Immunocytochemical evidence for methamphetamine‐induced serotonergic axon loss in the rat brain

Abstract

Central serotonin (5-HT) axons were visualized by immunocytochemistry to assess both acute and long-lasting changes in innervation density following methamphetamine administration to rats. Two morphologically distinct subtypes of 5-HT axons (fine and beaded) were differentially affected by d-methamphetamine (d-MA); the density of fine serotonergic axons was selectively decreased both 4 hours and 2 weeks after administration of d-MA. Acute depletion of 5-HT from fine axons, but not from beaded axons, was observed in the brains of all rats treated 4 hours previously with either a 100 mg/kg or 15 mg/kg dose of d-MA. Persistent loss of 5-HT axons was observed in 30% of rats treated 1 or 2 weeks previously with doses of d-MA which produce long-term deficits in biochemical markers for 5-HT. In the fraction of animals that exhibited denervation, fine serotonergic fibers were selectively ablated by d-MA, but beaded serotonergic fibers were spared. Thus, d-MA is similar to other amphetamine derivatives (e.g., p-chloroamphetamine, 3,4-methylenedioxyamphetamine) in that it acts selectively upon a morphologically distinct class of 5-HT axons but differs in that it produces long-lasting axon loss in only a fraction of animals. These data provide morphologic evidence of 5-HT axon loss following methamphetamine administration and further confirm the differential vulnerability of a particular morphological subtype of serotonergic axons to the neurotoxic effects of substituted amphetamines.

Impaired Object Recognition Memory Following Methamphetamine, but not p-Chloroamphetamine- or d-Amphetamine-Induced Neurotoxicity

“…In sufficient doses, mAMPH causes long-term damage to DA terminals in the striatum and to forebrain 5-HT terminals, as evidence by long-term depletions in these two neurotransmitters, their synthetic enzymes, metabolites, and plasma membrane transporters (Koda and Gibb, 1973;Hotchkiss and Gibb, 1980;Schmidt et al, 1985;Wagner et al, 1979;Ricaurte et al, 1982;Axt and Molliver, 1991;Friedman et al, 1998;Chapman et al, 2001). The mAMPH-induced depletions of DA reverse with a very slow time course (Cass and Manning, 1999).…”

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology.

“…In addition, neurotransmitter immunohistochemistry may augment the interpretation of other biochemical data. This approach has been applied to neurotoxicity evaluations that characterize the loss of serotonin immunoreactivity in adult rats after treatment with drugs known to act on this neurotransmitter system (34,35). These studies have shown not only the loss of serotonin immunoreactivity but also changes in the morphologic appearance of the serotonin nerve terminal network.…”

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

“…Evidence from animal and human studies suggests that long-term exposure or high dosages of amphetamines causes neuronal damage. Anatomical evidence supporting the neurotoxic potential of METH stems from studies showing that a high dose of METH given to rats caused degeneration of dopamine (DA) nerve terminals, and loss of tyrosine hydroxylase (TH), DA transporter (DAT), tryptophan hydroxylase (TPH), and 5-hydroxytryptamine (5-HT) axon terminals (Axt and Molliver, 1991;Gibb et al, 1990;Ricaurte et al, 1982;Seiden and Sabol, 1996). Further support for the neurotoxic potential of METH comes from evidence that (a) high doses of METH cause striatal gliosis as shown by an increase of glial fibrillary acidic protein (GFAP) in rats and mice (Battaglia et al, 2002;O'Callaghan and Miller, 1994;Sheng et al, 1994), and (b) apoptotic pathways are involved in METH-induced neuronal injury .…”