Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice

doi:10.1016/0014-2999(80)90351-9

European Journal of Pharmacology

Volume 65, Issue 4, 8 August 1980, Pages 439-443

https://doi.org/10.1016/0014-2999(80)90351-9 Get rights and content

Abstract

Continuous release of p-chloroamphetamine from subcutaneously implanted minipumps for 3 days decreased brain 5-hydroxytryptamine, but not norepintamine or dopamine, when analyzed 2 weeks later. In contrast, 2 weeks after infusion of amphetamine, whole brain dopamine but not 5-hydroxytryptamine or norepinephrine, was decreased. Also, the high affinity uptake of [³H]dopamine was markedly and selectively reduced in striatal synaptosomes. Thus, neurotoxicity is apparently not unique to halogenated amphetamine derivatives, but is produced by amphetamine itself if administered continuously.

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Vulnerabilities of ventral mesencephalic neurons projecting to the nucleus accumbens following infusions of 6-hydroxydopamine into the medial forebrain bundle in the rat
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Dopamine-containing projections to the human striatum, including the Acb, degenerate in Parkinson's disease [49,57], mesocorticolimbic dementia [47,51], psychostimulant drug abuse [31,55] and other kinds of poisoning [40,46]. In laboratory animals these fibers degenerated under a variety of experimental neurotoxic circumstances involving, e.g. 6-hydroxydopamine (6-OHDA), MPTP and psychostimulants [1,16,17,24,41,48,54,59]. Consistent with the complex chemical neuroanatomical organization of the dopaminergic mesostriatal innervation, non-uniform losses of dopaminergic mesostriatal fibers occur following administration of a number of neurotoxins [1,16,44,48,59].
The terminal arbors of dopaminergic projections in the nucleus accumbens (Acb) core degenerate more rapidly, completely and permanently in a variety of neurotoxic circumstances than do those in the medial shell. It is unknown if this always reflects purely losses of the distal parts of axons from the core (as proposed in methamphetamine intoxication), or whether, in some circumstances, the disproportionate loss of core axons may also stem from an intrinsic vulnerability to degeneration of core-projecting neuronal perikarya. Experiments described here addressed this issue in the following manner. Three days after Fluoro-Gold (FG), a retrogradely transported tracer, had been iontophoresed selectively into the core or medial shell of male Sprague–Dawley rats, each received an infusion of saline vehicle containing or lacking 6-hydroxydopamine (6-OHDA) in the ipsilateral medial forebrain bundle (MFB). Twenty-one days later the brains were processed to exhibit ventral mesencephalic neurons containing FG. Application of an unbiased sampling method revealed substantially greater losses of FG labeled neurons relative to controls in rats that had received 6-OHDA lesions and deposition of FG in the Acb core as compared to the medial shell. Of the few core-projecting neurons that remained in the ventral mesencephalon after these lesions, 54% did not co-localize tyrosine hydroxylase immunoreactivity (TH-ir) and, thus, were not expected to degenerate. The capacity to selectively remove core-projecting dopaminergic neurons may be useful in the determination of molecular correlates of vulnerability and resistance to neurotoxicity and to possibly test the role of the core in reinforcement paradigms.
Brain-derived neurotrophic factor rescues neuronal death induced by methamphetamine
2004, Biological Psychiatry
Citation Excerpt :
Given that Stumm et al (1999) have shown that amphetamine-induced apoptosis is accompanied by differential expression of anti- and proapoptotic Bcl-xL/S splice variants in cortical neurons (Stumm et al 1999), Akt might produce neuroprotective effect via regulation of Bcl-x splicing in MA-exposed cortical neuron. The MA-induced neurotoxicity on axon terminal arbors has been widely studied in animals (O'Callaghan and Miller 1994; Preston et al 1985; Ricaurte et al 1980; Steranka and Sanders-Bush 1980), nonhuman primates (Villemagne et al 1998), and humans (Sekine et al 2001; Wilson et al 1996). In contrast, only a few studies have focused on its toxic effects on neural cell bodies (Deng and Cadet 2000; Deng et al 1999, 2002).
Methamphetamine (MA) induces degeneration of various regions of the brain, resulting in neuropsychiatric damage. Although the underlying mechanisms of MA-induced neurotoxicity have been studied, there are few reports to date regarding the factor(s) that can effectively prevent MA-induced neurotoxicity. Because brain-derived neurotrophic factor (BDNF) has been known to prevent many kinds of neuronal cell death, we investigated whether BDNF inhibits MA-induced neuronal death.
Using primary cortical neurons, we examined the effect of BDNF on MA-induced neuronal death. In addition, using pharmacologic and molecular biological tools, we elucidated which pathways are involved in this effect.
Brain-derived neurotrophic factor dose-dependently blocked MA-induced neuronal death, and this effect was inhibited by phosphatidylinositol-3-kinase inhibitors. In addition, overexpression of activated Akt protects neurons against MA. Furthermore, expression of kinase-defective Akt blocked the effect of BDNF on MA-induced neuronal death.
Brain-derived neurotrophic factor effectively blocks MA-induced neuronal death, and Akt activation is necessary and sufficient for this effect.
Recovery from methamphetamine induced long-term nigrostriatal dopaminergic deficits without substantia nigra cell loss
2000, Brain Research
Citation Excerpt :
In this instance, the implicit supposition is that degeneration of striatal terminals occurred while indeterminate lengths of their remaining axons and corresponding cell bodies remained intact. In our previous METH studies in the vervet monkey [34–37], we showed that acute METH administration protocols (2 doses of 2 mg/kg; 4 h apart) produced striatal dopamine deficits similar to those previously characterized as long-term METH neurotoxicity in both rodents and non-human primates [37,51,52,58,61,65]. However, further characterization of those long-term METH effects with 6-[18F]fluoro-l-DOPA (FDOPA)-PET showed that an essentially complete recovery of DA synthesis capacity occurred over 8 months.
After administration of methamphetamine (METH) (2×2 mg/kg, 6 h apart) to vervet monkeys, long term but reversible dopaminergic deficits were observed in both in vivo and post-mortem studies. Longitudinal studies using positron emission tomography (PET) with the dopamine transporter (DAT)-binding ligand, [¹¹C]WIN 35,428 (WIN), were used to show decreases in striatal WIN binding of 80% at 1 week and only 10% at 1.5 years. A post-mortem characterization of other METH subjects at 1 month showed extensive decreases in immunoreactivity (IR) profiles of tyrosine hydroxylase (TH), DAT and vesicular monoamine transporter-2 (VMAT) in the striatum, medial forebrain bundle and the ventral midbrain dopamine (VMD) cell region. These IR deficits were not associated with a loss of VMD cell number when assessed at 1.5 years by stereological methods. Further, at 1.5 years, IR profiles of METH subjects throughout the nigrostriatal dopamine system appeared similar to controls although some regional deficits persisted. Collectively, the magnitude and extent of the dopaminergic deficits, and the subsequent recovery were not suggestive of extensive axonal degeneration followed by regeneration. Alternatively, this apparent reversibility of the METH-induced neuroadaptations may be related primarily to long-term decreases in expression of VMD-related proteins that recover over time.
Orphan neurones and amine excess: The functional neuropathology of Parkinsonism and neuropsychiatric disease
1998, Brain Research Reviews
The aetiology and treatment of Parkinsonism is currently conceptualised within a dopamine (DA) deficiency-repletion framework. Loss of striatal DA is thought to cause motor impairment of which tremor, bradykinaesia and rigidity are prominent features. Repletion of deficient DA should at least minimise parkinsonian signs and symptoms. In Section 2, based on extensive pre-clinical and clinical findings, the instability of this approach to Parkinsonism is scrutinised as the existing negative findings challenging the DA deficiency hypothesis are reviewed and reinterpreted. In Section 3it is suggested that Parkinsonism is due to a DA excess far from the striatum in the area of the posterior lateral hypothalamus (PLH) and the substantia nigra (SN). This unique area, around the diencephalon/mesencephalon border (DCMCB), is packed with many ascending and descending fibres which undergo functional transformation during degeneration, collectively labelled `orphan neurones'. These malformed cells remain functional resulting in pathological release of transmitter and perpetual neurotoxicity. Orphan neurone formation is commonly observed in the PLH of animals and in man exhibiting Parkinsonism. The mechanism by which orphan neurones impair motor function is analogous to that seen in the diseased human heart. From this perspective, to conceptualise orphan neurones at the DCMCB as `Time bombs in the brain' is neither fanciful nor unrealistic [E.M. Stricker, M.J. Zigmond, Comments on effects of nigro-striatal dopamine lesions, Appetite 5 (1984) 266–267] as the DA excess phenomenon demands a different therapeutic approach for the management of Parkinsonism. In Section 4the focus is on this novel concept of treatment strategies by concentrating on non-invasive, pharmacological and surgical modification of functional orphan neurones as they affect adjacent systems. The Orphan neurone/DA excess hypothesis permits a more comprehensive and defendable interpretation of the interrelationship between Parkinsonism and schizophrenia and other related disorders.
Amphetamine induces hydroxyl radical formation in the striatum of rats
1997, Life Sciences
Amphetamine-induced hydroxyl radical formation in the striatum of rats was investigated in this study. With the utilization of the microdialysis and HPLC-ECD, the striatal dopamine (DA) release and the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), derived from the reaction of hydroxyl radicals (·-OH) and salicylate in perfusion, were monitored and detected during desipramine and/or amphetamine (AMPH) administration. Our data revealed that after desipramine treatment AMPH injections not only amplified striatal DA release and 2,3-DHBA formation, but also intensified the stereotyped behaviors induced by AMPH. Furthermore, we discovered that α-methyl-para-tyrosine (α-MT) pretreatment prevented the onset of the above responses. In desipramine-treated rats, the tissue homogenization study demonstrated that a single dose of AMPH produced long-term depletion of striatal DA; this was not seen in saline-treated rats. Moreover, striatal DA depletion could be lessened by pretreatment with mannitol, a·.OH scavenger. These results indicate that AMPH-induced striatal.OH formation might be DA-related in desipramine-treated rats, and suggest that ·.OH formation might be correlated with AMPH-induced neurodegeneration.
Methamphetamine-induced hyperthermia in mice: Examination of dopamine depletion and heat-shock protein induction
1997, Brain Research
Methamphetamine (METH) is a common drug of abuse and a clinical anoretic which is known to cause neurotoxicity in rodents as evidenced by a depletion of dopamine (DA) and by decreased numbers of DA uptake sites in the striatum. It is also known to cause hyperthermia which is believed to induce the production of the 72-kDa heat-shock protein (HSP-72). In the present study, we evaluated whether METH induced the production of HSP-72 in both the mouse hippocampus and striatum and also attempted to correlate this induction with monoamine depletion. Adult male C57BL/6N mice received METH (20 mg/kg, i.p.) in an ambient temperature of 27°C and body temperatures were monitored up to 240 min after treatment. Animals were sacrificed 12, 18, 24, 39, and 48 h after treatment. One striatum was examined for DA, DOPAC, and HVA levels using HPLC–EC and the contralateral striatum, along with the hippocampus, was prepared for immunoblotting. HPLC–EC analysis revealed a significant depletion of DA, DOPAC, and HVA at all time points. There was, however, a significant increase in DA at 48 vs. 39 h. A biphasic production of HSP-72, in both the hippocampus and striatum, was detected by immunoblot. HSP-72 production was strong at 12 h which corresponds to neuronal induction. However, at 18 h in the striatum and 24 h in the hippocampus, the induction appears to be reduced. A second phase of HSP-72 induction occurred at 39 h in both regions. In a second experiment, mice were dosed according to the same paradigm and were perfused at 18 h after treatment for immunohistochemical analysis. HSP-72 immunoreactivity was found in neurons of the CA1 and CA4 regions of the hippocampus; however, no detectable response was evident in the striatum. In conclusion, these data demonstrate that a single injection of METH can lead to hyperthermia which may then result in both the induction of HSP-72 and depletion of DA concentration.

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^∗: Present address: Department of Pharmacology, Indiana University of, North West Cancer for Medical Education, 3400 Broadway, Gary, Indiana 46408, U.S.A.

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Short communicationLong-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice

Abstract

European J. Pharmacol.

Biochem. Pharmacol.

European.J. Pharmacol.

Biochem. Pharmacol.

Neuropharmacology

Short communication
Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice