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M H Joseph

Publications and source records attributed to M H Joseph.

At least 37 records · Page 2Linked to original sources
PubMed1993

Latent inhibition of conditioned dopamine release in rat nucleus accumbens.

Classical conditioning both to rewarding and to aversive stimuli is sensitive to drugs which act on the dopaminergic system: amphetamine enhances conditioning and neuroleptics attenuate it. Many lines of evidence point to the nucleus accumbens as being part of an anatomical substrate for reward. We have examined the release of dopamine in the nucleus accumbens during classical aversive conditioning using microdialysis in the unrestrained rat. Two mild footshocks caused a release of dopamine, which was potentiated when each footshock was immediately preceded by a novel tone or light stimulus. Presentation of either of these stimuli after conditioning elicited an increase in dopamine, only to that stimulus which had been conditioned; presentation of either stimulus after footshock alone without conditioning produced no dopamine response. Latent inhibition is a process whereby pre-exposure to a stimulus without consequence impairs learning about that stimulus at subsequent conditioning. This process too is believed to be under the control of dopaminergic systems, particularly in nucleus accumbens. Pre-exposure to the tone stimulus both markedly attenuated the potentiation of dopamine release at conditioning and abolished the conditioned release of dopamine at subsequent tone presentation. This is the first report of direct measurement of potentiated dopamine release during conditioning, and may provide a neurochemical basis for the effects of dopaminergic drugs on conditioning and latent inhibition. The results also support the hypothesis that disrupted latent inhibition in schizophrenia reflects increased mesolimbic dopamine function.

Acoustic Stimulation↗
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↗
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

Effects of chronic and subchronic nicotine on tyrosine hydroxylase activity in noradrenergic and dopaminergic neurones in the rat brain.

Chronic nicotine (0.8 mg/kg by daily subcutaneous injection) over a 7 to 28-day period was found to increase the activity of tyrosine hydroxylase in predominantly noradrenergically innervated regions but not in dopaminergic projection areas. Increases in tyrosine hydroxylase activity were observed in dopaminergic cell body regions only after nicotine treatment for 3 to 5 days. The increase in tyrosine hydroxylase activity in noradrenergic neurones was evident first in the cell bodies in the locus coeruleus from 3 to 7 days, reaching 223% of control activities, and was followed by increases of up to 205% in the terminals up to 3 weeks later. It was then established that nicotine for 7 days was sufficient to increase the activity of the enzyme to the same extent in the terminals at 21 days even without further nicotine administration. This is consistent with axonal transport preceded by induction of the enzyme in noradrenergic cell bodies, whereas "delayed activation" might account for the transient effect seen in dopaminergic cell body regions. The response in the locus coeruleus to nicotine for 7 days was completely blocked by daily preinjection with mecamylamine but not with hexamethonium, which is consistent with the effect of nicotine on tyrosine hydroxylase being mediated by central nicotinic receptors.

Animals↗
PubMed1990

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen.

Using in vivo dialysis and voltammetry, the effect of acute administration of (-)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxy-indoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrate-anaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4-dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate. These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Lever pressing for food reward and changes in dopamine turnover and uric acid in rat caudate and nucleus accumbens studied chronically by in vivo voltammetry.

The neurotransmitter dopamine (DA) is widely held to be involved in the maintenance of positively reinforced behaviour, on the basis of self-stimulation experiments and of the effects of drugs which alter DA transmission on self-stimulation, and on behaviours controlled by natural reinforcers. We have used the technique of linear sweep voltammetry at chronically implanted carbon paste electrodes to demonstrate that 30-min sessions of responding on a variable interval schedule for food pellet reward increases first uric acid and then homovanillic acid (HVA, the DA metabolite) in rat caudate. Ascorbic acid levels are reduced, but at later times. We have now established that very similar responses in magnitude and timing are seen in the nucleus accumbens. Furthermore, in individual animals, the response rates, the increases in dopamine turnover, and the changes in uric acid and ascorbic acid remain stable when studied periodically over a 3 month period. Our previous results are broadly consistent with those obtained by others using indirect single-point methods (ex vivo neurochemistry) or in vivo dialysis. However, our present extended observations made possible by the use of paste electrodes (rather than fibre electrodes or dialysis probes) open the possibilities of studying the evolution of neurochemical responses during learning, and the covariation of neurochemical and behavioural effects of drugs within individual animals.

Animals↗
PubMed1989

Regionally specific effects of acute and chronic nicotine on rates of catecholamine and 5-hydroxytryptamine synthesis in rat brain.

Acute (-)-nicotine administration (0.4 and 0.8 mg/kg s.c.) produced a regionally specific increase in the rate of catecholamine synthesis in the rat nucleus accumbens, hypothalamus and hippocampus but not elsewhere, including the caudate-putamen. In all regions rates of 5-hydroxytryptamine synthesis were unaffected. (-)-Cotinine (0.4 and 0.8 mg/kg), the major metabolite of (-)-nicotine was without effect. (-)-Nicotine-induced increase in catecholamine synthesis occurred by a direct stimulation of central nicotinic receptors, as mecamylamine (5 mg/kg) but not hexamethonium (5 mg/kg) was an effective antagonist. Following repeated daily injections of (-)-nicotine (0.8 mg/kg) for up to 28 days, the induced catecholamine response following a subsequent challenge was unaffected in the nucleus accumbens and hypothalamus, but was increased in the hippocampus. This effect persisted for up to 14 days following withdrawal. Rates of 5-hydroxytryptamine synthesis remained unaltered after chronic pretreatment.

Animals↗
PubMed1989

The effects of kynurenic acid, quinolinic acid and other metabolites of tryptophan on the development of the high pressure neurological syndrome in the rat.

The effects of some biologically active metabolites of tryptophan on the high pressure neurological syndrome (HPNS) were studied. Kynurenic acid, quinolinic acid, 5-hydroxytryptophan, kynurenine and 3-hydroxyanthranilic acid, at doses within the physiological range, were administered exogenously to rats prior to exposure to increased pressure and any effects on the tremor, myoclonus and convulsion end points of the high pressure neurological syndrome were observed. Quinolinic acid (25 and 50 mg/kg) and kynurenine (50 mg/kg) reduced the onset pressure for tremor, but not myoclonus or convulsions. Kynurenic acid (100 mg/kg) increased tremor onset pressure; 5-hydroxytryptophan (20 mg/kg) slightly increased onset pressure for tremor but decreased that for myoclonus. 3-Hydroxyanthranilic acid (20 mg/kg) had no significant effect on any of the motor signs of the syndrome. These data provide further support for the idea that the motor events seen in the high pressure neurological syndrome are not produced by a single mechanism. Differences between the responses to related metabolites suggest that the precise balance between compounds such as kynurenic acid and quinolinic acid may be important in the appearance of the high pressure neurological syndrome.

Animals↗
PubMed1989

Lever pressing for food reward and in vivo voltammetry: evidence for increases in extracellular homovanillic acid, the dopamine metabolite, and uric acid in the rat caudate nucleus.

Linear sweep voltammetry at chronically implanted carbon paste electrodes was used to study extracellular levels of homovanillic acid, a metabolite of dopamine, in the caudate nucleus of freely moving rats. Local infusion of homovanillic acid close to the electrode confirmed that peak 3, at about 550 mV, could be used for this purpose. Thirty minutes of lever pressing for food reward was followed by an increase in homovanillic acid, maximal about 30 min later (+42%). An earlier and larger (+51%) increase in peak 2 (350-400 mV) was seen, highly correlated (r = 0.98) with the rate of lever pressing across individuals. A smaller decrease (-23%) in peak 1 (200 mV; ascorbic acid) was seen 75 min after the behavioural session. Administration of allopurinol, an inhibitor of uric acid production, selectively abolished peak 2. Allopurinol prior to lever pressing reduced the increase in peak 2 very substantially (by 77%), confirming that this too was mainly due to uric acid. These results indicate that linear sweep voltammetry can be used to study the time course of changes in dopamine metabolism, and in other neurochemicals, in individual freely moving rats in relation to behaviour under experimental control. More specifically, they demonstrate directly that rewarded lever pressing increases dopamine metabolism in the caudate, which had previously only been inferred from indirect approaches. The level of uric acid is also increased, and it is suggested that this may serve as an index of metabolic activity.

Allopurinol↗
PubMed1985

MHPG excretion in endogenous depression: relationship to clinical state and the effects of ECT.

In a group of 70 patients with endogenous depression entering a controlled trial of real versus sham ECT, urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion was significantly reduced by comparison with previously studied groups of control subjects, of acute and chronic schizophrenic patients and of anxious patients. However, urinary MHPG was unrelated to severity of depression, or to the presence of delusions, retardation or agitation. MHPG excretion did not predict clinical outcome, or the response to ECT. Urinary MHPG content at trial entry was unrelated to past tricyclic antidepressant or benzodiazepine medication, although an influence of the latter on the findings cannot be excluded, since all patients received benzodiazepine (nitrazepam) night sedation during the trial. During the 4-week trial MHPG excretion remained low and did not increase in relation to change in clinical state, although there was a small but significant increase in patients who received real ECT. The findings confirm that urinary MHPG excretion is reduced in depression, but establish that such reductions are not state dependent. Since the increase in MHPG excretion with ECT is not related to changes in clinical state, the former presumably does not reflect the mechanism of action of ECT.

Adult↗
PubMed1984

Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides.

In patients with Alzheimer-type dementia, in addition to the well-known losses of cholinergic neurones, there is evidence of degeneration of the noradrenergic and serotonergic innervation of the cerebral cortex. While noradrenergic and cholinergic receptors are preserved there is a loss of serotonin S1 and S2 receptors, particularly in the temporal lobe. The loss of serotonin S2 receptors may occur at an early stage of the disease and, in temporal and frontal cortex, is correlated with the loss of somatostatin immunoreactivity. In patients dying in hospital with depression, and in individuals committing suicide, there are no consistent changes in monoamine metabolites. Noradrenergic, serotonergic, and other neurotransmitter receptors were found to be unchanged, although there was a moderate decrease in imipramine binding in a small group (n = 6) of subjects with a history of depression, who had committed suicide.

Aged↗
PubMed1983

Electrochemical activity of o-phthalaldehyde-mercaptoethanol derivatives of amino acids. Application to high-performance liquid chromatographic determination of amino acids in plasma and other biological materials.

o-Phthalaldehyde-mercaptoethanol (OPA) reagent is used to increase the sensitivity of post-column detection of amino acids after chromatographic separation. OPA-amino acids themselves chromatograph well on reversed-phase high-performance liquid chromatographic (HPLC) columns and can be determined by fluorimetric detection, enabling OPA to be used as a pre-column derivatisation reagent. In this paper electrochemical detection (in the 0.4-0.7 V range) of OPA-amino acids following reversed-phase HPLC is described. Using fluorimetric and electrochemical detection in series, confirmation of the identities of the amino acids can be obtained in a single chromatographic run. Particular amino acids (e.g. basic amino acids) are active at the lower potentials, so that they can be selectively detected if required. Other amino acids and peptides whose OPA derivatives have little or no fluorescent activity are electroactive, permitting their detection by HPLC of their OPA derivatives. Application of this methodology to divers biological samples is illustrated. OPA derivatisation of amines is an example of a reaction in which the product is electroactive at a lower potential than the reactants. This type of reaction is likely to be particularly useful in extending the applications of electrochemical detection in HPLC.

Aldehydes↗