Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models.

BACKGROUND: Serotoninergic transmission in the basal ganglia is known to influence dopaminergic mechanisms and motor function. OBJECTIVE: To evaluate the possibility that serotoninergic 5-HT1A autoreceptors (by regulating the release of serotonin as well as dopamine formed from exogenous levodopa) affect the response alterations complicating levodopa treatment of PD. METHODS: The 5-HT1A receptor agonist sarizotan (EMD128130) was systemically administered alone and together with levodopa to parkinsonian rats and nonhuman primates. RESULTS: In 6-hydroxydopamine-lesioned rats, sarizotan (2.5 mg/kg PO) had no effect on the acute rotational response to levodopa but did attenuate the shortening in motor response duration induced by chronic levodopa treatment. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, sarizotan (2 mg/kg PO) alone had no effect on parkinsonian severity or on the antiparkinsonian response to levodopa. In contrast, the same dose of sarizotan reduced levodopa-induced choreiform dyskinesias by 91 +/- 5.9%. In both species, the motoric effects of sarizotan were blocked by the selective 5-HT1A antagonist WAY100635 (0.1 mg/kg SC), indicating that the observed sarizotan responses were probably mediated at the 5-HT1A autoreceptor. CONCLUSION: Pharmaceuticals acting to stimulate 5-HT1A receptors could prove useful in the treatment of the motor response complications in parkinsonian patients.     

LY293558, an AMPA glutamate receptor antagonist, prevents and reverses levodopa-induced motor alterations in Parkinsonian rats.

To evaluate the possible involvement of glutamate AMPA receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of LY293558, a competitive AMPA receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion or prevention of these levodopa effects. In the first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immediately before levodopa. In the second set of experiments, rats were treated daily for 22 days with levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) administration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after daily levodopa treatment was studied. The duration of the rotational behavior induced by chronic levodopa decreased by 30% after 22 days. Acute administration of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with levodopa and LY293558 did not show the decrease in this motor response duration. Chronic levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the response to the D-2 agonist quinpirole. LY293558 did not reverse the effect of levodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in levodopa-treated animals by 40%. Our results demonstrate that an AMPA receptor antagonist reverses and prevents levodopa-induced motor alterations in parkinsonian rats and that this effect on motor fluctuations induced by chronic levodopa is probably due to a modulation of the indirect output pathway of the basal ganglia.     

Adenosine A2A antagonism reverses levodopa-induced motor alterations in hemiparkinsonian rats

To evaluate the possible involvement of adenosine A(2A) receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of CSC (8-(3-chlorostryryl) caffeine), a selective adenosine A(2A) receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of CSC was studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 CSC (5 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and CSC (5 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of CSC on day 23 reversed levodopa-induced shortening in motor response duration (P < 0.01). Chronic CSC administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the adenosine A(2A) receptor antagonist CSC reverses but does not prevent levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for adenosine A(2A) receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the antagonism of adenosine A(2A) receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.     

Serotoninergic mechanisms of immunomodulation under different psychoemotional states: I. A role of 5-HT 1A receptor subtype

The present study demonstrates the involvement of serotonin (5-HT) receptors of the 5-HT 1A type in immunoinhibitory effect of 5-HTergic system of the brain. A selective agonist of 5-HT 1A receptors 8-OH-DPAT (1 mg/kg) induces the immunosuppression, whereas 5-HT 1A blockade with WAY-100635 (1 mg/kg) resulted in immunostimulation. It is also shown that immunomodulating effects of the drugs were dependent on psychoemotional status of animals acquired aggressive or submissive behavior under social conflict conditions. Activation of 5-HT 1A receptors produced a decrease of the immunity in aggressive mice, whereas 5-HT 1A receptor blockade caused immunostimulation in submissive animals.     

Involvement of 5-HT1A receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test

This study investigated the involvement of 5-HT1 and 5-HT2 receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test (FST). The pre-treatment of mice with PCPA (100mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), NAN-190 (0.5mg/kg, i.p., a 5-HT1A receptor antagonist), pindolol (32 mg/kg, i.p., a 5-HT1A/1B receptor/beta-adrenoceptor antagonist) or WAY100635 (0.1 and 0.3mg/kg, s.c., a selective 5-HT1A receptor antagonist), but not with ketanserin (5mg/kg, i.p., a 5-HT2A/2C receptor antagonist), prevented the antidepressant-like effect of adenosine (10mg/kg, i.p.) in the FST. Moreover, the pre-treatment of animals with WAY100635 (0.1mg/kg, s.c.) blocked the decrease in immobility time in the FST elicited by adenosine (5 or 10mg/kg, i.p.), but produced a synergistic effect with a sub-effective dose of adenosine (1mg/kg, i.p.) and did not cause any alteration at the highest dose of adenosine administered (50mg/kg, i.p.). Adenosine (1mg/kg, i.p.) produced a synergistic antidepressant-like effect with pindolol (32 mg/kg), NAN-190 (0.5mg/kg, i.p.), WAY100635 (0.03 mg/kg, s.c.), 8-OH-DPAT (1mg/kg, i.p., a 5-HT1A receptor agonist), but not with DOI (1mg/kg, i.p., a preferential 5-HT2A receptor agonist) or ketanserin. The pre-treatment of mice with DPCPX (2mg/kg, i.p., a selective adenosine A1 receptor antagonist) or ZM241385 (1mg/kg, i.p., a selective adenosine A2A receptor antagonist) did not prevent the effect of fluoxetine (32 mg/kg, i.p., a preferential serotonin reuptake inhibitor) in the FST. Besides that, adenosine (1mg/kg, i.p.) did not produce a synergistic antidepressant-like effect with fluoxetine (10mg/kg, i.p.). Taken together, the results indicate that the antidepressant-like effect of adenosine in the FST appears to be mediated, at least in part, by an interaction with 5-HT1A receptors.     

The 5-HT1A receptor and recognition memory. Possible modulation of its behavioral effects by the nitrergic system

Functional activation of the 5-HT1A receptor inhibits cognition, although discrepant findings have also been reported. The present study was designed to investigate the role of the 5-HT1A receptor on recognition memory in the rat. For this purpose, the effects induced by the 5-HT1A agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) and the 5-HT1A antagonist WAY 100635 on memory were evaluated by using the object recognition task. In addition, the possible involvement of the nitrergic system on 5-HT1A receptor's effects was also assessed by using the same behavioral procedure. In the first dose-response study, post-training administration of 8-OH-DPAT (0.1 and 0.3 mg/kg, subcutaneously (s.c.)) dose-dependently impaired animals' performance in this test. WAY 100635 (0.3 and 1 mg/kg, intraperitoneally (i.p.)) successfully antagonized these 8-OH-DPAT-induced performance deficits. The NO donor molsidomine (2 and 4 mg/kg, i.p.) counteracted cognition deficits produced by the highest dose of 8-OH-DPAT (0.3 mg/kg). Our findings indicate (a) that the 5-HT1A receptor is involved in recognition memory, and (b) that a NO component modulates the effects of the 5-HT1A receptor on learning and memory.     

Evidence that the 5-HT1A autoreceptor is an important pharmacological target for the modulation of cocaine behavioral stimulant effects

The psychostimulant effects of cocaine critically depend on the serotonergic (5-HT) system, of which the 5-HT1A receptor is an essential component. We recently showed divergent contributions of various pre- and postsynaptic 5-HT1A receptor populations to the behavioral effects of cocaine. Here, we further investigate the role of 5-HT1A autoreceptors in the acute and chronic stimulant effects of cocaine using 5-HT1A receptor ligands in autoreceptor preferring doses. In experiment 1, four groups of rats (N = 10) received either saline or the 5-HT1A agonist, 8-OHDPAT (0.05 mg/kg) 20 min prior to a saline or cocaine (10 mg/kg) injection on 9 consecutive days. In experiment 2, six groups (N = 10) were given either saline, the 5-HT1A antagonist, WAY 100635 (0.05 mg/kg) or 8-OHDPAT (0.05 mg/kg) plus WAY 100635 (0.05 mg/kg) 20 min before a saline or cocaine (10.0 mg/kg) treatment on 9 consecutive days. Initially, both the 8-OHDPAT and WAY 100635 pretreatments completely blocked the locomotor stimulant effects of cocaine whereas the combined 8-OHDPAT plus WAY 100635 pretreatment had no effect. In saline treated groups, neither the WAY 100635 nor the 8-OHDPAT plus WAY 100635 pretreatment influenced spontaneous activity levels, whereas the 8-OHDPAT alone severely reduced spontaneous activity. These effects persisted over the course of the 9 test sessions. A different pattern of results was obtained for the cocaine treatment groups. With repeated treatments, the WAY 100635 treatment always blocked the locomotor activation effect of cocaine, whereas the effects of 8-OHDPAT were transformed from an inhibition to an enhancement of cocaine locomotor stimulation. The combined 8-OHDPAT plus WAY 100635 pretreatment did not affect the stimulant effect of cocaine. These findings demonstrate that low dose autoreceptor preferring treatments with a 5-HT1A agonist and antagonist can strongly modify the behavioral stimulant effects of cocaine and suggest that the 5-HT1A autoreceptor may be an important pharmacological target for the development of treatments for cocaine addiction.     

Effects of serotonergic 5-HT1A and 5-HT1B ligands on ventral pallidal neuronal activity

To clarify the role of the 5-HT system in limbic outputs, the present study compared the effects of the 5-HT1A agonist 8-OH-DPAT and the 5-HT1B agonist CP-94253 with the non-selective 5-HT agonist TFMPP on the firing rate of ventral pallidal (VP) neurons recorded in chloral hydrate-anesthetized rats. 8-OH-DPAT (0.25-256 microg/kg i.v.) dose-dependently enhanced (9/26 neurons) or suppressed (8/26) activity, and the 5-HT1A antagonist (+)WAY-100135 often attenuated these responses. TFMPP (0.011-1.453 mg/kg i.v.) dose-dependently reduced the firing rate of 7/8 VP neurons tested. In contrast, CP-94253 (0.013-12.8 mg/kg i.v.) had little or no effect. In sum, these data suggest that the 5-HT1A receptor appears to be particularly important in influencing limbic outputs mediated via the VP.     

Inhibition of hippocampal 5-HT synthesis by fluoxetine and paroxetine: evidence for the involvement of both 5-HT1A and 5-HT1B/D autoreceptors

Hippocampal serotonin (5-hydroxytryptamine, 5-HT) synthesis, as determined by the accumulation of 5-hydroxytryptophan (5-HTP) following inhibition of L-aromatic amino acid decarboxylase with NSD 1015, was inhibited by systemic administration of the selective serotonin reuptake inhibitors fluoxetine (10 mg/kg i.p.) and paroxetine (3 mg/kg i.p.). Pretreatment of rats with the selective 5-HT1A receptor antagonist WAY 100635 for a period of 7 days using subcutaneously implanted osmotic minipumps (1 mg/kg/day) was sufficient to block the inhibition of 5-HT synthesis following the 5-HT 1A receptor agonist 8-OH-DPAT (0.3 mg/kg s.c.), but failed to inhibit the decrease of hippocampal 5-HT synthesis by fluoxetine (10 mg/kg i.p.) or paroxetine (3 mg/kg i.p.). Similarly, pretreatment of rats with GR 127935 (5 mg/kg i.p.), an antagonist with high affinity for 5-HT1B/D receptors, blocked the reduction of hippocampal 5-HT synthesis following the 5-HT receptor agonist TFMPP (3 mg/kg s.c.) without affecting the reduction of hippocampal 5-HT synthesis by either fluoxetine or paroxetine. In contrast, pretreatment with WAY 100635 (1 mg/kg/day, for 7 days s.c. in osmotic minipumps) in combination with GR 127935 (5 mg/kg i.p.) significantly attenuated the decrease of hippocampal 5-HT synthesis by both fluoxetine and paroxetine. These results indicate that both 5-HT1A and 5-HT1B/1D receptors, which function in the rat as inhibitory somatodendritic and nerve terminal autoreceptors, independently regulate hippocampal 5-HT synthesis and must be simultaneously blocked to prevent the inhibition of 5-HT synthesis by selective serotonin reuptake inhibitors which increase 5-HT availability at both nerve terminals in hippocampus and 5-HT cell bodies in the raphe nuclei.     

Investigation of mechanisms mediating 8-OH-DPAT-induced impairment of spatial memory: involvement of 5-HT1A receptors in the dorsal hippocampus in rats

The purpose of this study was to identify mechanisms that mediate the impairment of spatial memory induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A/5-HT7 receptor agonist, in the eight-arm radial maze in rats. WAY-100635 and NAN-190, 5-HT1A receptor antagonists, reversed the impairment of spatial memory induced by systemic injection of 8-OH-DPAT (1 mg/kg, i.p.). On the other hand, the alpha1-adrenoceptor antagonist prazosin and a selective 5-HT7 receptor antagonist SB269970 had no effect on 8-OH-DPAT-induced impairment of spatial memory. Bilateral microinjection of 8-OH-DPAT (4 microg/side) impaired spatial memory when injected into the dorsal hippocampus (DH). Contrastingly, spatial memory was unaffected by microinjections of 8-OH-DPAT into the other six areas examined: ventral hippocampus (VH), central amygdaloid nucleus (ACE), lateral hypothalamus (LH), nucleus accumbens (NAc), and dorsal (DR) and median (MR) raphe nucleus. Furthermore, NAN-190 significantly reversed the impairment of spatial memory induced by intra-DH injection of 8-OH-DPAT. These findings suggest that 5-HT1A receptors in the DH play an important role in the mechanisms underlying the 8-OH-DPAT-induced impairment of spatial memory in rats.     

Fluoxetine reduces L-DOPA-derived extracellular DA in the 6-OHDA-lesioned rat striatum

We investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on L-DOPA-derived extracellular dopamine (DA) levels in the striatum of rats with nigrostriatal dopaminergic denervation using in vivo microdialysis. Treatment with fluoxetine (10 mg/kg, i.p.) induced a 41% reduction in the cumulative amount of extracellular DA during 300 min following L-DOPA administration (50 mg/kg, i.p.; p < 0.01). This effect was antagonized by pretreatment with WAY-100635, a potent 5-HT1A antagonist, indicating that this effect of fluoxetine is due to its indirect 5-HT1A agonistic property. These results suggest that SSRIs may impair motor functions in patients with Parkinson's disease by reducing efflux of exogenous L-DOPA-derived DA.     

Evaluation of the antibradykinetic actions of 5-HT1A agonists using the mouse pole test

To clarify the role and mechanism of the 5-HT1A receptor in modulating extrapyramidal motor disorders, we studied the actions of 5-HT1A agonists in the mouse pole test, a valid model of parkinsonian bradykinesia. Haloperidol markedly delayed pole-descending behavior of mice in the pole test, and this effect was alleviated by the antiparkinsonian agent trihexyphenidyl (a muscarinic antagonist). The selective 5-HT1A agonists, 8-hydroxydipropylaminotetraline (8-OH-DPAT) and tandospirone, significantly attenuated haloperidol-induced bradykinesia in a dose-dependent manner. The alleviation of haloperidol-induced bradykinesia by 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT1A antagonist), but was unaffected by cerebral 5-HT depletion with p-chlorophenylalanine (PCPA) treatment (300 mg/kg, i.p. for 3 days). These results suggest that 5-HT1A agonists improve extrapyramidal motor disorders associated with antipsychotic treatments by stimulating the postsynaptic 5-HT1A receptor.     

Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats

The purpose of this study was to investigate the effect of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of "wearing-off" phenomena in hemiparkinsonian rats. Catechol-O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines "wearing-off" motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.     

Mice over-expressing the 5-HT(1A) receptor in cortex and dentate gyrus display exaggerated locomotor and hypothermic response to 8-OH-DPAT

The serotonin 1A (5-HT(1A)) receptor is one of the best described receptor subtypes of the serotonergic system. Due to the complex distribution pattern, the pre- and postsynaptic localisation, the impact on various monoamines, as well as the influence on a wide range of physiological functions, the contribution of 5-HT(1A) receptors to behavioural outcomes is difficult to define. In this study, we present a new transgenic mouse model with a prominent over-expression of the 5-HT(1A) receptor in the outer cortical layers (I-III) and the dentate gyrus. Behavioural studies revealed a slight decrease in baseline motor activity of homozygous mice during the open field test. Moreover, core body temperature of male transgenic mice was significantly lower than that of wild-type mice. Pharmacological studies with the 5-HT(1A) receptor agonist 8-OH-DPAT (0.1-2.5 mg/kg, i.p.) revealed an exaggerated drug response in mutant mice. 8-OH-DPAT led to a drastic decrease in motor activity in the open field and elevated plus maze test. This significant effect on motor activity became more apparent by investigating the serotonergic syndrome induced by 8-OH-DPAT. Concentration as low as 0.5 mg/kg 8-OH-DPAT caused immobility in transgenic mice for 30 min, head weaving behaviour, and backward walking, whereas in wild-type animals, typical behaviours of the serotonin syndrome were first observed at concentrations of 1.5 mg/kg and more. In addition, the 8-OH-DPAT induced hypothermia was more pronounced in mutant mice than in wild-type animals. Therefore, these genetically modified mice represent a promising model for further investigations of the role of 5-HT(1A) receptors.     

MDMA and fenfluramine reduce L-DOPA-induced dyskinesia via indirect 5-HT1A receptor stimulation

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as dyskinesia. Clinical and experimental studies indicate that indirect serotonin agonists can suppress dyskinesia without affecting the efficacy of L-DOPA. While the mechanism by which these effects occur is not clear, recent research suggests that serotonin 5-HT1A receptors may play a pivotal role. To test this, male Sprague-Dawley rats with unilateral 6-hydroxydopamine medial forebrain bundle lesions received 1 week of daily treatment with L-DOPA (12 mg/kg, i.p.) plus benserazide (15 mg/kg, i.p.). Beginning on the 8th day of treatment and every 3rd or 4th day thereafter, rats were pretreated with vehicle (0.9% NaCl), the serotonin and dopamine releaser 3,4-methylenedioxymethamphetamine (MDMA; 0.25 or 2.5 mg/kg, i.p.) or the serotonin releaser fenfluramine (FEN; 0.25 or 2.5 mg/kg, i.p.) 5 min prior to L-DOPA, after which abnormal involuntary movements (AIMs) and rotations were quantified every 20th minute for 2 h. Pretreatment with 2.5 mg/kg of either MDMA or FEN reduced AIMs. To determine the contribution of the 5-HT1A receptor to these effects, another group of L-DOPA-primed 6-hydroxydopamine-lesioned rats were pretreated with the 5-HT1A antagonist WAY100635 (0.5 mg/kg, i.p.), MDMA + WAY100635 (2.5 + 0.5 mg/kg, i.p.) or FEN + WAY100635 (2.5 + 0.5 mg/kg, i.p.) 5 min prior to L-DOPA and subsequent AIMs and rotation tests. The antidyskinetic effects of MDMA and FEN were reversed by cotreatment with WAY100635. These results suggest that 5-HT-augmenting compounds such as MDMA and FEN probably convey antidyskinetic properties in part via stimulation of 5-HT1A receptors.     

Key role of 5-HT1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knock-out mice.

The involvement of 5-HT1B receptors in the regulation of vigilance states was assessed by investigating the spontaneous sleep-waking cycles and the effects of 5-HT receptor ligands on sleep in knock-out (5-HT1B-/-) mice that do not express this receptor type. Both 5-HT1B-/- and wild-type 129/Sv mice exhibited a clear-cut diurnal sleep-wakefulness rhythm, but knock-out animals were characterized by higher amounts of paradoxical sleep and lower amounts of slow-wave sleep during the light phase and by a lack of paradoxical sleep rebound after deprivation. In wild-type mice, the 5-HT1B agonists CP 94253 (1-10 mg/kg, i.p.) and RU 24969 (0.25-2.0 mg/kg, i.p.) induced a dose-dependent reduction of paradoxical sleep during the 2-6 hr after injection, whereas the 5-HT1B/1D antagonist GR 127935 (0.1-1.0 mg/kg, i.p.) enhanced paradoxical sleep. In addition, pretreatment with GR 127935, but not with the 5-HT1A antagonist WAY 100635, prevented the effects of both 5-HT1B agonists. In contrast, none of the 5-HT1B receptor ligands, at the same doses as those used in wild-type mice, had any effect on sleep in 5-HT1B-/- mutants. Finally, the 5-HT1A agonist 8-OH-DPAT (0.2-1.2 mg/kg, s.c.) induced in both strains a reduction in the amount of paradoxical sleep. Altogether, these data indicate that 5-HT1B receptors participate in the regulation of paradoxical sleep in the mouse.     

Effect of acute and chronic administration of U50,488, a kappa opioid receptor agonist,in 6-OHDA-lesioned rats chronically treated with levodopa

To evaluate the possible involvement of kappa opioid receptor-mediated mechanisms in levodopa-induced motor fluctuations, we have investigated the effects of U50,488, a selective kappa opioid agonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of U50,488 has been studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, ip) for 22 days and, on Day 23 U50,488 (0.5, 1, or 3 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and U50,488 (1 or 3 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of U50,488 on Day 23 reversed this effect when low doses were administered (P < 0.05). Chronic U50,488 administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the kappa opioid receptor agonist U50,488 reverses but does not prevents levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for kappa opioid receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the stimulation of kappa opioid receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.     

Serotonin 1A receptor inhibits the status epilepticus induced by lithium-pilocarpine in rats

Status epilepticus (SE) is a life-threatening neurological emergency associated with a high mortality rate. The serotonin 1A (5-HT_1A) receptor is a possible target for the treatment of SE, but its role in animal models and the precise area of brain involved remain controversial. The hippocampus is a candidate site due to its key role in the development of SE and the existence of a high density of 5-HT_1A receptors. Therefore, we investigated the effects of subcutaneous and intrahippocampal activation of 5-HT_1A receptors in lithium-pilocarpine-induced SE, and tested whether the hippocampus is a true effector site. We developed SE in male Sprague-Dawley rats by giving lithium chloride (LiCl; 3 meq/kg, i.p.) 22–24 h prior to pilocarpine (25 mg/kg, i.p.), and found that 8-OH-DPAT, a 5-HT_1A receptor agonist administered subcutaneously (s.c.) at 0.5 or 1.0 mg/kg 1 h before pilocarpine injection increased the latency to the first epileptiform spikes, the electrographic SE, and the behavioral generalized seizures (GS), while reducing the total EEG seizure time (P <0.01). The duration of GS was shortened only by 1.0 mg/kg 8-OH-DPAT s.c. (P <0.05). All these effects were inhibited by combined administration of WAY-100635 (1.0 mg/kg, s.c.) (P <0.05), an antagonist of the 5-HT_1A receptor, but WAY-100635 alone and low doses of 8-OHDPAT (0.01 and 0.1 mg/kg) did not alter seizure activity. Furthermore, intrahippocampal 8-OH-DPAT only shortened the GS duration (P <0.05). These findings imply that the 5-HT_1A receptor is a promising therapeutic target against the generation and propagation of SE, and hippocampal receptors are involved in reducing the seizure severity.     

Effect of locus coeruleus denervation on levodopa-induced motor fluctuations in hemiparkinsonian rats

Parkinson's disease (PD) is characterized not only by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) but also by a degeneration of locus coeruleus (LC) noradrenergic neurons. It has been suggested that deficient LC noradrenergic mechanisms might play a critical role in symptomatology and in the progression of PD. However, the effect of LC depletion on levodopa-induced motor complications, such as the motor fluctuations, is still unknown. Male Sprague-Dawley rats received 50 mg/kg intraperitoneal (i.p.) of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP-4) or saline 7 days before the day of 6-hydroxydopamine (6-OHDA, 8 mug) administration in the medial forebrain bundle. Four weeks later, animals were treated with levodopa (25 mg/kg with benserazide, twice at day, i.p.) for 22 days. Rotational behavior was measured on days 1 and 22 of levodopa administration. Tyrosine hydroxylase (TH) immunohistochemistry was performed to evaluate the neurodegeneration in the SNc and LC. Striatal dopamine transporter (DAT) immunohistochemistry was performed to evaluate DA depletion. As expected, levodopa administration decreased the duration of the motor response in the vehicle-pretreated group (P < 0.01). A potentiation of levodopa-induced shortening in the duration of motor response was not achieved after LC depletion since no significant differences were observed in the duration of rotational behavior between these two groups on day 22. In addition, LC depletion did not potentiate either the total number of rotations or the maximal peak of rotation induced by levodopa treatment. These results suggest that LC depletion might not be involved in the pathophysiology of levodopa-induced motor fluctuations.     

Evidence for serotonin receptor subtypes involvement in agmatine antidepressant like-effect in the mouse forced swimming test

This study investigated the involvement of 5-HT(1) and 5-HT(2) receptors in the antidepressant-like effect of agmatine in the mouse forced swimming test (FST). Pretreatment with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, intraperitoneally (i.p.), an inhibitor of serotonin synthesis, for 4 consecutive days), methysergide (5 mg/kg, i.p., a serotonin (5-HT) antagonist), pindolol (32 mg/kg, i.p., a 5-HT(1A/1B) receptor/beta-adrenoceptor antagonist), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635; 0.3 mg/kg, subcutaneously (s.c.), a selective 5-HT(1A) receptor antagonist), 1-(2-methoxyphenyl)-4[-(2-phthalimido)butyl]piperazine) (NAN-190; 0.5 mg/kg, i.p., a 5-HT(1A) receptor antagonist), 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane; 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT(2) antagonist) or ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), prevented the effect of agmatine (10 mg/kg, i.p.) in the FST. A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with pindolol (32 mg/kg), NAN-190 (0.5 mg/kg, i.p.), WAY 100635 (0.03 mg/kg, s.c.), (+)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT; 0.01 mg/kg, i.p., a 5-HT(1A) receptor agonist), R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI; 1 mg/kg, i.p., a preferential 5-HT(2A) receptor agonist), or fluoxetine (10 mg/kg, i.p., a selective serotonin reuptake inhibitor, SSRI) but not with isamoltane (2.5 mg/kg, i.p.), ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or ketanserin (5 mg/kg, i.p.). Taken together, the results firstly demonstrate that agmatine antidepressant-like effects in the FST seem to be mediated, at least in part, by an interaction with 5-HT(1A/1B) and 5-HT(2) receptors.