Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers

doi:10.1016/0006-8993(84)91221-6

Brain Research

Volume 303, Issue 2, 15 June 1984, Pages 359-364

https://doi.org/10.1016/0006-8993(84)91221-6 Get rights and content

Abstract

Methamphetamine and amphetamine were continuously administered to rats for 3 days by means of subcutaneously implanted osmotic minipumps. The total daily dose of each drug was approximately 4 mg/day. Dopamine, norepinephrine and serotonin determinations two weeks later indicated that both amphetamines produced a selective striatal dopamine depletion. Anatomical studies indicated that this depletion was associated with striatal nerve fiber degeneration. To determine whether this fiber degeneration induced by amphetamines was dopaminergic, the long-lasting dopamine depletion produced by methamphetamine was antagonized with α-methyl-para-tyrosine. This prevented the appearance of nerve fiber degeneration after methamphetamine. These findings suggest that amphetamines produce a long-term striatal dopamine depletion by destroying striatal dopamine nerve fibers.

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Methamphetamine (MA) is an addictive drug with neurotoxic effects on the brain producing cognitive impairment and increasing the risk for neurodegenerative disease. Research has focused largely on examining the neurochemical and behavioral deficits induced by injecting relatively high doses of MA [30 mg/kg of body weight (bw)] identifying the upper limits of MA-induced neurotoxicity. Accordingly, we have developed an appetitive mouse model of voluntary oral MA administration (VOMA) based on the consumption of a palatable sweetened oatmeal mash containing a known amount of MA. This VOMA model is useful for determining the lower limits necessary to produce neurotoxicity in the short-term and long-term as it progresses over time. We show that mice consumed on average 1.743 mg/kg bw/hour during 3 hours, and an average of 5.23 mg/kg bw/day over 28 consecutive days on a VOMA schedule. Since this consumption rate is much lower than the neurotoxic doses typically injected, we assessed the effects of long-term chronic VOMA on both spatial memory performance and on the levels of neurotoxicity in the hippocampus. Following 28 days of VOMA, mice exhibited a significant deficit in short-term spatial working memory and spatial reference learning on the radial 8-arm maze (RAM) compared to controls. This was accompanied by a significant decrease in memory markers protein kinase Mzeta (PKMζ), calcium impermeable AMPA receptor subunit GluA2, and the post-synaptic density 95 (PSD-95) protein in the hippocampus. Compared to controls, the VOMA paradigm also induced decreases in hippocampal levels of dopamine transporter (DAT) and tyrosine hydroxylase (TH), as well as increases in dopamine 1 receptor (D1R), glial fibrillary acidic protein (GFAP) and cyclooxygenase-2 (COX-2), with a decrease in prostaglandins E2 (PGE2) and D2 (PGD2). These results demonstrate that chronic VOMA reaching 146 mg/kg bw/28d induces significant hippocampal neurotoxicity. Future studies will evaluate the progression of this neurotoxic state.
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Citation Excerpt :
Successful behavioural inhibition relies principally on dopaminergic and serotonergic prefrontal-subcortical pathways (for a review, see Jentsch and Pennington, 2014), and behavioural inhibition in the stop-signal task is associated with dopamine release in the prefrontal inhibitory control network (Albrecht et al., 2014). Acute administration of stimulant drugs is associated with increased availability of dopamine (either by stimulating their release or inhibiting reuptake; Goldstein and Volkow, 2002; Everitt and Robbins, 2005), and chronic administration results in long-term damage (Ricaurte et al., 1984; Volkow et al., 2001; Wang et al., 2004). Thus, the strong deficits observed for most stimulants is likely due to the damage caused by chronic administration of dopaminergic drugs and the key role that dopamine, and dopaminergic areas of brain, play in behavioural inhibition.
Deficits in behavioural inhibitory control are attracting increasing attention as a factor behind the development and maintenance of substance dependence. However, evidence for such a deficit is varied in the literature. Here, we synthesised published results to determine whether inhibitory ability is reliably impaired in substance users compared to controls.
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Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers

Abstract

Brain Research

Life Sci.

Neurosci. Lett.

Neuropharmacology

Brain Research

Brain Research

Europ. J. Pharmacol.

Brain Research

The metabolism of14C methamphetamine in man, the guinea pig and the rat

Biochem. J.

Long-term changes in dopaminergic innervation of caudate nucleus after continuous amphetamine administration

Science

The metabolism of¹⁴C methamphetamine in man, the guinea pig and the rat