Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson's disease

N-methyl-D-aspartate (NMDA) receptor antagonists have antiakinetic and antidyskinetic effects in animals models of Parkinson's disease (PD). However, non-selective inhibition of NMDA receptors throughout the central nervous system may result in undesired effects such as ataxia and psychosis. We therefore studied Ro 25-6981, an activity-dependent antagonist of NMDA receptors containing the NR2B subunit which are predominantly expressed in the striatum. Ro 25-6981 induced contraversive rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats without stimulating locomotion in normal rats and reversed parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-treated common marmosets. Due to the small number of marmosets, there were no significant differences between Ro 25-6981 and vehicle though there was a significant trend toward differences, as shown by the Page test. Furthermore, Ro 25-6981 potentiated the action of levodopa in both species and attenuated the maximal levodopa response in 6-OHDA-lesioned rats chronically treated with levodopa without reducing the overall response. Ro 25-6981 also potentiated the action of the dopamine receptor agonists apomorphine, A68930 and quinpirole in 6-OHDA-lesioned rats. The present observations suggest a therapeutic potential of NR2B-selective NMDA receptor antagonists in the management of PD.     

Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD

AMPA and NMDA receptors, abundantly expressed on striatal medium spiny neurons, have been implicated in the regulation of corticostriatal synaptic efficacy. To evaluate the contribution of both glutamate receptor types to the pathogenesis of motor response alterations associated with dopaminergic treatment, we studied the ability of the selective AMPA receptor antagonist GYKI-47261 and the selective NMDA receptor antagonists, MK-801 and amantadine, to mitigate these syndromes in rodent and primate models of Parkinson's disease. The effects of GYKI-47261 and amantadine (or MK-801), alone and in combination, were compared for their ability to modify dyskinesias induced by levodopa. In rats, simultaneous administration of subthreshold doses of AMPA and NMDA receptor antagonists completely normalized the wearing-off response to acute levodopa challenge produced by chronic levodopa treatment (P < 0.05). In primates, the glutamate antagonists GYKI-47261 and amantadine, co-administered at low doses (failing to alter dyskinesia scores), reduced levodopa-induced dyskinesias by 51% (P < 0.05). The simultaneous AMPA and NMDA receptor blockade acts to provide a substantially greater reduction in the response alterations induced by levodopa than inhibition of either of these receptors alone. The results suggest that mechanisms mediated by both ionotropic glutamate receptors make an independent contribution to the pathogenesis of these motor response changes and further that a combination of both drug types may provide relief from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone.     

Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline,CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias

This study assessed striatal N-methyl-D-aspartate (NMDA) glutamate receptors of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with levodopa (L-DOPA)-induced dyskinesias (LID). In a first experiment, four MPTP monkeys receiving L-DOPA/Benserazide alone developed dyskinesias. Four MPTP monkeys received L-DOPA/Benserazide plus CI-1041 an NMDA antagonist selective for NR1/NR2B and four were treated with L-DOPA/Benserazide plus a small dose of cabergoline; one monkey of each group developed mild dyskinesias at the end of treatment. In a second experiment, a kynurenine 3-hydroxylase inhibitor Ro 61-8048, combined with L-DOPA/Benserazide, reduced dyskinesias in MPTP monkeys. Drug-treated MPTP monkeys were compared to intact monkeys and saline-treated MPTP monkeys. Glutamate receptors were investigated by autoradiography using [³H]CGP-39653 (NR1/NR2A antagonist) and [³H]Ro25-6981 (NR1/NR2B antagonist). In general, striatal [³H]CGP-39653 specific binding was unaltered in all experimental groups. MPTP lesion decreased striatal [³H]Ro25-6981 specific binding; these levels were enhanced in the L-DOPA-alone-treated MPTP monkeys and decreased in antidyskinetic drugs treated monkeys. Maximal dyskinesias scores of the MPTP monkeys correlated significantly with [³H]Ro25-6981 specific binding in the rostral and caudal striatum. Hence, MPTP lesion, L-DOPA treatment and prevention of LID with CI-1041 and cabergoline, or reduction with Ro 61-8048 were associated with modulation of NR2B/NMDA glutamate receptors.     

Phosphorylation of glutamate receptors: a potential mechanism for the regulation of receptor function and psychostimulant action

Ionotropic glutamate receptors, N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), are densely distributed in the mammalian brain and actively regulate a variety of cellular activities. Expression and function of these receptors are also under a tight regulation by many molecular mechanisms. Protein phosphorylation represents one of the important mechanisms for the posttranslational modulation of these receptors. Constitutive and regulatory phosphorylation occurs at distinct sites (serine, threonine, or tyrosine) on the intracellular C-terminal domain of almost all subunits capable of assembling a functional channel. Several key protein kinases, such as protein kinase A, protein kinase C, Ca(2+)/calmodulin-dependent protein kinases, and tyrosine kinases are involved in the site-specific catalyzation and regulation of NMDAR and AMPAR phosphorylation. Through the phosphorylation mechanism, these protein kinases as well as protein phosphatases control biochemical properties (biosynthesis, delivery, and subunit assembling), subcellular distribution, and interactions of these receptors with various synaptic proteins, which ultimately modify the efficacy and strength of excitatory synapses containing NMDARs and AMPARs and many forms of synaptic plasticity. Emerging evidence shows that psychostimulants (cocaine and amphetamine) are among effective agents that profoundly alter the phosphorylation status of both receptors in striatal neurons in vivo. Thus, psychostimulants may modulate NMDAR and AMPAR function through the phosphorylation mechanism to shape the excitatory synaptic plasticity related to additive properties of drugs of abuse.     

Metabotropic glutamate receptors are involved in calcium-induced LTP of AMPA and NMDA receptor-mediated responses in the rat hippocampus

Effects of metabotropic glutamate (mGlu) receptors on calcium-induced long-term potentiation (LTP) of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated components were investigated in rat hippocampal slices using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs). Calcium-induced LTP comprises a parallel, long-lasting increase of AMPA and NMDA receptor-mediated components. The calcium-induced LTP of the AMPA receptor-mediated component can be significantly attenuated by the use of a selective NMDA antagonist. (R.S)-α-methyl-4-carboxyphenylglycine (MCPG), a selective antagonist of mGlu receptors, abolished the long-lasting increase of both AMPA and NMDA receptor-mediated components observed in calcium-induced LTP. In current clamp mode, the application of a high calcium alone or Schaffer fiber stimulation alone (20 Hz) only generated a short-term increase in the firing rate of evoked action potentials. Conversely, a long-term increase in the firing rate was observed if Schaffer fiber stimulation (20 Hz) accompanied the perfusion of high calcium. These results suggest that calcium-induced LTP involves a parallel, long-lasting enhancement in ionotropic AMPA and NMDA receptor-mediated components. More importantly, the mGlu receptor plays a critical role in the establishment of both AMPA and NMDA receptor-mediated components underlying calcium-induced LTP. In addition, the present study also described an experimental condition in which the coapplication of the high calcium pulse and Schaffer fiber stimulation (20 Hz) can synergistically elicit a long-term increase of neuronal excitability.     

Inhibition of glutamate/glutamine cycle in vivo results in decreased benzodiazepine binding and differentially regulated GABAergic subunit expression in the rat brain

Purpose: The astrocytic enzyme glutamine synthetase (GS) is a key regulator of glutamate and γ‐aminobutyric acid (GABA) metabolism in the glutamate/glutamine cycle (GGC). Inhibition of GS results in changes of neurotransmitter release and recycling. However, little is known about the influence of GGC on neurotransmitter receptor expression. In the pentylenetetrazole model of epilepsy, GS becomes nitrated and partially inhibited, and we demonstrated alterations of neurotransmitter receptor expression in the same model. Therefore, we hypothesized similar changes of neurotransmitter receptor expression when GS is inhibited in vivo. Methods: Rats were treated with a single dose (100 mg/kg bodyweight) of l ‐methionine sulfoximine (MSO), an irreversible inhibitor of GS. We used ³H‐receptor autoradiography to measure glutamatergic [α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazol‐propionic acid (AMPA), kainate, N‐methyl‐d ‐aspartate (NMDA)], GABAergic (GABA_A, GABA_B and GABA_A‐associated benzodiazepine (BZ) binding sites], dopamine D₁, and adenosine A₁ receptor subtypes. In addition, we performed saturation analysis of BZ binding sites on cerebral membrane homogenates and investigated the expression of GABA_Aα₁ and γ₂ subunits (which primarily mediate BZ binding) by western blot analysis. Results: We demonstrated a significant reduction of BZ binding in the somatosensory, piriform, and entorhinal cortices and in the amygdala, 24 and 72 h after MSO treatment. Saturation analysis revealed decreased BZ binding (B_max) on cerebral membrane homogenates 72 h after MSO treatment, without changes in binding site affinity (K_D). Furthermore, we found differential changes of α₁, γ₂, and phosphorylated γ₂ subunits following MSO treatment. Conclusion: On the basis of our findings, we conclude that the glutamate/glutamine cycle directly influences GABAergic neurotransmission by regulating GABA_A subunit composition, thereby affecting its modulation by endogenous benzodiazepines.     

Acute morphine associated alterations in the subcellular location of the AMPA‐GluR1 receptor subunit in dendrites of neurons in the mouse central nucleus of the amygdala: Comparisons and contrasts with other glutamate receptor subunits

Within the amygdala, AMPA receptors expressing the AMPA‐GluR1 (GluR1) subunit play an important role in basal glutamate signaling as well as behaviors associated with exposure to drugs of abuse like opiates. Although the ultrastructural location of GluR1 is an important functional feature of this protein, the basal distribution of GluR1, as well as its sensitivity to acute morphine, has never been characterized in the mouse central nucleus of the amygdala (CeA). Electron microscopic immunocytochemistry employing visually distinct gold and peroxidase markers was used to explore the distribution of GluR1 and its relationship with the mu‐opioid receptor (µOR) in the mouse CeA under basal conditions and after morphine. We also looked at the effect of morphine on other glutamate receptor subunits, including AMPA‐GluR2 (GluR2) and NMDA‐NR1 (NR1). In opiate naive animals, GluR1 and µOR were present in diverse populations of neuronal profiles, but mainly in somatodendritic structures that expressed exclusive labeling for either antigen, as well as those co‐expressing both proteins. Compared to saline treated animals, mice given morphine showed significant differences in the subcellular location of GluR1 in dendrites without co‐expression of µOR. Although GluR2 also showed similar changes in non‐µOR expressing dendrites, contrasting effects were seen in GluR2 and µOR co‐expressing profiles. These results provide the ultrastructural basis for basal interactions involving the modulation of GluR1 or µOR activity in the mouse CeA. Further, they indicate that the subcellular distribution of GluR1 is modified by acute opiates in a manner that compares, as well as contrasts, with GluR2. Synapse 67:692–704, 2013 . © 2013 Wiley Periodicals, Inc.     

Odor identification deficits are associated with increased risk of neuropsychiatric complications in patients with Parkinson's disease

Olfactory deficits appear early in the course of Parkinson's disease (PD) but their prognostic significance is not known. The goal of this study was to determine whether the severity of olfactory impairment is associated with subsequent risk of developing complications of PD. One hundred patients with PD self‐administered the University of Pennsylvania Smell Identification Test (UPSIT). Testing was done, on average, 3.6 years from the time of initial diagnosis. The incidence of neuropsychiatric features of PD, including cognitive decline and visual hallucinations, was ascertained through chart review after an average of 6.8 years of follow‐up. Incidence of motor outcomes including falls and dyskinesias was also obtained. There was a significant trend for increased risk of neuropsychiatric complications across declining quartiles of olfactory test scores. In addition, subjects in the lowest quartile of olfactory performance had a significantly higher adjusted risk of hallucinations (HR = 4.70, 95% CI 1.64, 13.42) and cognitive decline (HR = 3.10, 95% CI 1.05, 9.21) than those in the reference quartile. There was no association between olfactory dysfunction and dyskinesias, and a very modest association with risk of falls. These findings suggest that severity of olfactory impairment early in the disease course may be a useful marker for the risk of neuropsychiatric complications of PD. © 2010 Movement Disorder Society     

A1 and A2A adenosine receptors and A1 mRNA in mouse brain: effect of long-term caffeine treatment

The effect of oral treatment with caffeine, in doses that are known to produce marked adaptive effects, was investigated on A₁ and A_2A receptors in the mouse brain. Caffeine (0.1, 0.3 or 1 g/l) was added to the drinking water and the animals were sacrificed after a 14-day treatment period. Ligand binding to A₁ receptors was studied, using quantitative autoradiography, with the agonist [³H]cyclohexyladenosine (CHA) and the antagonist [³H]1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Caffeine did not remain in the sections during the autoradiography experiments. Caffeine treatment (1 g/l, but not 0.1 or 0.3 g/l) tended to increase [³H]CHA binding to the CA3 subfield of the hippocampus, but in no other region studied. There was no change in the number of A₁ receptors since [³H]DPCPX binding to the CA3, cerebral and cerebellar cortex was not influenced by caffeine treatment. There was similarly no change in the ability of CHA to displace [³H]DPCPX binding, suggesting that there are no major changes in the proportion of A₁ receptors that are coupled to G-proteins. mRNA for the A₁ receptor, measured by in situ hybridization, did not differ significantly between caffeine-treated and control mice in the structures examined. Thus, higher doses of caffeine can cause an increase in A₁ agonist binding without a corresponding change in A₁ mRNA or in A₁ antagonist binding, suggesting that the adaptive changes seen upon prolonged caffeine treatment may be in sites different from A₁ receptors. Caffeine (1 g/l) increased A_2A receptors in the striatum measured as binding of the agonist [³H]CGS 21680 suggesting that up-regulation of A_2A receptors may be an adaptive effect of caffeine intake.     

Plasma levels of soluble tumor necrosis factor receptors are associated with cognitive performance in Parkinson's disease

Inflammatory mechanisms have been implicated in a series of neuropsychiatric conditions, including behavioral disturbances, cognitive dysfunction, and affective disorders. Accumulating evidence also strongly suggests their involvement in the pathophysiology of Parkinson's disease (PD). This study aimed to evaluate plasma levels of inflammatory biomarkers, and their association with cognitive performance and other non‐motor symptoms of PD. PD patients and control individuals were subjected to various psychometric tests, including the Mini‐Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Beck's Depression Inventory (BDI). Biomarker plasma levels were measured by enzyme‐linked immunosorbent assay (ELISA). PD patients exhibited worse performance on MMSE and the programming task of FAB, and presented higher soluble tumor necrosis factor receptor (sTNFR) plasma levels than control individuals. Among PD patients, increased sTNFR1 and sTNFR2 concentrations were associated with poorer cognitive test scores. After multiple linear regression, sTNFR1 and education remained a significant predictor for FAB scores. Our data suggest that PD is associated with a proinflammatory profile, and sTNFRs are putative biomarkers of cognitive performance, with elevated sTNFR1 levels predicting poorer executive functioning in PD patients. © 2013 International Parkinson and Movement Disorder Society     

Experience-dependent regulation of zif268 gene expression and spatial learning

Environmental enrichment (EE) is known to enhance the cognitive ability of rodents. To translate EE to the human condition, it is important to understand the parameters of its efficacy. In this study, we examine if the cognitive enhancement associated with EE is permanent and whether a developmental window exists for its efficacy. Rats were housed in continuous isolation (ISO), continuous enrichment (EE), enrichment from postnatal day (PN) 21-50, and then isolation from PN50-79 (PM), or isolation from PN21-50 and then enriched from PN50-79 (CW). Spatial learning ability and basal expression of the immediate-early genes zif268 and Arc as well as the NR1 subunit of the NMDA receptor were assessed. Rats housed in an enriched environment at the time of testing (EE and CW) performed significantly better in the spatial learning task than rats housed in an isolated environment at the time of testing (ISO and PM). Enhanced performance in the spatial learning task was associated with a higher expression of zif268 only in the CA3/CA4 region of the hippocampus. Our study further defines parameters that make environmental enrichment effective in enhancing learning performance and the findings may be helpful in the translation of this intervention to the human condition.     

Expression of glutamate receptors in the human and rat basal ganglia: Effect of the dopaminergic denervation on AMPA receptor gene expression in the striatopallidal complex in parkinson's disease and rat with 6-OHDA lesion

The overactivity of subthalamopallidal and corticostriatal glutamatergic neurons observed in Parkinson's disease (PD) suggests that antagonists of glutamate receptor could be used to alleviate the motor symptoms of the disease. In this study, we analysed two features of the striatopallidal complex: (1) the distribution of α-amino-3 hydroxy-5-methyl-4-isoxasol-propionate (AMPA) and kainate receptors and their corresponding mRNA by immunohistochemistry and in situ hybridisation and (2) the effect of dopaminergic denervation on AMPA receptor gene expression in PD patients and rats with 6-hydroxydopamine (6-OHDA)-induced degeneration of the nigrostriatal dopaminergic system. All AMPA receptor mRNAs and proteins (GluR1–4) were detected in the internal segment of the globus pallidus (GPi). Among kainate receptors, only KA1 and KA2 were detectable and only at a low level. Only GluR4 protein was detected in the neuropil of the GPi. In the striatum, GluR1, GluR2, and GluR3 were detected in about 70% of medium-sized and large neurons. By contrast, GluR4 mRNA was detected in only a small number of large and medium-sized neurons. Among kainate receptors, GluR6, GluR7, and KA2 were detected in about 50–60% of medium-sized neurons, whereas GluR5 and KA1 were restricted to 1–2% and 20–30% of these neurons, respectively. These results suggest that antagonists of AMPA and kainate receptors could be effective in alleviating motor symptoms in Parkinson's disease by blocking the overstimulation of pallidal and striatal neurons by glutamate. A significant decrease in GLuR1 gene expression (−33%) was observed in the neurons of the GPi in PD patients and in rat entopeduncular nucleus ipsilateral to the 6-OHDA lesion (−20%). GluR2, GluR3, and GluR4 mRNA levels in the GPi and GluR1–4 mRNA levels in the striatum were unchanged in PD patients and 6-OHDA-lesioned rats compared with their respective controls. These data suggest that dopamine positively regulates only GluR1 gene expression in the GPi. © 1996 Wiley-Liss, Inc.     

Changes in extracellular glutamate and GABA levels in the hippocampal CA3 and CA1 areas and the induction of glutamic acid decarboxylase-67 in dentate granule cells of rats treated with kainic acid

For the evaluation of glutamatergic and GABAergic transmission during seizures, rat hippocampal CA₁ and CA₃ areas were separately assessed by brain microdialysis, and extracelluar glutamate and GABA were measured through the course of the seizures after a systemic administration of kainic acid (KA). The generalized convulsion started at about 1.5 h and was suppressed by diazepam at 2 h after the KA treatment. In the CA₃ area, extracellular glutamate started to increase soon after the KA injection and returned to the control level at about 1.5 h. A decrease and then slight increase of the extracellular glutamate level in CA₃ followed the diazepam injection. In the CA₁ area, in contrast, a long-lasting decrease of extracellular glutamate was observed. The extracellular GABA concentration in the CA₃ area increased immediately after the systemic administration of KA and returned to the normal level at about 3.5 h. A second increase in the extracellular GABA in this area began at about 4.5 h after the KA treatment. In the CA₁ area, an increase of extracellular GABA began at about 3.5 h after KA administration (much later than that observed in the CA₃ area) and was maintained throughout the observation. In situ hybridization showed a transient expression of glutamic acid decarboxylase (GAD)-67 mRNA in the granule cell layer of the dentate gyrus at 4 and 6 h, whereas GAD65 mRNA was unaffected. GABA immunoreactivity in the same area and mossy fibers in the CA₃ were increased most significantly at 8 h after administration of KA. The possible relation of GABA induction in mossy fibers with the delayed increase in extracellular GABA in CA₃ was discussed.     

NMDA receptors mediate heat shock protein induction in the mouse brain following administration of the ibotenic acid analogue AMAA

Expression of inducible heat shock protein-70 (HSP-70) and hsp-70 mRNA were studied in the adult mouse brain following systemic administration of the ibotenic acid analogue (±)-2-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMAA), which is a potent N-methyl- d-aspartate (NMDA) agonist. At the dose of 20 mg/kg, AMAA produced excitatory behaviours in adult mice but overt convulsions were not seen. This treatment did not result in any detectable morphological brain damage at 4 days following administration. At 2.5 h and 5 h following treatment induction of hsp-70 mRNA expression was found in the pyramidal cell layers of CA1 and, to a lesser extent, CA3 fields of hippocampal Ammon's horn, amygdala, olfactory lobes, tenia tecta, hypothalamic nuclei and a superficial layer of cingulate, frontal and retrosplenial cortices. The presence of HSP-70 was detected by immunohistochemistry at 24 h following drug administration in those regions previously showing hsp-70 mRNA induction. AMAA-induced hsp-70 mRNA expression was prevented by pre-treatment with the non-competitive NMDA antagonist MK-801. These results suggest that NMDA receptors are involved in the stress response induced by AMAA.     

Lack of LTP-like plasticity in primary motor cortex in Parkinson's disease

In this study in patients with Parkinson's disease (PD), off and on dopaminergic therapy, with and without L-dopa-induced dyskinesias (LIDs), we tested intermittent theta-burst stimulation (iTBS), a technique currently used for non-invasively inducing long-term potentiation (LTP)-like plasticity in primary motor cortex (M1). The study group comprised 20 PD patients on and off dopaminergic therapy (11 patients without and 9 patients with LIDs), and 14 age-matched healthy subjects. Patients had mild-to-moderate PD, and no additional neuropsychiatric disorders. We clinically evaluated patients using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). The left M1 was conditioned with iTBS at 80% active motor threshold intensity. Twenty motor evoked potentials (MEPs) were recorded from right first interosseous muscle before and at 5, 15 and 30 min after iTBS. Between-group analysis of variance (ANOVA) testing healthy subjects versus patients with and without LIDs, on and off therapy showed a significant interaction between factors “Group” and “Time”. After iTBS, MEP amplitudes in healthy subjects increased significantly at 5, 15 and 30 min (p < 0.01 at all time-points) but in PD patients with and without LIDs, on and off therapy, remained unchanged. In PD patients with and without LIDs, on and off therapy iTBS fails to increase MEP responses. This finding suggests lack of iTBS-induced LTP-like plasticity in M1 in PD regardless of patients' clinical features.     

Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA,LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine

Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r = + 0.97; P = 0.001) and immobility (r = − 0.90; P = 0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with “emotional” impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins.