C2,6,6-2H2]glucose, in conjunction with microdialysis techniques, to measure cerebral PPP activity in vivo, in freely moving rats. Metabolism of [1,6-13C2,6,6-2H2]glucose through glycolysis produces [3-13C]lactate and [3-13C,3,3-2H2]lactate, whereas metabolism through the PPP produces [3-13C,3,3-2H2]lactate and unlabeled lactate. The ratios of these lactate isotopomers can be quantified using gas chromatography/mass spectrometry (GC/MS) for calculation of PPP activity, which is reported as the percentage of glucose metabolized to lactate that passed through the PPP. Following addition of [1,6-13C2,6,6-2H2]glucose to the perfusate, labeled lactate was easily detectable in dialysate using GC/MS. Basal forebrain and intracerebral 9L glioma PPP values (mean +/- SD) were 3.5 +/- 0.4 (n = 4) and 6.2 +/- 0.9% (n = 4), respectively. Furthermore, PPP activity could be stimulated in vivo by addition of phenazine methosulfate, an artificial electron acceptor for NADPH, to the perfusion stream. These results show that the activity of the PPP can now be measured dynamically and regionally in the brains of conscious animals in vivo.

Animals↗

PubMed1994

The effects of methamphetamine and cocaine on motor behavior and extracellular dopamine in the ventral striatum of Lewis versus Fischer 344 rats.

The effects of an acute systemic injection of methamphetamine (mAMP) or cocaine (COC) on motor behavior (stereotypy, locomotor activity, and rearing) and extracellular dopamine (DA) in the ventral striatum were compared in Lewis (LEW) versus Fischer 344 (F344) rats, using in vivo microdialysis in awake freely moving animals. In addition, the behavioral response to repeated mAMP injections (i.e. sensitization) was characterized in LEW and F344 rats, as was the possibility of strain differences in drug pharmacokinetics. The major findings were: (i) LEW rats showed greater behavioral activation to an acute injection of both mAMP and COC, as indicated by a shift to the left in the dose-effect curves relative to F344 rats. (ii) LEW rats were more susceptible to mAMP sensitization. (iii) An acute injection of mAMP or COC enhanced the extracellular concentration of DA to a greater extent in LEW rats, as indicated by a significant shift to the left in the dose-effect curve relative to F344 rats. (iv) Strain differences in the behavioral and neurochemical effects of these drugs were characterized largely by differences in the duration of the drug response. (v) LEW rats had higher plasma and brain levels of mAMP and COC than F344 rats, suggesting that strain differences in pharmacokinetics may contribute to strain differences in the behavioral and neurochemical effects of these drugs.

Animals↗

PubMed1994

Withdrawal from morphine or amphetamine: different effects on dopamine in the ventral-medial striatum studied with microdialysis.

The effect of withdrawal from chronic morphine or amphetamine treatment on dopamine (DA) neurotransmission in the ventral-medial striatum was studied by use of in vivo microdialysis. There was no effect of 24 h of amphetamine withdrawal on the basal concentration of DA in the ventral-medial striatum. Spontaneous morphine withdrawal (24 h) was associated with a significant decrease in the basal concentration of DA in dialysate, but following morphine replacement and naloxone-precipitated withdrawal variations in withdrawal symptoms were not related to variations in the concentration of DA in dialysate. It is suggested that: (1) the correlation between the extracellular concentration of DA in the ventral-medial striatum and the symptoms of morphine withdrawal may not be indicative of a necessary, causal relationship; and (2) a decrease in the extracellular concentration of DA in the ventral-medial striatum is not a common feature of drug withdrawal syndromes.

Amphetamine↗

PubMed1994

Relationship between asymmetries in striatal dopamine release and the direction of amphetamine-induced rotation during the first week following a unilateral 6-OHDA lesion of the substantia nigra.

In animals with a large unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) system the traditional "rotational behavior model" states that amphetamine will induce circling behavior towards the denervated striatum (ipsiversive), that is, away from the side where there is greater amphetamine-stimulated DA release and greater DA receptor stimulation. It is puzzling, therefore, why amphetamine induces contraversive rotation in rats tested 4 days after a unilateral 6-OHDA lesion, despite a 90-95% loss of the dopaminergic input to the striatum by this time. Rats reverse their direction of amphetamine-induced rotation by 8 days post-lesion and turn in the ipsiversive direction thereafter. To try and resolve this paradox, bilateral striatal microdialysis was used to estimate the effects of amphetamine on DA neurotransmission on Day 4 and Day 8 following a large unilateral 6-OHDA lesion of the substantia nigra. On Day 4 post-lesion, amphetamine produced a moderate (around 50% of control) increase in the extracellular concentration of DA in the denervated striatum. This amphetamine-releasable pool of DA was exhausted by a single amphetamine-challenge, because a second injection of amphetamine given 3 h after the first did not produce a comparable increase in DA. It is suggested that on Day 4 post-lesion the amount of DA released by amphetamine in the denervated striatum is sufficient to produce greater DA receptor stimulation on that side, because of DA receptor supersensitivity, and this leads to contraversive rotation. On Day 8 post-lesion, amphetamine induced DA release in the intact striatum but had no effect on extracellular DA in the denervated striatum (DA was nondetectable). On Day 8, therefore, DA receptor stimulation would be greatest in the intact striatum, leading to ipsiversive rotation. In conclusion, it is suggested that the seemingly paradoxical reversal in the direction of amphetamine-induced rotation that occurs over the first week following a unilateral 6-OHDA lesion is consistent with the traditional rotational model, and is due to time-dependent changes in the ability of amphetamine to release DA in the denervated striatum.

Amphetamine↗

PubMed1994

Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis.

The relationship between circadian changes in spontaneous motor activity in rats and dopamine (DA) neurotransmission in the dorsal or ventral striatum was assessed with on-line in vivo microdialysis. The concentration of DA and DA metabolites in the dorsolateral caudate nucleus increased significantly at night. In contrast, DA in the nucleus accumbens did not change significantly across the light-dark cycle. The concentration of DA metabolites in the nucleus accumbens did show circadian variation, however, which was comparable with that seen in the dorsolateral caudate nucleus. Although there was a significant positive correlation between the concentration of DA in both the dorsal and ventral striatum and spontaneous nocturnal motor activity, the relationship was very weak, especially for the accumbens. This suggest that regulating the level of spontaneous motor activity per se is not a primary function of the mesostriatal DA system.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Time course of recovery of extracellular dopamine following partial damage to the nigrostriatal dopamine system.

Partial damage to the nigrostriatal dopamine (DA) system can produce severe behavioral deficits, from which animals gradually recover. Although the compensatory neuroadaptations that contribute to recovery of function have received considerable attention, the exact role of presynaptic versus postsynaptic contributions remains unclear. For example, it has been suggested that presynaptic adaptations may not be sufficient to account for recovery of function, because compensatory increases in DA biosynthesis, metabolism, and release are maximal within 3 d following a unilateral 6-hydroxydopamine (6-OHDA) lesion, before behavioral recovery is complete. The purpose of this study was to examine another presynaptic adaptation, the normalization of extracellular DA. If this is also complete within 3 d postlesion, it, too, would be insufficient to account for the protracted time course of behavioral recovery. But if the normalization of extracellular DA proceeds more gradually, it could potentially account for the time course behavioral recovery. To address this issue, the extracellular concentration of striatal DA ipsilateral and contralateral to a unilateral 6-OHDA lesion was estimated with microdialysis, either 4 d or 3-4 weeks following the lesion. After estimating the basal extracellular concentration of DA, the ability to increase DA release further was assessed by administering an amphetamine challenge. It was found that in animals with a 6-OHDA lesion, the concentration of DA in dialysate was higher than would be predicted by the extent of DA denervation. Furthermore, in groups matched for lesion size, extracellular DA was significantly higher 3-4 weeks following a 6-OHDA lesion than 4 d following the lesion. These findings suggest that the normalization of extracellular DA may be a relatively gradual process, and therefore may be sufficient to account for the protracted time course of behavioral recovery.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Basal extracellular dopamine in the nucleus accumbens during amphetamine withdrawal: a 'no net flux' microdialysis study.

The basal extracellular concentration of dopamine in the nucleus accumbens was quantified using the 'no net flux' microdialysis method, in rats undergoing withdrawal from D-amphetamine. Rats were initially pretreated with saline, or an escalating dose amphetamine regimen known to produce a robust withdrawal syndrome, and extracellular dopamine was quantified 3 or 28 days after the last pretreatment injection. There was no effect of amphetamine pretreatment on the basal extracellular concentration of dopamine in the nucleus accumbens, or on the 'in vivo recovery' of dopamine, estimated by 'no net flux' microdialysis. It is suggested that amphetamine withdrawal is not necessarily accompanied by changes in the basal extracellular concentration of dopamine in the nucleus accumbens.

Animals↗

PubMed1993

A microdialysis study of ventral striatal dopamine during sexual behavior in female Syrian hamsters.

Microdialysis was used to study the effects of exposure to a male hamster on extracellular concentrations of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in the ventral striatum of ovariectomized female Syrian hamsters pretreated with either estradiol and progesterone, or a similar regimen of oil injections. The hormone-treated females showed high levels of lordosis throughout the hour of exposure to the male. In hormone-treated females, there was a rapid elevation of dialysate dopamine within the first 15 min of exposure to the male. Dialysate dopamine gradually declined over the next 45 min, though remaining significantly above baseline during the entire period of exposure to the male. None of the oil-treated females showed any indication of lordosis, and the addition of the male produced only a small increase in dopamine at 30 min, after which dopamine returned to pre-male basal levels. DOPAC, HVA, and 5-HIAA were all elevated following introduction of the male for both groups of females. These results suggest that ovarian hormones modulate the responsivity of ventral striatal dopamine to incentive stimuli associated with mating behavior in females, although extracellular levels of dopamine in the ventral striatum do not seem to be directly coupled to the display of lordosis.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Effects of cortical serotonin depletion induced by 3,4-methylenedioxymethamphetamine (MDMA) on behavior, before and after additional cholinergic blockade.

Repeated treatment with high doses of 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") produces a long-lasting depletion of brain serotonin, presumably because of the degeneration of serotonin axon terminals. However, very little is known about the long-term behavioral consequences of MDMA neurotoxicity. The experiments reported here were designed to evaluate the effects of MDMA neurotoxicity on a number of behavioral tests known to be sensitive to neocortical and hippocampal damage. Also, the effect of additional cholinergic blockade in MDMA-pretreated rats was evaluated because loss of both the serotonergic and cholinergic inputs to the cortex produces a functional decortication and a behavioral syndrome reminiscent of human global dementia. Partial depletion of neocortical serotonin (72.6%) did not produce deficits on a variety of behavioral tests, including a place navigation learning-set task, skilled forelimb use, or the ability to make complex judgements regarding the stimulus properties of food in a foraging situation, and neither did additional cholinergic blockade. MDMA-pretreated rats had a mild impairment in rapidly developing an efficient search strategy in the place navigation task, but once the goal was located, MDMA pretreated rats performed at control levels and showed no deficits in memory for spatial location. It is concluded that the extent of serotonergic denervation produced by MDMA is not sufficient to produce marked and lasting behavioral deficits, possibly because of neurocompensatory changes in the remaining serotonin terminals.

3,4-Methylenedioxyamphetamine↗

PubMed1992

Recovery from lateralized neocortical damage: dissociation between amphetamine-induced asymmetry in behavior and striatal dopamine neurotransmission in vivo.

It has been hypothesized that neocortical damage is accompanied by secondary changes in other brain areas (the shock or diaschisis of von Monakow), which contributes to initial non-specific behavioral depression. The relation between behavioral changes and dopamine (DA), serotonin (5-HT), and their metabolites, measured with intracerebral microdialysis in freely moving rats and by tissue assay postmortem, was examined during postsurgical recovery from unilateral hemidecortications. Rats were tested for rotational asymmetry and extracellular concentration of DA was measured both during rest and after amphetamine (1.5 mg/kg). It was found that: (1) during the first few postsurgical days the hemidecorticate rats rotated ipsilateral to their lesions after amphetamine but thereafter on tests given up to 121 days postsurgery concentration of DA or its metabolites at any time after surgery; (3) the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was elevated acutely for a few days following surgery; (4) during the first 3 postoperative days, both baseline extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and amphetamine-induced DA release were significantly elevated bilaterally. These findings demonstrate that the acute behavioral asymmetry in rotation produced by hemidecortication is not related to unilateral changes in striatal DA activity and its metabolites. Thus, the behavioral asymmetries might be related to other striatal changes (i.e. 5-HIAA) or other damage, such as to the corticospinal projections of the lesioned hemisphere. Nevertheless, unilateral lesions did produce acute bilateral increases in DA levels, which may be a correlate of generalized neural shock produced by the lesion.

3,4-Dihydroxyphenylacetic Acid↗