L‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease is associated with the fluctuational release of norepinephrine in the sensorimotor striatum

L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia (LID) is the most common complication of standard L‐DOPA therapy for Parkinson's disease experienced by most parkinsonian patients. LID is associated with disruption of dopaminergic homeostasis in basal ganglia following L‐DOPA administration. Norepinephrine (NE) is another important catecholaminergic neurotransmitter that is also believed to be involved in the pathogenesis of LID. This study compared NE release in the ipsilateral sensorimotor striatum of dyskinetic and nondyskinetic 6‐hydroxydopamine‐lesioned hemiparkinsonian rats treated chronically with L‐DOPA. After L‐DOPA injection, the time‐course curves of NE levels in the sensorimotor striatum were significantly different between dyskinetic and nondyskinetic rats. Several metabolic kinetic parameters of NE levels were also differentially expressed between the two groups. In comparison with nondyskinetic rats, the ΔC_max of NE was significantly higher in dyskinetic rats, whereas T_max and t_1/2 of NE were significantly shorter. Intrastriatal perfusion of NE into the lesioned sensorimotor striatum revealed a moderate dyskinesia in dyskinetic rats, which was similar to the dyskinetic behavior after L‐DOPA administration. The L‐DOPA‐related dyskinetic behavior was inhibited significantly by a further pretreatment of noradrenergic neurotoxin N‐?(2‐?chloroethyl)?‐?N‐?ethyl‐?2‐?bromobenzylamine or intrastriatal administration of the α₂‐adrenoceptor antagonist idazoxan, accompanied by significant changes in metabolic kinetic parameters of NE in the sensorimotor striatum. The results provide evidence to support the correlation between abnormal NE neurotransmission and the induction of LID and suggest that the aberrant change of the quantitative and temporal releasing of NE in the sensorimotor striatum might play an important role in the pathogenesis of LID. © 2014 Wiley Periodicals, Inc.     

Serotonin (5‐HT) regulates neurite outgrowth through 5‐HT1A and 5‐HT7 receptors in cultured hippocampal neurons

Serotonin (5‐HT) production and expression of 5‐HT receptors (5‐HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5‐HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5‐HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G‐protein‐coupled 5‐HT_1AR and 5‐HT₇R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5‐HT promotes neurite outgrowth through 5‐HT_1AR and 5‐HT₇R. The involvement of 5‐HT_1AR and 5‐HT₇R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5‐HT and specific antagonists for 5‐HT_1AR and 5‐HT₇R (WAY‐100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5‐HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT₇R was blocked, the addition of 5‐HT increased the number of primary neurites, suggesting that 5HT₇R could inhibit neuritogenesis. In contrast, 5‐HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY‐100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5‐HT_1AR and 5‐HT₇R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth. © 2014 Wiley Periodicals, Inc.     

The highly selective mGlu2 receptor positive allosteric modulator LY‐487,379 alleviates l‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat model of Parkinson's disease

l ‐3,4‐Dihydroxyphenylalanine (l ‐DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu_2/3) receptor activation with LY‐354,740 alleviates dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset and the 6‐hydroxydopamine (6‐OHDA)‐lesioned rat. Here, we sought to determine the role played by selective mGlu₂ activation in the anti‐dyskinetic effect of mGlu_2/3 stimulation and have investigated the effect of the highly selective mGlu₂ positive allosteric modulator LY‐487,379 at alleviating established, and preventing the development of, l ‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat. First, dyskinetic 6‐OHDA‐lesioned rats were administered l ‐DOPA in combination with LY‐487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6‐OHDA‐lesioned rats were administered LY‐487,379 (0.1 or 1 mg/kg), started concurrently with l ‐DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY‐487,379 on l ‐DOPA anti‐parkinsonian effect. We found that acute challenges of LY‐487,379 0.1 mg/kg in combination with l ‐DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l ‐DOPA/LY‐487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l ‐DOPA/vehicle. LY‐487,379 did not impair l ‐DOPA anti‐parkinsonian activity. These results suggest that mGlu₂ activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.     

Brain 5-HT(2A) receptors in MPTP monkeys and levodopa-induced dyskinesias

Levodopa‐induced dyskinesias (LIDs) are abnormal involuntary movements induced by the chronic use of levodopa (l ‐Dopa) limiting the quality of life of Parkinson’s disease (PD) patients. We evaluated changes of the serotonin 5‐HT_2A receptors in control monkeys, in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned monkeys and in l ‐Dopa‐treated MPTP monkeys, without or with adjunct treatments to inhibit the expression of LID: CI‐1041, a selective NR1A/2B subunit antagonist of glutamate N‐methyl‐d ‐aspartic acid (NMDA) receptor, or Cabergoline, a long‐acting dopamine D₂ receptor agonist. All treatments were administered for 1 month and animals were killed 24 h after the last dose of l ‐Dopa. Striatal concentrations of serotonin were decreased in all MPTP monkeys investigated, as measured by high‐performance liquid chromatography. [³H]Ketanserin‐specific binding to 5‐HT_2A receptors was measured by autoradiography. l ‐Dopa treatment that induced dyskinesias increased 5‐HT_2A receptor‐specific binding in the caudate nucleus and the anterior cingulate gyrus (AcgG) compared with control monkeys. Moreover, [³H]Ketanserin‐specific binding was increased in the dorsomedial caudate nucleus in l ‐Dopa‐treated MPTP monkeys compared with saline‐treated MPTP monkeys. Nondyskinetic monkeys treated with CI‐1041 or Cabergoline showed low 5‐HT_2A‐specific binding in the posterior dorsomedial caudate nucleus and the anterior AcgG compared with dyskinetic monkeys. No significant difference in 5‐HT_2A receptor binding was observed in any brain regions examined in saline‐treated MPTP monkeys compared with control monkeys. These results confirm the involvement of serotonergic pathways and the glutamate/serotonin interactions in LID. They also support targeting 5‐HT_2A receptors as a potential treatment for LID.     

Behavioral and electrophysiological effects of 5‐HT in globus pallidus of 6‐hydroxydopamine lesioned rats

Anatomical studies have shown that the globus pallidus receives abundant 5‐hydroxytryptamine (5‐HT) innervations from raphe nuclei. 5‐HT may occupy an important position in the modulation of motor function through its affect on the activity of globus pallidus. In the present study, intrapallidal microinjection of 5‐HT (0.1 mM) alone did not induce any motor behavior or postural asymmetry in the unilateral 6‐hydroxydopamine (6‐OHDA)‐lesioned rats. However, when infused concomitantly with a low dose of 3, 4‐dihydroxyphenylalanine (L‐DOPA, 3 mg/kg i.p.), which itself can induce modest contralateral rotational behavior, 5‐HT significantly potentiated the number of contralateral rotations. To elucidate the cellular mechanism, in vivo extracellular recordings were performed to examine the effects of 5‐HT on globus pallidus neurons. In normal rats, the predominant effect of micropressure ejection of 5‐HT on pallidal neurons was excitation. In 6‐OHDA‐lesioned rats, although 5‐HT increased the firing rate in most pallidal neurons, 5‐HT‐induced inhibitory effects was stronger than that on the unlesioned side as well as normal rats. Furthermore, 5‐HT_1B receptors are mainly involved in 5‐HT‐induced excitation while 5‐HT_1A receptors are involved in 5‐HT‐induced inhibition. The results suggest that 5‐HT may potentiate the antiparkinsonian effect of L‐DOPA through modulating the activity of globus pallidus. © 2009 Wiley‐Liss, Inc.     

Antidepressant medication exposure and 5‐HT1A autoreceptor binding in major depressive disorder

Objective: We have previously reported higher brain serotonin 1A (5‐HT_1A) autoreceptor binding in antidepressant‐naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5‐HT_1A receptor binding after medication discontinuation. Methods: Positron emission tomography (PET) imaging with the 5‐HT_1A receptor radioligand [¹¹C]WAY‐100635 was performed in 66 individuals with current DSM‐IV MDD to examine relationships between 5‐HT_1A binding and time since most recent antidepressant treatment. All subjects were medication‐free for at least 2 weeks prior to scanning. Thirty‐two additional MDD comparison subjects were antidepressant naïve. Results: No differences in [¹¹C]WAY‐100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [¹¹C]WAY‐100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. Conclusion: These results indicate that any antidepressant‐associated downregulation of 5‐HT_1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness‐related binding levels.     

Increased levels of 5‐HT1A receptor binding in ventral visual pathways in Parkinson's disease

Visual hallucinations are common in advanced Parkinson's disease (PD). The pathophysiology of visual hallucinations may involve enhanced serotonergic neurotransmission. The atypical antipsychotics clozapine and quetiapine, which have affinity for 5‐HT_2A and 5‐HT_1A receptors, are effective against visual hallucinations in PD. 5‐HT_2A receptors are increased in ventral visual pathways in PD patients with visual hallucinations, and we hypothesized that 5‐HT_1A receptors were also involved in visual hallucinations in PD. Autoradiographic binding using [³H]‐WAY‐100,635 and NAN‐190 was performed in brain sections from 6 PD patients with visual hallucinations, 6 PD patients without visual hallucinations, and 5 age‐matched controls. All PD subjects had been treated with L ‐dopa. Brain areas studied were the orbitofrontal, inferolateral temporal, and motor cortices, as well as the striatum, globus pallidus, substantia nigra, and thalamus. 5‐HT_1A‐binding levels were dramatically increased in the ventral visual pathways of all PD patients compared with controls (0 vs 11 and 0 vs 100 nmol/mg, respectively; both P < .05). There was no significant difference in 5‐HT_1A‐binding levels in PD patients with visual hallucinations compared with PD patients without visual hallucinations or with controls in any of the brain areas studied (P > .05). Gross abnormalities in 5‐HT_1A levels in ventral visual areas occurred in all PD patients exposed to L ‐dopa. However, as there was no difference in 5‐HT_1A‐binding levels between hallucinators and nonhallucinators, alterations in 5‐HT_1A receptor levels may not contribute specifically to visual hallucinations in PD. However, the discrete anatomical distribution of rises to the ventral visual areas suggests some role in predisposing to visual hallucinations. © 2012 Movement Disorder Society     

Interactions of serotonin (5‐HT)2 receptor‐targeting ligands and nicotine: Locomotor activity studies in rats

Male Wistar rats were used to verify the hypothesis that serotonin (5‐HT)_2A or 5‐HT_2C receptors may control the locomotor effects evoked by nicotine (0.4mg/kg). The 5‐HT_2A receptor antagonist (M100,907), the 5‐HT_2A receptor agonist (DOI), the 5‐HT_2C receptor antagonist (SB 242,084), and the 5‐HT_2C receptor agonists (Ro 60‐0175 and WAY 163,909) were used. M100,907 (0.5–2mg/kg) did not alter, while DOI (1 mg/kg) enhanced the nicotine‐induced hyperlocomotion. The effect of DOI was antagonized by M100,907 (1 mg/kg). SB 242,084 (0.25–1 mg/kg) augmented, while Ro 60‐0175 (1 and 3 mg/kg) and WAY 163,909 (1.5 mg/kg) decreased the overall effect of acute nicotine; effects of Ro 60‐0175 and WAY 163,909 were attenuated by SB 242,084 (0.125 mg/kg). In another set of experiments, M100,907 (2 mg/kg) on Day 10 attenuated, while DOI (0.1–1 mg/kg) enhanced the nicotine‐evoked conditioned hyperlocomotion in rats repeatedly (Days 1–5) treated with nicotine in experimental chambers. SB 242,084 (0.125 or 1 mg/kg) did not change, while Ro 60‐0175 (1 mg/kg) or WAY 163,909 (1.5 mg/kg) decreased the expression of nicotine‐induced conditioned hyperactivity. Only DOI (0.3 and 1 mg/kg) and SB 242,084 (1 mg/kg) enhanced the basal locomotion. The present data indicate that 5‐HT_2A receptors are significant for the expression of nicotine‐evoked conditioned hyperactivity. Conversely, 5‐HT_2C receptors play a pivotal role in the acute effects of nicotine. Pharmacological stimulation of 5‐HT_2A receptors enhances the conditioned hyperlocomotion, while activation of 5‐HT_2C receptors decreases both the response to acute nicotine and conditioned hyperactivity. Synapse 63:653–661, 2009. © 2009 Wiley‐Liss, Inc.     

Higher pretreatment 5‐HT1A receptor binding potential in bipolar disorder depression is associated with treatment remission: A naturalistic treatment pilot PET study

Bipolar disorder is a major cause of disability and a high risk for suicide. The pathophysiology of the disorder remains largely unknown. Medication choice for bipolar depression patients involves trial and error. Our group reported previously that brain serotonin 1A (5‐HT_1A) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5‐HT_1A levels correlates with antidepressant medication outcome. Forty‐one medication‐free DSM‐IV diagnosed, bipolar patients in a major depressive episode had brain PET scans performed using [¹¹C]WAY‐100635 and a metabolite corrected arterial input function. The patients then received naturalistic psychopharmacologic treatment as outpatients and a follow up Hamilton Depression Rating Scale (HDRS) after 3 months of treatment. Patients with 24 item HDRS scores less than 10 were considered to have remitted. A linear mixed effects model was used to compare BP_F (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and nonremitters. Thirty‐four patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and nonremitters did not differ in age, sex, or recent medication history with serotonergic medications. Remitters had higher [¹¹C]WAY‐100635 BP_F across all brain regions compared with nonremitters (P = 0.02). Higher pretreatment brain 5‐HT_1A receptor binding was associated with remission after 3 months of pharmacological treatment in bipolar depression. Prospective treatment studies are warranted to determine whether this test predicts outcome of specific types of treatment. Synapse 67:773–778, 2013 . © 2013 Wiley Periodicals, Inc.     

Differential effects of serotonin (5‐HT)2 receptor‐targeting ligands on locomotor responses to nicotine‐repeated treatment

We verified the hypothesis that serotonin (5‐HT)₂ receptors control the locomotor effects of nicotine (0.4 mg kg⁻¹) in rats by using the 5‐HT_2A receptor antagonist M100907, the preferential 5‐HT_2A receptor agonist DOI, the 5‐HT_2C receptor antagonist SB 242084, and the 5‐HT_2C receptor agonists Ro 60‐0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5‐HT₂ receptor ligands, M100907 (2 mg kg⁻¹) or DOI (1 mg kg⁻¹) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg⁻¹), Ro 60‐0175 (1 mg kg⁻¹), and WAY 163909 (1.5 mg kg⁻¹) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1–5, 10) with nicotine, none of 5‐HT₂ receptor ligands administered during the second withdrawal period (Days: 11–14) to nicotine‐treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5‐HT_2A receptors (but not 5‐HT_2C receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5‐HT_2A receptors enhances the development of nicotine sensitization and activation of 5‐HT_2C receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5‐HT₂ receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization. Synapse 64:511–519, 2010. © 2010 Wiley‐Liss, Inc.     

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Aromatic L‐amino acid decarboxylase (AAAD) is an essential enzyme for the formation of catecholamines, indolamines, and trace amines. Moreover, it is a required enzyme for converting L‐DOPA to dopamine when treating patients with Parkinson's disease (PD). There is now substantial evidence that the activity of AAAD in striatum is regulated by activation and induction, and second messengers play a role. Enzyme activity can be modulated by drugs acting on a number of neurotransmitter receptors including dopamine (D1–4), glutamate (NMDA), serotonin (5‐HT_1A, 5‐HT_2A) and nicotinic acetylcholine receptors. Generally, antagonists enhance AAAD activity; while, agonists may diminish it. Enhancement of AAAD activity is functional, as the formation of dopamine from exogenous L‐DOPA mirrors activity. Following a lesion of nigrostriatal dopaminergic neurons, AAAD in striatum responds more robustly to pharmacological manipulations, and this is true for the decarboxylation of exogenous L‐DOPA as well. We review the evidence for parallel modulation of AAAD activity and L‐DOPA decarboxylation and propose that this knowledge can be exploited to optimize the formation of dopamine from exogenous L‐DOPA. This information can be used as a blue print for the design of novel L‐DOPA treatment adjuvants to benefit patients with PD.     

In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate

[F‐18]Mefway was developed to provide an F‐18 labeled positron emission tomography (PET) neuroligand with high affinity for the serotonin 5‐HT_1A receptor to improve the in vivo assessment of the 5‐HT_1A system. The goal of this work was to compare the in vivo kinetics of [F‐18]mefway, [F‐18]MPPF, and [C‐11]WAY100635 in the rhesus monkey. Methods: Each of four monkeys were given bolus injections of [F‐18]mefway, [C‐11]WAY100635, and [F‐18]MPPF and scans were acquired with a microPET P4 scanner. Arterial blood was sampled to assay parent compound throughout the time course of the PET experiment. Time activity curves were extracted in the high 5‐HT_1A binding areas of the anterior cingulate cortex (ACG), mesial temporal cortex, raphe nuclei, and insula cortex. Time activity curves were also extracted in the cerebellum, which was used as a reference region. The in vivo kinetics of the radiotracers were compared based on the nondisplaceable distribution volume (V_ND) and binding potential (BP_ND). Results: At 30 min, the fraction of radioactivity in the plasma due to parent compound was 19%, 28%, and 29% and cleared from the arterial plasma at rates of 0.0031, 0.0078, and 0.0069 (min^?1) ([F‐18]mefway, [F‐18]MPPF, [C‐11]WAY100635). The BP_ND in the brain regions were mesial temporal cortex: 7.4 ± 0.6, 3.1 ± 0.4, 7.0 ± 1.2, ACG: 7.2 ± 1.2, 2.1 ± 0.2, 7.9 ± 1.2; raphe nuclei: 3.7 ± 0.6, 1.3 ± 0.3, 3.3 ± 0.7; and insula cortex: 4.2 ± 0.6, 1.2 ± 0.1, 4.7 ± 1.0 for [F‐18]mefway, [F‐18]MPPF, and [C‐11]WAY100635 respectively. Conclusions: In the rhesus monkey, [F‐18]mefway has similar in vivo kinetics to [C‐11]WAY100635 and yields greater than 2‐fold higher BP_ND than [F‐18]MPPF. These properties make [F‐18]mefway a promising radiotracer for 5‐HT_1A assay, providing higher counting statistics and a greater dynamic range in BP_ND. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

l‐Stepholidine‐induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5‐HT1A receptor partial agonistic activity

Rationale: l‐Stepholidine (l‐SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D₁/5‐HT_1A agonist and a D₂ antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l‐SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. To further explore the antipsychotic mechanisms of the drug, we studied the effects of l‐SPD on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single‐unit recording technique in rats. Result: We found that l‐SPD increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, l‐SPD, not clozapine, reversed d‐amphetamine‐induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of l‐SPD is associated with its partial agonistic action for the 5‐HT_1A receptor since the 5‐HT_1A receptor antagonist WAY100635 could block the l‐SPD‐induced excitatory effect. However, activation of 5‐HT_1A receptor alone by specific agonist (±)‐8‐Hydroxy‐2‐(dipropylamino) tetralin (8‐OH‐DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8‐OH‐DPAT on VTA DA neurons was elicited in the presence of D₂‐like receptors antagonist raclopride. Collectively, these results indicate that l‐SPD excited VTA DA neurons requiring its D₂‐like receptors antagonistic activity and 5‐HT_1A receptor agonistic activity. Conclusion: The present data demonstrate that D₂ receptor antagonist/5‐HT_1A receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between l‐SPD and other atypical antipsychotic drugs. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Alterations in 5‐HT2A receptor binding in various brain regions among 6‐hydroxydopamine‐induced Parkinsonian rats

The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5‐hydroxytryptamine (5‐HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6‐hydroxydopamine (6‐OHDA). 5‐HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [³H]ketanserin‐binding autoradiography. In the 6‐OHDA‐induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [³H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [³H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5‐HT_2A receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5‐HT_2A receptors in treating neurodegenerative disorders and implicates 5‐HT_2A receptors as a novel therapeutic target in the treatment of PD. Synapse 64:224–230, 2010. © 2009 Wiley‐Liss, Inc.     

5‐HT2A receptor blockade and 5‐HT2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate‐putamen

Both the 5‐HT_2A receptor (R) antagonist M100907 and the 5‐HT_2CR agonist MK212 attenuate cocaine‐induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose‐effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5‐HT_2A/5‐HT_2CR interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1‐h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine‐induced Fos expression in the dorsolateral caudate‐putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5‐HT_2ARs and 5‐HT_2CRs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5‐HT₂R subtypes on behavior. Further research investigating combined 5‐HT_2AR antagonism and 5‐HT_2CR agonism as a treatment for cocaine dependence is warranted. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

5‐HT1A and NMDA receptors interact in the rat medial septum and modulate hippocampal‐dependent spatial learning

Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal‐dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5‐HT_1A receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5‐HT_1A receptors are important for hippocampal‐dependent long‐term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal‐dependent spatial memory. Intraseptal infusion of the 5‐HT_1A receptor agonist (R)‐8‐OH‐DPAT (1 or 4 μg/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 μg/rat). While intraseptal administration of (R)‐8‐OH‐DPAT (4 μg) combined with a subthreshold dose of the NMDA receptor antagonist D‐AP5 (1 μg) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5‐HT_1A receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5‐HT_1A and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal‐dependent long‐term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5‐HT_1A receptor activation on memory, which may be clinically relevant. © 2009 Wiley‐Liss, Inc.     

On the role of 5‐HT1A receptor gene in behavioral effect of brain‐derived neurotrophic factor

Experiments were made on a congenic AKR.CBA‐D13Mit76C (76C) mouse strain created by transferring a chromosome 13 fragment containing the 5‐HT_1A receptor gene from a CBA strain to an AKR background. It was shown that 76C mice differed from AKR mice by decreased 5‐HT_1A receptor and tryptophan hydroxylase‐2 (tph‐2) genes expression in the midbrain. Functional activity of 5‐HT_2A receptors and 5‐HT_2A receptor mRNA levels in the midbrain and hippocampus of 76C mice were decreased compared with AKR mice. Central brain‐derived neurotrophic factor (BDNF) administration (300 ng i.c.v.) reduced 5‐HT_1A and 5‐HT_2A receptor mRNA levels in the frontal cortex and tph‐2 mRNA level in the midbrain of AKR mice. However, BDNF failed to produce any effect on the expression of 5‐HT_1A, 5‐HT_2A, and tph‐2 genes in 76C mice but decreased functional activity of 5‐HT_2A receptors in 76C mice and increased it in AKR mice. BDNF restored social deficiency in 76C mice but produced asocial behavior (aggressive attacks towards young mice) in AKR mice. The data indicate that a small genetic variation altered the response to BDNF and show an important role of 5‐HT_1A receptor gene in the 5‐HT system response to BDNF treatment and in behavioral effects of BDNF. © 2014 Wiley Periodicals, Inc.     

Combined fenobam and amantadine treatment promotes robust antidyskinetic effects in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned primate model of Parkinson's disease

Amantadine, an N‐methyl‐D‐aspartate glutamate receptor antagonist, is currently the only pharmacological treatment for levodopa‐induced dyskinesia (LID) in Parkinson's disease (PD), but causes adverse effects on the central nervous system at therapeutic doses. Fenobam, a negative modulator of metabotropic glutamate receptor subtype 5, has recently been reported to attenuate LID in MPTP‐treated macaques. The aim of the current study was to investigate the treatment interactions of fenobam and amantadine on LID in the MPTP‐treated macaque model of PD. The antidyskinetic and ‐parkinsonian effects were measured after administration of fenobam (10‐30 mg/kg) and amantadine (10‐30 mg/kg) alone and in combination. Fenobam (30 mg/kg) and amantadine (30 mg/kg) alone reduced LID, whereas lower doses of either drug did not cause any significant effects. A combined treatment of fenobam and amantadine at subthreshold doses (10 and 20 mg/kg) significantly reduced LID without worsening PD disability. These data suggest that a low‐dose combination of fenobam and amantadine can be used for alleviating dyskinesia without causing adverse motor effects. Such combined therapies may offer a new therapeutic strategy for treatment of LID in PD patients. © 2014 International Parkinson and Movement Disorder Society