Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model.

BACKGROUND: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model. METHODS: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). RESULTS: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. CONCLUSIONS: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society.

4,4'-Methylenedianiline Alters Serotonergic Transport in a Novel, Sex-Specific Model of Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3-4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4'-Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite [Formula: see text], were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2-hydroxyestradiol (2-OHE1)/16α-hydroxyestrogen (16α-OHE1). In females, ET-1,[Formula: see text] , and 2-OHE1/16α-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM-induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis.

Norepinephrine transporter inhibition with desipramine exacerbates L-DOPA-induced dyskinesia: role for synaptic dopamine regulation in denervated nigrostriatal terminals.

Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI + L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI + L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI + L-DOPA group compared with the L-DOPA- and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.

Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model.

Excess glutamatergic neurotransmission may contribute to excitotoxic loss of nigrostriatal neurons in Parkinson's disease (PD). Here, we determined if increasing glutamate uptake could reduce the extent of tyrosine hydroxylase (TH) loss in PD progression. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a glutamate transporter that plays a major role in glutamate clearance in central nervous system and may attenuate adverse behavioral or neurobiological function in other neurodegenerative disease models. In association with >80% TH loss, we observed a significant decrease in glutamate uptake in the established 6-hydroxydopamine (6-OHDA) PD model. Ceftriaxone (200 mg/kg, i.p.) increased striatal glutamate uptake with >5 consecutive days of injection in nonlesioned rats and lasted out to 14 days postinjection, a time beyond that required for 6-OHDA to produce >70% TH loss (∼9 days). When ceftriaxone was given at the time of 6-OHDA, TH loss was ∼57% compared to ∼85% in temporally matched vehicle-injected controls and amphetamine-induced rotation was reduced about 2-fold. This attenuation of TH loss was associated with increased glutamate uptake, increased GLT-1 expression, and reduced Serine 19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. These results reveal that glutamate uptake can be targeted in a PD model, decrease the rate of TH loss in a calcium-dependent manner, and attenuate locomotor behavior associated with 6-OHDA lesion. Given that detection of reliable PD markers will eventually be employed in susceptible populations, our results give credence to the possibility that increasing glutamate uptake may prolong the time period before locomotor impairment occurs.

Influence of depression symptoms on history-independent reward and punishment processing.

Prior research indicates that depressed individuals are less responsive to rewards and more sensitive to punishments than non-depressed individuals. This study examines decision-making under reward maximizing or punishment minimizing conditions among adults with low (n=47) or high (n=48) depression symptoms. We utilized a history-independent decision-making task where learning is experience-based and the participants' goal is to enhance immediate payoff. Results indicated a significant interaction between incentive condition (reward maximizing, punishment minimizing) and depression group. Within the low depression group, better performance was observed for reward maximization than punishment minimization. In contrast, within the high depression group, better performance was observed for punishment minimization than reward maximization. Further, the high depression group outperformed the low depression symptom group in the punishment minimization condition, but no depression group differences were observed in the reward maximization condition. Computational modeling indicated that the high depression group was more likely to choose options with the highest expected reward, particularly in the punishment condition. Thus, decision-making is improved for people with elevated depression symptoms when minimizing punishment relative to maximizing rewards.

Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser(19).

Three glutamate transporters, GLT-1, GLAST, and EAAC1, are expressed in striatum. GLT-1 and, to a lesser extent, GLAST are thought to play a primary role in glutamate reuptake and mitigate excitoxicity. Progressive tyrosine hydroxylase (TH) loss seen in Parkinson's disease (PD) is associated with increased extracellular glutamate. Glutamate receptor antagonists reduce nigrostriatal loss in PD models. These observations suggest that excess synaptic glutamate contributes to nigrostriatal neuron loss seen in PD. Decreased GLT-1 expression occurs in neurodegenerative disease and PD models, suggesting decreased GLT-1-mediated glutamate reuptake contributes to excitotoxicity. To determine how transient GLT-1 blockade affects glutamate reuptake dynamics and a Ca(2+)-dependent process in nigrostriatal terminals, ser(19) phosphorylation of TH, the GLT-1 inhibitor dihydrokainic acid (DHK) was delivered unilaterally to striatum in vivo and glutamate reuptake was quantified ex vivo in crude synaptosomes 3h later. Ca(2+)-influx is associated with excitotoxic conditions. The phosphorylation of TH at ser(19) is Ca(2+)-dependent, and a change resulting from GLT-1 blockade may signify the potential for excitotoxicity to nigrostriatal neurons. Synaptosomes from DHK infused striatum had a 43% increase in glutamate reuptake in conjunction with decreased ser(19) TH phosphorylation. Using a novel GLAST inhibitor and DHK, we determined that the GLAST-mediated component of increased glutamate reuptake increased 3-fold with no change in GLAST or GLT-1 protein expression. However, GLT-1 blockade increased EAAC1 protein expression ~20%. Taken together, these results suggest that GLT-1 blockade produces a transient increase in GLAST-mediated reuptake and EAAC1 expression coupled with reduced ser(19) TH phosphorylation. These responses could represent an endogenous defense against excitotoxicity to the nigrostriatal pathway.

Dopamine transporter loss in 6-OHDA Parkinson's model is unmet by parallel reduction in dopamine uptake.

The dopamine transporter (DAT) regulates synaptic dopamine (DA) in striatum and modulation of DAT can affect locomotor activity. Thus, in Parkinson's disease (PD), DAT loss could affect DA clearance and locomotor activity. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. Using the unilateral 6-OHDA rat PD model, we examined [(3)H]DA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase (TH) protein loss compared with contralateral intact striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. As other monoamine transporters can transport DA, we determined if norepinephrine (NE) and serotonin (5-HT) differentially modulated DA uptake in lesioned striatum. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against [(3)H]DA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting [(3)H]DA uptake. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited [(3)H]DA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited [(3)H]DA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. Increased inhibition of DA uptake by L-DOPA and its preferential inhibition of NE over DA uptake, indicates that NET-mediated DA uptake may be modulated by L-DOPA when DAT loss exceeds 70%. These results indicate a novel mechanism for DA uptake during PD progression and provide new insight into how L-DOPA affects DA uptake, revealing possible mechanisms of its therapeutic and side effect potential.

Normal aging and the dissociable prototype learning systems.

Dissociable prototype learning systems have been demonstrated behaviorally and with neuroimaging in younger adults as well as with patient populations. In A/not-A (AN) prototype learning, participants are shown members of category A during training, and during test are asked to decide whether novel items are in category A or are not in category A. Research suggests that AN learning is mediated by a perceptual learning system. In A/B (AB) prototype learning, participants are shown members of category A and B during training, and during test are asked to decide whether novel items are in category A or category B. In contrast to AN, research suggests that AB learning is mediated by a declarative memory system. The current study examined the effects of normal aging on AN and AB prototype learning. We observed an age-related deficit in AB learning, but an age-related advantage in AN learning. Computational modeling supports one possible interpretation based on narrower selective attentional focus in older adults in the AB task and broader selective attention in the AN task. Neuropsychological testing in older participants suggested that executive functioning and attentional control were associated with better performance in both tasks. However, nonverbal memory was associated with better AN performance, while visual attention was associated with worse AB performance. The results support an interactive memory systems approach and suggest that age-related declines in one memory system can lead to deficits in some tasks, but to enhanced performance in others.