Postnatal manganese exposure attenuates cocaine-induced locomotor activity and reduces dopamine transporters in adult male rats
Introduction
Manganese chloride (Mn) is a complex trace mineral that in high amounts causes schizophrenic-like symptoms in humans [2], [53] and with continued exposure produces severe extrapyramidal motor impairments that are similar to Parkinson's Disease [2], [11], [52]. It has been reported that children may be more susceptible to Mn toxicity than adults [12], [45], [46], [70], [71], [75] and there is increasing concern that chronic exposure to lower amounts of Mn may have long-term neurotoxic effects [51], [52]. A consistent finding is that neurobehavioral and neuropsychiatric symptomology are apparent long after blood levels and body burden of Mn have returned to normal [34], [35], [36].
When administered to adult rats via drinking water, intraperitoneal injection, or inhalation, excess Mn accumulates in various basal ganglia structures, including the striatum (caudate and putamen), globus pallidus, and brain stem [5], [10], [16], [18], [32], [40], [65]. Nigrostriatal dopamine neurons appear to be particularly sensitive to Mn-induced toxicity [17], [62], [63], because a preponderance of studies have shown that intense or prolonged Mn exposure in adulthood causes long-term reductions in striatal dopamine levels [5], [30], [39], [43] and induces a loss of autoreceptor control over dopamine release [16]. Extracellular Mn primarily enters dopamine neurons through calcium channels [3] and via receptor-mediated endocytosis [66], although there is also evidence that Mn is actively taken up by the dopamine transporter [40]. In the latter case, Mn absorption is significantly reduced after pretreatment with the dopamine reuptake blocker cocaine. Whether Mn directly or indirectly damages dopamine transporters of adult rats is uncertain, however there is abundant evidence that the dopamine transporter is susceptible to the effects of neurotoxins [20], [27], [60], [64].
Locomotor responses of adult rats and mice are often sensitive to perturbations of the nigrostriatal dopamine system. For this reason, it is surprising that Mn has been reported to increase [10], [57], [65], decrease [39], [68], or have no effect [18] on spontaneous locomotor activity. These inconsistent results could be due to differences in species, strain, dosing regimens, or testing procedures; however, it is interesting that the locomotor activity of Mn-treated rats has been reported to vary depending on the length of exposure [8], [57], with Mn causing an initial increase in locomotor activity followed by a long-term decline in spontaneous locomotion [8]. Because toxins often alter neuronal functioning at the synaptic level, a pharmacological challenge can be used to “unmask” motoric changes that are not observed, or inconsistently observed, during basal conditions [1], [38]. Using this strategy, Nachtman et al. [57] showed that rats were more responsive to the effects of d-amphetamine (an indirect dopamine agonist) both 14 and 29 weeks after initial Mn administration. When these finding are combined with results from neurochemical studies, it appears that exposing rats to Mn in adulthood impacts the functioning of the nigrostriatal dopamine system and alters behavioral responding after amphetamine administration.
In comparison to adult rats, Mn accumulates more readily in the brains of preweanling rats [4], [18], [25], [45], [67] due to the immaturity of the blood–brain barrier [66] and, more importantly, the almost complete lack of biliary excretion [4], [15]. Despite the excess accumulation of Mn, there is surprisingly little evidence that Mn acts as a teratogen in preweanling rats. For example, most developmental studies have reported the absence of Mn-induced histopathological effects [18], [47], with striatal dopamine levels at, or slightly above, control values at the conclusion of Mn exposure [18], [44], [61]. In an early study, however, Chandra and Shukla [13] reported that postnatal Mn exposure caused marked neuronal degeneration in cerebral and cerebellar cortices, as well as glial proliferation in the cerebral cortex and caudate nucleus. More recently, Tran and colleagues found that striatal dopamine levels were significantly reduced 40 days after Mn treatment on PD 1–20 [70], [71], suggesting that the impact of early Mn exposure does not become fully evident until either a sufficient period of time has elapsed or a specific developmental stage has been reached. The effects of early Mn exposure on the locomotor activity of adult rats had yet to be assessed, although exposing rats to Mn on PD 1–21 does not affect spontaneous locomotor activity when measured on PD 13, PD 17, or PD 21 [18].
The purpose of the present study was to determine whether postnatal Mn exposure would have long-term behavioral and neurochemical effects detectable in adulthood. We used a dosing paradigm similar to that described in Tran et al. [70], [71] (i.e., oral administration of 0, 250, or 750 μg Mn on PD 1–21), because they reported that Mn-exposed rats exhibited long-term reductions in striatal dopamine levels and impaired responding on a passive avoidance task. After being exposed to Mn on PD 1–21, rats were left undisturbed until adulthood with basal and cocaine-induced locomotor activity being assessed on PD 91. Striatal dopamine transporter binding sites were then measured using [3H]GBR 12935. Dopamine transporters were examined because: (a) they are a gateway for neurotoxins as well as a sensitive measure of dopamine neurotoxicity [27], [54]; and (b) they are the primary cellular structure mediating the pharmacological effects of cocaine [7], [29], [42]. It was hypothesized, therefore, that Mn exposure on PD 1–21 would cause a persistent reduction in striatal dopamine transporters [see also [24], [37] and attenuate cocaine-induced locomotor activity in adulthood. In addition to assessing behavior in adulthood, Mn-treated and control rats were given a standard battery of tests during the preweanling period to compare physical development, sensory functioning, and motoric ability. In a separate experiment, rats received oral administrations of Mn (0 or 750 μg) on PD 1–21, with striatal Mn and iron (Fe) levels being measured on PD 14, PD 21, and PD 90. Because elevated Mn levels have been reported to decrease Fe absorption [76], serum Fe levels were also measured in these rats.
Section snippets
Animals
Subjects were 121 male rats of Sprague–Dawley descent (Harlan), born and raised at California State University, San Bernardino (CSUSB). A total of 73 male rats (n = 8–9 per group) were used to assess Mn-induced changes in developmental landmarks, sensory and motor behavior, and dopamine transporter binding, while an additional 48 male rats (n = 8 per group) were used to assess striatal Mn and Fe accumulation and serum Fe levels. Litters were culled to 10 pups on PD 1. Rats were weaned on PD 24 and
Neonatal assessments
When assessed across the preweanling period, both doses of Mn caused a relative decline in body weight when compared to the vehicle group, with 750 μg Mn depressing weight gain more than 250 μg Mn (Table 3) [Mn main effect, F(2,102) = 4.92, p < 0.01]. The effects of Mn did not vary uniquely across postnatal days [Mn × Day interaction, F(20,1020) = 1.53, p > 0.05). Mn did not alter age at eye opening, pina detachment, or incisor eruption (Table 4). Mn exposure did affect performance on the negative
Discussion
Evidence suggests that exposure to Mn can result in behavioral and neurological changes in the developing central nervous system [13], [70], [71]. The present study examined whether early Mn exposure would affect basal and cocaine-induced locomotor activity in adult male rats and reduce the number of striatal dopamine transporter binding sites. Additionally, rat pups were evaluated on standard measures of sensory and motor development. Administering low to moderate doses of Mn (250 or
Acknowledgments
We thank Michelle Cyr for help with the DAT binding assay and Rita Hernandez-Fish for help with testing animals. This work was partially supported by an ASI research grant to C.M. Reichel.
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Present address: Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE 68588, USA.