Okay, i'm not really sure about the exact mechanisms at play in amp neurotoxiticy.
I think NR2(x) is referring to axon clipping which causes serious neurological problems.
However monoamine depletion is used as a measure for toxiticy, if this occurs in humans we would see a dramatic loss of effiacy in ADHD patients over time, wich usually doesnt occur because the D4 receptors dont downregulate.
Also i would "axon clipping" or any other damage expect to cause serieus neurological problems like you say but there arent any documented in the literature.
For example we know that antipsychotics cause tardive dyskinesia in 4% of all patients with long term use, and selling antipsychotics is big business so the argument that that would prevent long term side effects from being documented is nonsense.
Yet with amphetamine's we dont have any of those problems documented why? Is amphetamine supposed to be special were all long term side effects go unnoticed or something?
If you have a moment please review this: Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat
C. S. Lee**, H. Sauer*, † and A. Björklund
* Department of Medical Cell Research, University of Lund, Biskopsgatan 5, S-223 62, Lund, Sweden
** Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, Canada
Accepted 29 November 1995. ; Available online 2 March 1999.
6-Hydroxydopamine-induced nerve terminal lesion of the nigrostriatal system may provide a partial lesion model of Parkinson's disease useful for the assessment of neuroprotective treatments and behavioral recovery after therapeutic intervention. The aim of the present study was to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra and the associated behavioral and neurochemical consequences of intrastriatal injections of 6-hydroxydopamine in young adult rats. Four groups of rats were stereotaxically injected in the right striatum with graded doses of 6-hydroxydopamine ranging from 0 to 20 μg. Structural and functional deficits were quantified by tyrosine hydroxylase-immunoreactive nigral cell numbers, striatal dopamine content, skilled paw use, and drug-induced rotation. The results show that striatal 6-hydroxydopamine lesions produce dose-dependent decreases in striatal dopamine levels and tyrosine hydroxylase-immunoreactive cell numbers in the ipsilateral substantia nigra, accompanied by a significant long-lasting atrophy of the remaining dopaminergic neurons. Paw reaching test scores on the side contralateral to the lesion were non-linearly correlated with dopaminergic neuronal cell loss and exhibited a clear symptomatic threshold such that impaired paw use appeared only after > 50% loss of nigral dopamine neurons or a reduction of 60–80% of striatal dopamine levels. The behavioral, cellular, and neurochemical effects of the nerve terminal lesion thus bear some resemblance to the early stages of Parkinson's disease, where the severity of motor impairment is correlated with the loss of dopamine in the striatum and dopaminergic neuronal loss in the substantia nigra.
Rats with intrastriatal 6-hydroxydopamine lesions thus provide a model of progressive dopamine neuron degeneration useful not only for the exploration of neuroprotective therapeutic intervention but also for the study of mechanisms of functional and structural recovery after subtotal damage of the nigrostriatal dopamine system.
Author Keywords: substantia nigra; striatum; 6-hydroxydopamine; paw-reaching; degeneration; Parkinson's disease
Abbreviations: ANOVA, analysis of variance; DA, dopamine; DOPAC, 3,4-dihydroxyphenyl acetic acid; -IR, -immunoreactive; MTN, medial terminal nucleus of the accessory optic tract; NSS, normal swine serum; 6OHDA, 6-hydroxydopamine; PB, phosphate buffer; PD, Parkinson's disease; TH, tyrosine hydroxylase; VM, ventral mesencephalon