Fredric B. Weihmuller

Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity

Acutely, methamphetamine (m-AMPH) is known to stimulate a net efflux of dopamine (DA) in the striatum while inhibiting DA uptake, thus producing high extracellular concentrations of DA. Repeated administration of m-AMPH has been shown to damage DA terminals in the striatum. However, little direct information exists about the relationship between m-AMPH-induced DA overflow and neurotoxicity. In the present study, we used in vivo microdialysis to explore this topic. Four, but not 3, injections of m-AMPH (4 mg/kg, sc, at 2 h intervals) damaged striatal DA terminals as measured by a 43-51% decrease in post mortem striatal DA content 1 week later. Striatal microdialysis in awake animals during the course of m-AMPH treatment showed that DA overflow increased after each m-AMPH injection, but that approximately 1.5 h after the fourth m-AMPH injection, a striking increase in DA overflow occurred that was significantly larger than that seen after any of the previous 3 injections. Additionally, in animals receiving 4 injections of m-AMPH, cumulative DA overflow was negatively correlated with striatal DA content 1 week later (r = -0.74, P less than 0.05), suggesting that the substantial DA overflow seen after the fourth m-AMPH injection is especially important in m-AMPH neurotoxicity.

Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine

Methamphetamine (m-AMPH) or saline was repeatedly administered to rats. One week later, the caudate-putamen of the m-AMPH-treated rats revealed a decrease in both [3H]mazindol-labeled dopamine uptake sites and tissue dopamine content. Moreover, the resulting pattern of decline in these measures was regionally heterogeneous. The ventral caudate-putamen displayed the greatest decrease in both [3H]mazindol binding and dopamine content while the neighboring nucleus accumbens and the dorsal caudate-putamen remained relatively intact. These results indicate a regional difference in the susceptibility of striatal dopaminergic terminals to the neurotoxic effects of methamphetamine.

Methamphetamine-induced dopamine overflow and injury to striatal dopamine terminals : attenuation by dopamine D1 or D2 antagonists

Abstract: Pharmacological blockade of either D1 or D2 dopamine (DA) receptors prevents damage of striatal DA terminals by repeated doses of methamphetamine (m‐AMPH). Because the substantial DA overflow produced by multiple m‐AMPH treatments appears to contribute to the subsequent injury, we have investigated the effects of blockade of D1 or D2 receptors on m‐AMPH‐induced DA efflux using in vivo microdialysis. Four treatments with m‐AMPH (4 mg/kg, s.c., 2‐h intervals) produced large increases in striatal DA overflow, with particularly marked overflow (10 times the basal values) following the fourth injection. Administered by themselves, four injections of the D1 antagonist SCH 23390 or the D2 antagonist eticlopride (0.5 mg/kg, i.p., 2‐h intervals) significantly increased striatal DA overflow. However, treatment with either SCH 23390 or eticlopride 15 min before each of four m‐AMPH injections attenuated the marked DA peak otherwise seen after the fourth m‐AMPH injection. These effects on DA overflow were related to subsequent DA depletions. Although our m‐AMPH regimen produced a 54% reduction in striatal DA tissue content 1 week later, pretreatments with either the D1 or the D2 antagonist completely prevented subsequent DA content depletions. Furthermore, the DA content of striatal tissue remaining 1 week after m‐AMPH treatment was significantly correlated with the magnitude of the cumulative DA overflow during the m‐AMPH treatment (r= ‐0.69). Thus, the extensive DA overflow seen during neurotoxic regimens of m‐AMPH appears critical to the subsequent neurotoxicity, and the neuroprotective action of DA receptor antagonists seems to result from their attenuation of stimulant‐induced DA overflow.

MK-801 attenuates the dopamine-releasing but not the behavioral effects of methamphetamine: an in vivo microdialysis study

Neuroanatomical and pharmacological evidence suggests that important modulatory relationships exist between mesostriatal dopaminergic terminals and corticostriatal inputs. The present study used in vivo microdialysis in awake animals to examine the results of pharmacological manipulations of these systems on net striatal dopamine (DA) efflux and behavioral activation. A single methamphetamine (m-AMPH) treatment induced a prolonged (greater than 6 h) increase (6-fold peak response) in extracellular striatal DA and increased stereotypic behavior. When given alone, the non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 did not have a significant effect on extracellular striatal DA, but significantly increased stereotypic behaviors. Pretreatment with MK-801 markedly attenuated the m-AMPH-induced striatal DA overflow. In contrast to its effects on striatal DA overflow, MK-801 potentiated the locomotor effects of m-AMPH without reducing stereotypy rating scores. These findings suggest that the synaptic relationships between mesostriatal DA and corticostriatal excitatory amino acid terminals in the striatum are an important component in its behavioral output. Moreover, NMDA receptors appear to be capable of modulating striatal DA overflow.

Dopamine-glutamate interactions in methamphetaminc-induced neurotoxicity

Repeated administration of methamphetamine (m-AMPH) to rats induces dopamine (DA) terminal damage, and coadministration of antagonists of the N-methyl-D-aspartate (NMDA) or dopamine D1 or D2 receptors are protective. Striatal microdialysis of rats given a neurotoxic regimen of 4 × m-AMPH (4 mg/kg, s.c.) treatments revealed a dramatic and prolonged elevation of extracellular DA after the final m-AMPH administration. Neuroprotective regimens of MK-801, SCH 23390, or eticlopride greatly attenuated the overflow of DA resulting from the fourth m-AMPH treatment. By itself, MK-801 had no significant influence on striatal DA overflow, whereas either DA antagonist given alone elevated dialysate DA concentrations. A significant correlation was found between the magnitude of the m-AMPH-induced DA overflow of individual microdialyzed rats and their striatal DA content at sacrifice one week later. We conclude that the ability of non-competitive NMDA antagonists and of the D1 or D2 antagonists to protect against m-AMPH-induced striatal DA terminal injury can be accounted for by their attenuation of m-AMPH-evoked DA overflow. These findings underscore the important role played by elevated extracellular DA concentrations to the injurious effects of this stimulant drug.

Extracellular dopamine increases in the neonatal olfactory bulb during odor preference training.

Young rats learn to approach an odor that has been paired with tactile stimulation. This attraction is accompanied by changes in the metabolism and anatomy within the olfactory bulb glomerular layer. In this study, we examined the changes that occur in the olfactory bulb during early olfactory learning, rather than after such pairings have occurred. Specifically, we determined whether the pairing of an odor with tactile stimulation would produce a modified response by olfactory bulb glomerular-layer neurons. To monitor one large subgroup of these neurons during early learning, we used in vivo microdialysis to assess the activity of dopaminergic neurons in the olfactory bulb of postnatal day (PND) 3 rats during simultaneous presentation of odor and tactile stimulation, tactile stimulation alone, odor alone, or clean air alone. Clean air evokes no change in extracellular dopamine (DA), while both odor alone and stroking alone induce prolonged increases in DA peaking at about 200% of baseline. The combination of odor and tactile stimulation, which allows an olfactory preference to be formed, induces a prolonged increase in DA which peaks at about 400% of baseline. The level of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) increases only in pups receiving both odor and tactile stimulation and peaks at about 200% of baseline. With the exception of the pups exposed to clean air, all groups show an increase in homovanillic acid (HVA) of between 150-200% following stimulation. The large and prolonged increase in DA may be linked to the longer term anatomical and physiological changes in the glomerular layer of the bulb that form as a consequence of early olfactory preference training.

l-Dopa pretreatment potentiates striatal dopamine overflow and produces dopamine terminal injury after a single methamphetamine injection

Rats receiving L-dopa/carbidopa (70 mg/kg/17.5 mg/kg, i.p.) 1 h prior to a single methamphetamine (m-AMPH) (4 mg/kg, s.c.) pretreatment showed an extraordinary striatal dopamine (DA) overflow into the extracellular space (30-60 times basal overflow) as compared to the DA overflow elicited by m-AMPH alone (4-5 times basal). Animals treated with L-dopa/carbidopa plus m-AMPH, but not m-AMPH alone, had substantial (60%) decreases in striatal DA content 1 week later. These findings support the conclusion that the magnitude of m-AMPH-induced DA overflow contributes to the degree of nerve terminal damage and highlight the importance of extracellular DA in striatal terminal damage.