d‐Amphetamine in Elderly Patients Refractory to Rehabilitation Procedures

Clark, A. N. G.; Mankikar, G. D.

doi:10.1111/j.1532-5415.1979.tb06442.x

Cited by 50 publications

(11 citation statements)

References 8 publications

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“…Likewise, these individuals would be expected to exhibit a diminished responsiveness to drugs that normally interact with the DA transporter, such as the psychostimulants amphetamine, methylphenidate, and cocaine. In fact, the age-related loss of psychostimulant efficacy in individuals >60 yr old has been repeatedly documented (32)(33)(34)(35)(36)(37). Clearly, further studies are necessary to elucidate the mechanism(s) underlying the age-related loss of human DA transporter mRNA, the relationship between transporter mRNA in the substantia nigra and DA transporter protein levels in DA nerve terminals, and the functional consequences of altered DA transporter gene expression for DA neurons and their target cells.…”

Section: Discussionmentioning

confidence: 99%

Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.

Bannon

Poosch

Xia

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

155

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The dopamine transporter is the primary means of inactivating synaptic dopamine as well as a major site of action for psychostimulants (such as cocaine and amphetamine) and for neurotoxins that induce parkinsonism. In the present study, a human dopamine transporter partial cDNA clone obtained by polymerase chain reaction exhibited 87% and 89% identity at the nucleic acid and amino acid levels, respectively, with transmembrane domains 3-5 of the rat homolog. This clone was used to quantitate human dopamine transporter mRNA by nuclease protection assay. The postmortem content of dopamine transporter mRNA in the substantia nigrae of 18-to 57-yr-old subjects was relatively constant, while in subjects >57 yr old, a precipitous (>95%) decline in substantia nigra dopamine transporter mRNA was evident. In contrast, tyrosine hydroxylase mRNA in the same samples declined in a linear manner with increasing age. In situ hybridization experiments confirmed the profound loss of dopamine transporter gene expression in melanin-positive (presumptive dopamine) nigral neurons. These data may begin to shed light on compensatory changes occurring in human dopamine neurons during normal aging.The actions of many neurotransmitters are terminated by rapid reuptake into presynaptic nerve endings via neurotransmitter-specific, high-affinity, Na+-dependent membrane transporter proteins. The transporter for the neurotransmitter dopamine (DA) is apparently the receptor through which psychostimulants such as cocaine and amphetamine exert their potent reinforcing properties, leading to psychostimulant abuse and dependence (1). In addition, the DA transporter mediates the active accumulation of neurotoxins such as 1-methyl-4-phenylpyridine into DA neurons (2, 3), resulting in DA cell death and a parkinsonian syndrome. Thus, understanding the regulation of human DA transporter gene expression is an important step toward elucidation of the molecular bases of psychostimulant drug abuse and of neurotoxin-induced (and quite possibly idiopathic) parkinsonism.Ligand binding to the human DA transporter decreases with age (4, 5), in keeping with other evidence for an age-related loss of DA neurons (6). Nevertheless, surprisingly little is known about the nature of normal age-related changes in human DA neurons, a process apparently distinct from the neuronal changes seen in Parkinson disease (6, 7). In the present study, a human DA transporter cDNA clone was obtained by polymerase chain reaction, exploiting predicted sequence homology with the recently cloned, functionally related human norepinephrine transporter (8). With the use of this clone, a precipitous, age-related loss of DA transporter mRNA was observed in human substantia nigra, while tyrosine hydroxylase mRNA, another phenotypic marker of DA neurons, decreased more linearly with age. These data may shed light on some compensatory changes occurring in human DA neurons during the normal aging process. MATERIALS AND METHODSHuman substantia nigrae used for biochemical analyses (n = 36) w...

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Section: Discussionmentioning

confidence: 99%

Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.

Bannon

Poosch

Xia

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

155

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“…M. Meyer & D. R. Meyer, 1982). In one uncontrolled study, AMP enhanced recovery when given to geriatric patients (some with stroke) refractory to rehabilitation, and, significantly, the recovery endured after discontinuation of AMP (Clark & Mankikar, 1979). Two case reports also describe AMPinduced behavioral improvement after trauma (Bugiani & Gatti, 1980;Lipper & Tuchman, 1976).…”

Section: Discussionmentioning

confidence: 99%

The locus coeruleus and cerebral metabolism: Recovery of function after cortical injury

et al. 1985

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Cerebral metabolic effects of locus coeruleus (LC) lesion or drugs affecting LC were investigated after unilateral injury of sensorimotor cortex in rats. Sensoriomotor cortex ablation produced a widespread depression of cerebral 14C-2-deoxyglucose utilization which was reversed by amphetamine (AMP, 2 mg/kg) and worsened by haloperidol (HAL, 0.4 mg/kg). Lesion of LC alone did not affect cerebral oxidative metabolism, measured by a stain for the enzyme alphaglycerophosphate dehydrogenase (a-GPDH). Lesion of LC prior to undercut laceration of motor cortex shortened time to onset of a-GPDH cortical paling. Treatment with AMP (2 mg/kg) blocked cortical paling ofthe enzyme stain at 4 days postinjury, an effect prevented by concomitant HAL (0.3 or 0.6 mg/kg). Apomorphine (1 mg/kg) did not block cortical paling. These data parallel effects of these drugs on recovery of function. The results suggest that a metabolic "remote functional depression" (RFD) is alleviated by catecholamine activation after cortical injury, whereas onset of RFD is accelerated by LC lesions and exacerbated by catecholamine blockade.The locus coeruleus (LC) may have an important role in neuronal development and plasticity (Felton, Hallman,

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“…Although animal models obviously cannot directly study aphasia, they may be very informative in constraining the necessary human trials that could ultimately lead to improved recovery from aphasia. Amphetamine has been studied with animals and subsequently led to clinical trials with humans (Clark & Mankikar, 1979). Other drugs, such as tPA or Nimodipine have recently moved from laboratory to clinical trials (American Nimodipine Study Group, 1992;Feeney, 1997;Fischer, 1997).…”

Section: Differences Between Human and Animal Studiesmentioning

confidence: 98%