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Repeated administration of methamphetamine (m-AMPH) produces a prolonged elevation of extracellular dopamine (DA) levels in rat striatum and subsequent damage to striatal DA terminals. In the present study, a unilateral striatal infusion of quinolinic acid (QA) (15 ug/0.5 microliter) 2 weeks before repeated m-AMPH treatment (four injections of 4 mg/kg, s.c., at 2-hr intervals) protected that striatum from m-AMPH-induced DA terminal injury. One week after m-AMPH treatments, striatal DA contents were substantially below control values in the vehicle-infused striata, whereas the DA contents of the QA-infused striata were equal to those of animals not exposed to m-AMPH. The QA infusions alone injured striatal neurons, as indicated by decreased [3H]SCH 23390 and [3H]spiroperidol binding to D1 and D2 receptors, respectively. However, QA infusions by themselves did not significantly change the DA content or [3H]mazindol binding to the high-affinity DA transporter of the infused striata 3 weeks later. In vivo microdialysis was performed in the previously QA- or vehicle-infused striata during regimens of repeated m-AMPH or saline treatments. QA infusions that were effective in protecting against m-AMPH neurotoxicity did not significantly reduce stimulant-induced DA overflow, compared with the overflow that occurred in the vehicle-infused striata of m-AMPH-treated rats. Thus m-AMPH-induced DA overflow appears to be dissociated from the resulting DA terminal injury in the QA-infused striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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 x 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.

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.

Dopamine-glutamate interactions contribute to normal striatal function and have been implicated in neurotoxicity at nigrostriatal dopamine (DA) terminals. The present study examined the striata of idiopathic Parkinson's disease (PD) patients and age-matched controls for regional differences in the DA transporter and binding to N-methyl-D-aspartate (NMDA) receptors. [3H]Mazindol labeling of the DA transporter was reduced by 70-80% in the caudate and putamen of PD patients, with reductions being more extensive dorsally than ventrally. In contrast, L-[3H]glutamate binding to NDMA-sensitive receptors was 20-40% higher in PD cases than in controls. These findings raise the possibility that modifications occur within corticostriatal glutamate synapses of PD patients, possibly as a consequence of reduced nigrostriatal DA activity.

Repeated administrations of methamphetamine (m-AMPH) produce high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors has been shown previously to prevent m-AMPH-induced striatal DA terminal injury, but the mechanism for this protection is unclear. In the present study, in vivo microdialysis was used to determine the effects of blockade of NMDA receptors with the noncompetitive antagonist MK-801 on m-AMPH-induced striatal DA overflow. Four injections of MK-801 (0.5 mg/kg, ip) alone did not significantly change extracellular striatal DA concentrations from pretreatment values. Four treatments with m-AMPH (4.0 mg/kg, sc at 2-hr intervals) increased striatal DA overflow, and the overflow was particularly extensive following the fourth injection. This m-AMPH regimen produced a 40% reduction in striatal DA tissue content 1 week later. Treatment with MK-801 15 min before each of the four m-AMPH injections or prior to only the last two m-AMPH administrations attenuated the m-AMPH-induced increase in striatal DA overflow and protected completely against striatal DA depletions. Other MK-801 treatment regimens less effectively reduced the m-AMPH-induced striatal DA efflux and were ineffective in protecting against striatal DA depletions. Linear regression analysis indicated that cumulative DA overflow was strongly predictive (r = -.68) of striatal DA tissue levels measured one week later. These findings suggest that the extensive DA overflow seen during a neurotoxic regimen of m-AMPH is a crucial component of the subsequent neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

The contributions of dopamine (DA) receptor subtypes to sensorimotor behavior was studied in MPTP-treated mice. All DA antagonists studied produced akinesia and catalepsy in control and MPTP-treated mice. The rank order of potency was haloperidol greater than SCH 23390 much greater than L-sulpiride. Combined subthreshold doses of SCH 23390 and L-sulpiride induced marked motor impairments. Dose-response curves for each drug were shifted to the left in the MPTP-treated mice, suggesting behavioral supersensitivity. Pretreatment with the selective D1 agonist SKF 38393 or the selective D2 agonist quinpirole either alone or in subthreshold combination also prevented cold swim-induced motor deficits in the MPTP-treated animals. Haloperidol and SCH 23390 also produced somatosensory neglect in both control and MPTP-treated mice, with haloperidol greater than SCH 23390. Again, a shift of the dose-response curves to the left was observed in the MPTP-treated animals. L-Sulpiride, or another D2 antagonist spiperone, had only minimal effects on somatosensory orientation in both control and MPTP-treated mice. Our studies suggest that both D1 and D2 receptors participate in the expression of motor behavior, while D1 receptors appear to be predominantly responsible for somatosensory orientation.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) destroys dopamine-containing nigrostriatal neurons and increases the apparent Bmax of both D1 and D2 binding sites in the striatum. However, the changes of Bmax occur at different intervals after the lesion. Up-regulation of D2 sites becomes evident about 3 weeks after the lesion and lasts for about 3 months. In contrast, about 3 months are required for the up-regulation of D1 sites and increased binding is still evident after 5 months.

The role of age-dependent responses in infantile amnesia was examined. Ten- and 15-day old rats were trained in an approach-mother, avoid-shock paradigm and tested for retention immediately and after a 1-day delay. Ten-day-old rats were also tested after 6 days. Half of all the pups received a shock reactivation treatment before the delayed retention tests and half did not. In comparison to immediate retention, performance declined after 1 day but was reinstated by reactivation. A similar reactivation effect was found on 10-day-old pups tested after 6 days except that a different age-specific response was substituted for the original behavior. These effects were not found in untrained controls. These data show that learning may be expressed differently when acquisition and retention are measured at different developmental stages, a pattern that may be mistaken for infantile amnesia.

The ability of rat pups depleted of brain dopamine (DA) at either 3 or 15 days of age to increase fluid intake in response to intracellular dehydration was studied. Despite near-total depletions of striatal DA, animals depleted at either age ingested normal amounts of fluid even as soon as 3-7 days after incurring the brain damage. The effects of DA receptor blockade on ingestion and motor function were also studied. Haloperidol had markedly different effects as a function of the age at which the depletions were sustained. Weanlings that were depleted of DA at 3 days of age failed to exhibit the drug-induced adipsia, akinesia, and catalepsy seen in controls and animals that were depleted at 15 days of age. These findings suggest that the DA depletions were performed at different periods of brain organization. The resultant neural controls of ingestion and motor function are qualitatively different in the two groups of depleted animals. Rats depleted at 3 days of age utilize nondopaminergic mechanisms, whereas animals lesioned at 15 days of age continue to rely upon residual DA neurons for both behaviors.

The role of brain dopamine (DA) in the control of sensorimotor function was studied in normal rat pups and in animals depleted of DA at various stages of development. Acute administration of the DA antagonist haloperidol produced akinesia and catalepsy in normal pups as early as 3 days of age and resulted in impaired orientation to somatosensory stimulation by 15 days of age. In contrast, near-total depletions of striatal DA incurred on day 3, 15, or 20 produced no obvious deficits in sensorimotor function either soon after the depletion or after the animals reached adulthood. Rats depleted of DA on day 27 exhibited akinesia, catalepsy, and sensory neglect. These deficits resembled those seen in comparably depleted adults except that they were more transient, lasting 1 week rather than 4-5 weeks. Moreover, while rats depleted as adults became akinetic and cataleptic after the stress of a cold water swim, animals depleted on day 27 did not. These findings demonstrate that DA is involved in sensorimotor function during early development. The data also reveal an impressive degree of plasticity in the neural controls of sensorimotor function and that the extent of this plasticity is dependent upon the age at the time of damage.

Injection of a low dose of haloperidol, that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. GM1 ganglioside treatment eliminates all of these behavioral impairments and also partially restores striatal dopamine content. These observations suggest that the MPTP-treated mouse may be a valuable model for studying mechanisms underlying parkinsonism and that administration of GM1 ganglioside may be an effective therapy.

The present study evaluates the effects of MPTP-induced striatal DA depletions on sensorimotor behavior in mice. While MPTP produces no obvious behavioral deficits under normal conditions, acute stress (cold swim) or injection of low doses of haloperidol results in marked akinesia, catalepsy, and sensory neglect. Thus, significant behavioral impairments do accompany the neurotoxicity observed after MPTP administration in mice and render this a valuable animal model for studying mechanisms underlying Parkinson's disease.

Injection of a dose of haloperidol that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. Chronic GM1 ganglioside administration improves the behavioral impairments, partially restores striatal dopamine (DA) content and prevents DA D-2 receptor up-regulation. Discontinuation of GM1 ganglioside treatment results in a time-dependent decline of striatal DA content to pretreatment pathological levels, return of haloperidol-induced sensorimotor deficits and a rise of DA D-2 receptor density in the striatum. Apparently, continuous administration of GM1 ganglioside is necessary to maintain the biochemical and behavioral recovery in the MPTP-treated mouse. These observations may provide useful cues for understanding the mechanism of action of GM1 ganglioside.

Injection of a low dose of haloperidol, that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and somatosensory neglect in MPTP-treated mice. These neuroleptic-induced sensorimotor impairments are exhibited soon after MPTP treatments and coincide with a decrease in both striatal DA and DOPAC levels. DA and DOPAC content gradually return to near-control levels over a 3-5 month period. Interestingly, while the haloperidol-induced somatosensory deficits declined in parallel with the rise in DA and DOPAC levels, the motor deficits persisted for up to 5 months after MPTP administration. These data suggest subtle differences in the neurochemical mediation of these behaviors and that the persistence of neuronal impairments may not necessarily be revealed by near-normal transmitter levels.