I’ve been doing some research on amphetamine lately, and some studies seem to prove it has neuroprotective and neuroregenerative properties:
AbstractClinical improvements in Parkinson's disease produced by dopamine D3 receptor-preferring agonists have been related to their neuroprotective actions and, more recently, to their neuroregenerative properties. However, it is unclear whether dopamine agonists produce their neurotrophic effects by acting directly on receptors expressed by the mesencephalic dopaminergic neurons or indirectly on receptors expressed by astrocytes, via release of neurotrophic factors. In this study, we investigated the effects of the dopamine D3 receptor-preferring agonists quinpirole and 7-hydroxy-N,N-di-propyl-2-aminotetralin (7-OH-DPAT), as well as of the indirect agonist amphetamine, on dopaminergic neurons identified by tyrosine hydroxylase immunoreactivity (TH-IR). Experiments were performed on neuronal-enriched primary cultures containing less than 0.5% of astrocytes prepared from the mouse embryo mesencephalon. After 3 days of incubation, both quinpirole (1-10 microm) and 7-OH-DPAT (5-500 nm) dose-dependently increased the maximal dendrite length (P < 0.001), number of primary dendrites (P < 0.01) and [3H]dopamine uptake (P < 0.01) of TH-IR-positive mesencephalic neurons. Similar effects were observed with 10 microm amphetamine. All neurotrophic effects were blocked by the unselective D2/D3 receptor antagonist sulpiride (5 microm) and by the selective D3 receptor antagonist SB-277011-A at a low dose (50 nm). Quinpirole and 7-OH-DPAT also increased the phosphorylation of extracellular signal-regulated kinase (ERK) within minutes, an effect blocked by pretreatment with SB-277011-A. Inhibition of the D2/D3 receptor signalling pathway to ERK was obtained with PD98059, GF109203 or LY294002, resulting in blockade of neurotrophic effects. These data suggest that dopamine agonists increase dendritic arborizations of mesencephalic dopaminergic neurons via a direct effect on D2/D3 receptors, preferentially involving D3 receptor-dependent neurotransmission.
Source: http://www.ncbi.nlm.nih.gov/pubmed/18973551
One study stated that D-amphetamine promoted neurogenesis in the hippocampus when administered from early childhood to adulthood in rats:
AbstractAdderall is widely prescribed for attention deficit hyperactivity disorder (ADHD) though long term neurological effects of the main ingredient d-amphetamine are not well understood. The purpose of this study was to examine effects of clinically prescribed doses of d-amphetamine and one abuse dose administered from childhood to adulthood on adult hippocampal neurogenesis and activation of the granule layer of the dentate gyrus. Beginning in early adolescence (age 28 days) to adulthood (age 71), male C57BL/6J mice were administered twice daily i.p. injections of vehicle, 0.25, 0.5 or 2mg/kg d-amphetamine. Locomotor activity was measured in home cages by video tracking. At age 53-56, mice received bromodeoxyuridine (BrdU) injections to label dividing cells. Immunohistochemical detection of BrdU, neuronal nuclear protein (NeuN), doublecortin (DCX) and Ki67 was used to measure neurogenesis and cell proliferation at age 71. ΔFosB was measured as an indicator of repeated neuronal activation. An additional cohort of mice was treated similarly except euthanized at age 58 to measure activation of granule neurons from d-amphetamine (by detection of c-Fos) and cell proliferation (Ki67) at a time when the fate of BrdU cells would have been determined in the first cohort. d-Amphetamine dose-dependently increased survival and differentiation of BrdU cells into neurons and increased number of DCX cells without affecting the number of Ki67 cells. Low doses of d-amphetamine decreased c-Fos and ΔFosB in the granule layer. Only the high dose induced substantial locomotor stimulation and sensitization. Results suggest both therapeutic and abuse doses of d-amphetamine increase the number of new neurons in the hippocampus when administered from adolescence to adulthood by increasing survival and differentiation of cells into neurons not by increasing progenitor cell proliferation. Mechanisms for amphetamine-induced neurogenesis are unknown but appear activity independent. Results suggest part of the beneficial effects of therapeutic doses of d-amphetamine for ADHD could be via increased hippocampal neurogenesis.
Source: http://www.ncbi.nlm.nih.gov/pubmed/23178911
Amphetamine’s effect on BDNF and NGF seems to be varied. For example, multiple studies show that amphetamine acutely increases BDNF and NGF expression:
AbstractPrior work has shown that d-amphetamine (AMPH) treatment or voluntary exercise improves cognitive functions after traumatic brain injury (TBI). In addition, voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF). The current study was conducted to determine how AMPH and exercise treatments, either alone or in combination, affect molecular events that may underlie recovery following controlled cortical impact (CCI) injury in rats. We also determined if these treatments reduced injury-induced oxidative stress. Following a CCI or sham injury, rats received AMPH (1 mg/kg/day) or saline treatment via an ALZET pump and were housed with or without access to a running wheel for 7 days. CCI rats ran significantly less than sham controls, but exercise level was not altered by drug treatment. On day 7 the hippocampus ipsilateral to injury was harvested and BDNF, synapsin I and phosphorylated (P) -synapsin I proteins were quantified. Exercise or AMPH alone significantly increased BDNF protein in sham and CCI rats, but this effect was lost with the combined treatment. In sham-injured rats synapsin I increased significantly after AMPH or exercise, but did not increase after combined treatment. Synapsin levels, including the P-synapsin/total synapsin ratio, were reduced from sham controls in the saline-treated CCI groups, with or without exercise. AMPH treatment significantly increased the P-synapsin/total synapsin ratio after CCI, an effect that was attenuated by combining AMPH with exercise. Exercise or AMPH treatment alone significantly decreased hippocampal carbonyl groups on oxidized proteins in the CCI rats, compared with saline-treated sedentary counterparts, but this reduction in a marker of oxidative stress was not found with the combination of exercise and AMPH treatment. These results indicate that, whereas exercise or AMPH treatment alone may induce plasticity and reduce oxidative stress after TBI, combining these treatments may cancel each other's therapeutic effects.
Source: http://www.ncbi.nlm.nih.gov/pubmed/18479829
AbstractBehavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague-Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.
Source: http://www.ncbi.nlm....pubmed/21570990
Abstract
Exposure to psychostimulants increases brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the cerebral cortex and subcortical structures. Because BDNF is co-localized with dopamine and glutamate in afferents to the striatum of rats, it may be co-released with those neurotransmitters upon stimulation. Further, there may be an interaction between the intracellular signaling cascades activated by dopamine, glutamate, and TrkB receptors in medium spiny striatal neurons. In the present study, the effect of acute amphetamine administration on TrkB phosphorylation, as an indirect indicator of activation, and striatal gene expression, was evaluated. In Experiment 1, 15 min or 2 h after a single saline or amphetamine (2.5 mg/kg, i.p.) injection, the caudate-putamen (CPu), nucleus accumbens (NAc), and dorsomedial prefrontal cortex (dmPFC) were extracted and processed for phospho (p)-TrkB immunoreactivity. Immunoprecipitation analyses indicated that neither the tyrosine phosphorylation (p-Tyr) or autophosphorylation sites of TrkB (706) were changed in NAc, CPu, or dmPFC 15 min after amphetamine administration. In contrast, p-Tyr and the PLCγ phosphorylation site of TrkB (816) were increased in the NAc and CPu 2 h after amphetamine. In Experiment 2, intra-striatal infusion of the tyrosine kinase inhibitor, K252a, increased amphetamine-induced vertical activity but not total distance traveled. In addition, K252a inhibited amphetamine-induced preprodynorphin, but not preproenkephalin, mRNA expression in the striatum. These data indicate that acute amphetamine administration induces p-TrkB activation and signaling in a time- and brain region-dependent manner and that TrkB/BDNF signaling plays an important role in amphetamine-induced behavior and striatal gene expression.
Yet some studies show the opposite, with this one showing chronic treatment reduces BDNF and NGF:
AbstractAmphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.
Additionally, some studies demonstrate reduced DAT and VMAT2:
Two to 4 weeks after cessation of treatment, the first group of baboons (n = 3) that had self-administered escalating doses of the 3:1 mixture of dextro [S(+)]- and levo [R(–)]-amphetamine twice daily for approximately 4 weeks showed significant reductions in striatal dopamine concentration, the density of [3H]WIN 35,428-labeled DAT sites, the amount of DAT protein and the number of [3H]DTBZ-labeled VMAT2 sites; quantitative autoradiographic studies showed that the regional density of [125I]RTI-121-labeled DAT sites was comparably reduced (Fig. 1). A closer examination of regional monoamine data revealed lasting dopaminergic deficits in the caudate nucleus and putamen of comparable magnitude (44–47% depletions), although smaller, but significant, deficits (approximately 30%) were also evident in the nucleus accumbens
But perhaps this doesn’t necessarily signify neurotoxicity? I’m not too familiar with this, so correct me if i’m wrong, but doesn’t activation of TAAR1 cause dopamine transporters to internalize temporarily? This would explain why the DAT protein densities seem lower, because some of the DATs have internalized and will resurface eventually, not because they have been damaged.
Dopamine deficits could be explained by dopamine depletion and downregulation of Tyrosine hydroxylase, but is that indicative of neurotoxicity? I’m not entirely sure of some of these details, so if someone who is more knowledgeable than me on this topic, please clear up any misconceptions I may have.
If amphetamine is neurotoxic, perhaps its neuroprotective effects are similar to the antioxidant/prooxidant paradox. In this paradox, prooxidants increase lifespan:
More recently, Siegfried Hekimi, a biologist at McGill University, has bred roundworms that overproduce a specific free radical known as superoxide. “I thought they were going to help us prove the theory that oxidative stress causes aging,” says Hekimi, who had predicted that the worms would die young. Instead he reported in a 2010 paper in PLOS Biology that the engineered worms did not develop high levels of oxidative damage and that they lived, on average, 32 percent longer than normal worms. Indeed, treating these genetically modified worms with the antioxidant vitamin C prevented this increase in life span. Hekimi speculates that superoxide acts not as a destructive molecule but as a protective signal in the worms’ bodies, turning up the expression of genes that help to repair cellular damage. In a follow-up experiment, Hekimi exposed normal worms, from birth, to low levels of a common weed-controlling herbicide that initiates free radical production in animals as well as plants. In the same 2010 paper he reported the counterintuitive result: the toxin-bathed worms lived 58 percent longer than untreated worms. Again, feeding the worms antioxidants quenched the toxin’s beneficial effects.
Source: http://www.ucl.ac.uk/~ucbtdag/Wenner_2013.pdf
So if amphetamine is damaging, perhaps that conditions the human brain to upregulate neuroprotective and neuroregenerative mechanisms, thus leading to a net long term neuroprotective effect instead of a neurotoxic one?
Any and all opinions are welcome as this has been confusing me for quite some time.
