ABSTRACT
Dopamine (DA) and serotonin (5-HT) receptors are prime targets for the development of antipsychotics. The specific role of each receptor subtype to the pharmacological effects of antipsychotic drugs remains unclear. Understanding the relationship between antipsychotic drugs and their binding affinities at DA and 5-HT receptor subtypes is very important for antipsychotic drug discovery and could lead to new drugs with enhanced efficacies. We have previously disclosed SYA16263 (5) as an interesting compound with moderate radioligand binding affinity at the D2 & D3 receptors (Ki = 124 nM & 86 nM respectively) and high binding affinities towards D4 and 5-HT1A receptors (Ki = 3.5 nM & 1.1 nM respectively). Furthermore, we have demonstrated SYA16263 (5) is functionally selective and produces antipsychotic-like behavior but without inducing catalepsy in rats. Based on its pharmacological profile, we selected SYA16263 (5) to study its structure-affinity relationship with a view to obtaining new analogs that display receptor subtype selectivity. In this study, we present the synthesis of structurally modified SYA16263 (5) analogs and their receptor binding affinities at the DA and 5-HT receptor subtypes associated with antipsychotic action. Furthermore, we have identified compound 21 with no significant binding affinity at the D2 receptor subtype but with moderate binding affinity at the D3 and D4 receptors subtypes. However, because 21 is able to demonstrate antipsychotic-like activity in a preliminary test, using the reversal of apomorphine-induced climbing behavior experiment in mice with SYA16263 and haloperidol as positive controls, we question the essential need of the D2 receptor subtype in reversing apomorphine-induced climbing behavior.
Subject(s)
Antipsychotic Agents/pharmacology , Apomorphine/antagonists & inhibitors , Behavior, Animal/drug effects , Dopamine D2 Receptor Antagonists/pharmacology , Piperazines/pharmacology , Pyridines/pharmacology , Receptors, Dopamine D2/metabolism , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Apomorphine/pharmacology , Dopamine D2 Receptor Antagonists/chemical synthesis , Dopamine D2 Receptor Antagonists/chemistry , Dose-Response Relationship, Drug , Male , Mice , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: Parkinson's disease (PD) is a progressive and profound movement disorder resulting from neurodegeneration in the nigrostriatal dopaminergic system, but current treatment neither cures nor stops PD from advancing. Based on the ability to suppress oxidative stress, excitotoxicity, and neuroinflammation, the potential of honokiol as a novel neuroprotective agent for PD treatment was determined. METHODS: The hemi-parkinsonian model was used to investigate the protective and therapeutic effects of honokiol on motor dysfunctions and dopaminergic neurodegeneration in mice, with a single unilateral striatal injection of 6-hydroxydopamine (6-OHDA). RESULTS: One day after 6-OHDA-induced lesion, the mice exhibited spontaneous ipsilateral turning, motor imbalance, and incoordination which were mild with a single administration of honokiol prior to 6-OHDA injection. Thereafter, honokiol was continually applied daily for 14 days, which ameliorated apomorphine-induced contralateral rotation and reduced the loss of tyrosine hydroxylase-immunoreactive (TH-ir) fibers in the lesioned striatum. In addition, honokiol posttreatment, beginning on day 8 after 6-OHDA lesion, for 14 days efficiently rescued motor deficits and recovered the TH-ir neuronal loss in both the lesioned striatum and the ipsilateral substantia nigra. The 6-OHDA-induced increases in nigrostriatal expression of inducible nitric oxide synthase (iNOS) and decreases in that of nNOS were also reversed by honokiol posttreatment. CONCLUSIONS: These findings revealed that honokiol has both protective and therapeutic effects on motor impairments and dopaminergic progressive damage, at least in part through modulation of NOS signaling, in 6-OHDA-lesioned mice. Honokiol may represent a potential therapeutic candidate for the management of motor symptoms and neurodegeneration in PD.
Subject(s)
Biphenyl Compounds/pharmacology , Disease Models, Animal , Lignans/pharmacology , Motor Activity/drug effects , Neuroprotective Agents/pharmacology , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/prevention & control , Animals , Apomorphine/antagonists & inhibitors , Biphenyl Compounds/therapeutic use , Corpus Striatum/metabolism , Lignans/therapeutic use , Male , Mice , Microinjections , Neuroprotective Agents/therapeutic use , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide Synthase Type II/metabolism , Oxidopamine/administration & dosage , Postural Balance/drug effects , Substantia Nigra/metabolism , Tyrosine 3-Monooxygenase/metabolismABSTRACT
OBJECTIVES: Morin is a naturally occurring flavonoid with strong anti-oxidant and anti-inflammatory properties. Studies have shown that flavones modulate neurotransmission through enhancement of gamma amino butyric acid activity in the central nervous system; which led to the hypothesis that they could exert tranquilizing effects in rodents. Hence, this study was designed to evaluate the antipsychotic effect of morin on experimental animal models. METHODS: The antipsychotic effect of morin (25, 50 and 100 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced locomotion, apomorphine-induced stereotypy, ketamine-induced stereotypy, ketamine-induced hyperlocomotion and ketamine-enhanced immobility in forced swim test (FST). Catalepsy and rota rod tests were also carried out to evaluate the extrapyramidal side effects of morin. RESULTS: Morin (25, 50 and 100 mg/kg, i.p.) pretreatments significantly (p<0.05) demonstrated anti-schizophrenia-like behavior by inhibiting ketamine-induced hyperlocomotion in mice. Moreover, morin (50 and 100 mg/kg, i.p.) significantly (p<0.05) reduced spontaneous locomotor activity. Also, morin suppressed apomorphine-induced stereotypy and ketamine-induced stereotypy. The increase in immobility in FST due to ketamine administration was reduced by morin in a significant dose-dependent manner. Furthermore, the antipsychotic activity of morin was not associated with extrapyramidal side effects, as evidenced by decreased decent latency and increased motoric coordination and performance in mice. CONCLUSION: The results of the study revealed that morin demonstrated antipsychotic-like property devoid of extrapyramidal side effects in experimental animal models and may be beneficial in the treatment of schizophrenia-like behaviors; particularly in patients with behavioral hyperactivity and negative symptoms.
Subject(s)
Antipsychotic Agents/pharmacology , Catalepsy/prevention & control , Flavonoids/pharmacology , Immobility Response, Tonic/drug effects , Stereotyped Behavior/drug effects , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Ketamine/antagonists & inhibitors , Ketamine/pharmacology , Locomotion/drug effects , Male , Mice , Rotarod Performance TestABSTRACT
RATIONALE: The search for novel antipsychotic drugs to treat schizophrenia is driven by the poor treatment efficacy, serious side effects, and poor patient compliance of current medications. Recently, a class of compounds known as tetrahydroprotoberberines, which includes the compound d,l-govadine, have shown promise in preclinical rodent tests relevant to schizophrenia. To date, the effect of govadine on prepulse inhibition (PPI), a test for sensorimotor gating commonly used to assess the effects of putative treatments for schizophrenia, has not been determined. OBJECTIVES: The objective of the present study was to determine the effects of each enantiomer of govadine (d- and l-govadine) on PPI alone and its disruption by the distinct pharmacological compounds apomorphine and MK-801. METHODS: Male Long-Evans rats were treated systemically with d- or l-govadine and apomorphine or MK-801 prior to PPI. The PPI paradigm employed here included parametric manipulations of the prepulse intensity and the interval between the prepulse and pulse. RESULTS: Acute MK-801 (0.15 mg/kg) significantly increased the startle response to startle pulses alone, while both MK-801 and apomorphine (0.2 mg/kg) significantly increased reactivity to prepulse-alone trials. Both MK-801 and apomorphine disrupted PPI. In addition, d-govadine alone significantly disrupted PPI in the apomorphine experiment. Pretreatment with l-, but not d-, govadine (1.0 mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats with l-govadine alone (0.3, 1.0, 3.0 mg/kg) also dose-dependently increased PPI. CONCLUSIONS: Given the high affinity of l-govadine for dopamine D2 receptors, these results suggest that further testing of l-govadine as an antipsychotic is warranted.
Subject(s)
Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Berberine Alkaloids/pharmacology , Dizocilpine Maleate/pharmacology , Dopamine Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Prepulse Inhibition/drug effects , Animals , Antipsychotic Agents/chemistry , Apomorphine/antagonists & inhibitors , Berberine Alkaloids/chemistry , Dizocilpine Maleate/antagonists & inhibitors , Dose-Response Relationship, Drug , Male , Rats , Rats, Long-Evans , Receptors, Dopamine D2/drug effects , Reflex, Startle/drug effects , Schizophrenia/drug therapy , StereoisomerismABSTRACT
OBJECTIVE: To evaluate the effect of K+ channels inhibitors in treatment of parkinson`s disease (PD). METHODS: This prospective comparative study was conducted in the Qazvin University of Medical Sciences, Iran, from April 2015 to January 2016. Male rats (n=37) received intraperitoneal doses of TEA (2 and 5 mg/kg) or 4-AP (0.5 and 1 mg/kg) twice-daily, before a stereotactic injection of 6-hydroxydopamine (6-OHDA) for the following 7 days. The 6-OHDA was injected into right medial forebrain bundle (MFB) of the rat brains. Development and severity of PD were assessed using the apomorphine-induced rotational test, the elevated body swing test and rotarod tests. Concentration of malondialdehyde (MDA), a marker of oxidative stress, was measured in rat sera. RESULTS: Tetraethylammonium and 4-AP significantly reduced the number of apomorphine-induced rotations and improved motor learning in the rotarod test at both doses. Administration of 4-AP and TEA together was more effective than single administration of either agent. Malondialdehyde measurement showed that pretreatment with TEA could not prevent 6-OHDA-induced oxidative stress. CONCLUSION: Our results showed that pretreatment with TEA and 4-AP has a neuroprotective effect against 6-OHDA in dopaminergic neurons in the substantia nigra.
Subject(s)
4-Aminopyridine/pharmacology , Antiparkinson Agents/pharmacology , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/prevention & control , Potassium Channel Blockers/pharmacology , Tetraethylammonium/pharmacology , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Male , Malondialdehyde/blood , Medial Forebrain Bundle/drug effects , Neuroprotective Agents/pharmacology , Parkinson Disease, Secondary/blood , Rats , Rotarod Performance TestABSTRACT
The objective of this work was to formulate paliperidone palmitate-loaded d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) micelles for improved antipsychotic effect during short-term management of psychotic disorders. Vitamin E TPGS micelles containing paliperidone palmitate were prepared by the solvent casting method and control paliperidone palmitate formulations were prepared by simple sonication method. The prepared micelles and control paliperidone palmitate formulations were evaluated for different parameters. Particle sizes of prepared micelles, control paliperidone palmitate formulations were determined at 25 °C by dynamic light scattering technique and external surface morphology was determined by transmission electron microscopy analysis. The encapsulation efficiency was determined by spectrophotometery. In-vitro release studies of micelles and control formulations were carried out by dialysis bag diffusion method. The particle sizes of the paliperidone palmitate-loaded TPGS micelles were 26.5 nm. About 92% of drug encapsulation efficiency was achieved with micelles. The drug release from paliperidone palmitate-loaded TPGS micelles was sustained for more than 24 h with 40% of drug release. The TPGS product, i.e. paliperidone palmitate-loaded micelles, resulted in nano-sized delivery, solubility enhancement and permeability of the micelles which provided an improved and prolonged anti-psychotic effect in comparison to control paliperidone palmitate formulation.
Subject(s)
Antipsychotic Agents/administration & dosage , Antipsychotic Agents/therapeutic use , Paliperidone Palmitate/administration & dosage , Paliperidone Palmitate/therapeutic use , Psychotic Disorders/drug therapy , Vitamin E/analogs & derivatives , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Catalepsy/chemically induced , Catalepsy/drug therapy , Chemistry, Pharmaceutical , Drug Compounding , Drug Delivery Systems , Mice , Micelles , Particle Size , Polyethylene Glycols/chemistry , Vitamin E/chemistryABSTRACT
Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.
Subject(s)
Antipsychotic Agents/pharmacology , Piperazines/pharmacology , Piperazines/pharmacokinetics , Piperidines/pharmacokinetics , Pyridines/pharmacology , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Basal Ganglia Diseases/psychology , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/psychology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dose-Response Relationship, Drug , Gene Expression/drug effects , Haloperidol/pharmacology , Injections, Subcutaneous , Male , Mice , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Oncogene Proteins v-fos/biosynthesis , Oncogene Proteins v-fos/drug effectsABSTRACT
The adult rats received both neurotoxin 6-hidroxidophamine and neurotoxin and melatonin. It was investigated a link between the disturbances of the brain antioxidant enzymes activity and thymic endocrine function, as possible pathogenic factors of parkinsonism, with changes in the number of neural stem cells (NSC) in the bulbus olfactorius. Rats with motor asymmetry in the apomorphine test and significant damage of the dopaminergic neurons in the-substantia nigra have decreased levels of superoxide dismutase, catalase and glutathione peroxidase activities in striatum (1.3-1.4 times) and blood thymulin content (8 times) compared to control group. On the contrary, examined indices were not changed in rats without motor asymmetry and correspondingly partly damaged neurons. The number of nestin(+)-cells in the bulbus olfactorius of rats without motor asymmetry increased from 91.2% to 99.3% and remained unchanged after melatonin administration course (10 mg/kg during 18 days). Melatonin administration resulted in the decrease in the number of nestin(+)-cells along with significant elevation of the decreased antioxidant enzymes activity and blood thymulin content in rats with circulatory movements. Possibilities of the enhancement of NSC differentiation in bulbus olfactorius into neuronal direction in such animals has been discussed. The conclusion about the potential use of melatonin as a neuroprotector in parkinsonism therapy has been made.
Subject(s)
Antioxidants/pharmacology , Ataxia/prevention & control , Melatonin/pharmacology , Neuroprotective Agents/pharmacology , Olfactory Bulb/drug effects , Parkinson Disease, Secondary/drug therapy , Thymus Gland/drug effects , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Ataxia/chemically induced , Ataxia/genetics , Ataxia/pathology , Catalase/genetics , Catalase/metabolism , Cell Count , Cell Differentiation/drug effects , Dopamine Agonists/pharmacology , Gene Expression , Glutathione Peroxidase/genetics , Glutathione Peroxidase/metabolism , Male , Nestin/genetics , Nestin/metabolism , Neural Stem Cells/cytology , Neural Stem Cells/drug effects , Neural Stem Cells/metabolism , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/genetics , Parkinson Disease, Secondary/pathology , Rats , Rats, Wistar , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Thymic Factor, Circulating/genetics , Thymic Factor, Circulating/metabolism , Thymus Gland/metabolism , Thymus Gland/pathologyABSTRACT
Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose-dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal grooming that typically occurs immediately after the agitation phase has been terminated. Progressively higher doses were required to antagonize higher levels of apomorphine at earlier time intervals after the intravenous injection. The compounds also decreased palpebral opening, and most of them suppressed grooming behavior at higher doses. Compounds differed considerably in dose increments required for: 1) suppression of grooming, from 0.33 for clozapine to >600 for remoxipride, raclopride, and droperidol; 2) blockade of agitation at 5 minutes after apomorphine, from 2.6 for pimozide to 165 for chlorprothixene and 254 for remoxipride; 3) mild decrease of palpebral opening, from 0.21 for sertindole to 191 for remoxipride; and 4) pronounced decrease of palpebral opening, from 10 for melperone to >820 for raclopride. Only four compounds were able to advance grooming to 15 minutes postapomorphine, but again dose increments varied considerably: droperidol (3.4), pimozide (9.1), raclopride (42), and remoxipride (383). Based on these results obtained in a single animal model, compounds were differentiated in terms of behavioral specificity, incisiveness (the power to counteract the effects of progressively higher apomorphine concentrations), and sedative side-effect liability. Possible explanations for the observed differences and clinical relevance are discussed.
Subject(s)
Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Behavior, Animal/drug effects , Dopamine Agonists/pharmacology , Receptors, Dopamine/drug effects , Adrenergic alpha-Agonists/toxicity , Animals , Apomorphine/antagonists & inhibitors , Arousal/drug effects , Conjunctiva/drug effects , Dose-Response Relationship, Drug , Grooming/drug effects , Hypnotics and Sedatives , Linear Models , Male , Norepinephrine/toxicity , Psychomotor Agitation/drug therapy , Rats , Rats, Wistar , Receptors, Dopamine D1/agonists , Receptors, Dopamine D2/agonists , Stimulation, ChemicalABSTRACT
Doramectin (DOR) is an antiparasitic drug that is widely used in domestic animals. In mammals, DOR acts as a γ-aminobutyric acid receptor agonist. This neurotransmitter plays an important role in the regulation of sexual behavior. The present study investigated the effects of two medically relevant doses of DOR on sexual behavior in male rats. We also examined whether previous sexual experience modulates responses to DOR. General activity was first observed in an open field 24, 48, and 72 h after administration of 0.1 and 0.3 mg/kg DOR to determine the dose and time effects of the drug. Apomorphine-induced penile erection and sexual behavior in inexperienced male rats were then analyzed. The effects of previous sexual experience on subsequent sexual behavior in DOR-treated rats (0.3 mg/kg, 24 h prior to the test) were also assessed. The standard therapeutic dose (0.2 mg/kg) did not modify general activity or penile erection. A slightly concentrated dose of 0.3 mg/kg, which is still within the therapeutic range, decreased apomorphine-induced penile erection, whereas 0.2 mg/kg did not modify this behavior. Compared with controls, sexual behavior in inexperienced male rats was impaired after 0.3 mg/kg DOR. Previous sexual experience had little impact on the effects of 0.3 mg/kg DOR. In conclusion, the 0.2 mg/kg dose of DOR did not affect motor behavior or apomorphine-induced penile erection. At a more slightly higher dose level, the appetitive and consummatory phases of sexual behavior in inexperienced male rats were impaired. Previous sexual experience was unable to reverse this sexual impairment, suggesting that previous sexual experience does not exert a positive effect in attenuating sexual impairment produced by DOR treatment.
Subject(s)
Anthelmintics/adverse effects , Ivermectin/analogs & derivatives , Penile Erection/drug effects , Sexual Behavior, Animal/drug effects , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Dose-Response Relationship, Drug , Ivermectin/adverse effects , Male , Motor Activity/drug effects , RatsABSTRACT
Parkinson disease (PD) is the second most common neurodegenerative disease, and it cannot be completely cured by current medications. In this study, DJ-1 protein was administrated into medial forebrain bundle of PD model rats those had been microinjected with 6-hydroxydopamine (6-OHDA) or MG-132. We found that DJ-1 protein could reduce apomorphine-induced rotations, inhibit reduction of dopamine contents and tyrosine hydroxylase levels in the striatum, and decrease dopaminergic neuron death in the substantia nigra. In 6-OHDA lesioned rats, uncoupling protein-4, uncoupling protein-5 and superoxide dismutase-2 (SOD2) mRNA and SOD2 protein were increased when DJ-1 protein was co-injected. Simultaneously, administration of DJ-1 protein reduced α-synuclein and hypoxia-inducible factor 1α mRNA and α-synuclein protein in MG-132 lesioned rats. Therefore, DJ-1 protein protected dopaminergic neurons in two PD model rats by increasing antioxidant capacity and inhibiting α-synuclein expression.
Subject(s)
Antiparkinson Agents/therapeutic use , Dopaminergic Neurons/drug effects , Intracellular Signaling Peptides and Proteins/therapeutic use , Leupeptins/toxicity , Neuroprotective Agents/therapeutic use , Oncogene Proteins/therapeutic use , Oxidopamine/toxicity , Parkinsonian Disorders/prevention & control , Animals , Antiparkinson Agents/administration & dosage , Apomorphine/antagonists & inhibitors , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/pathology , Dopamine/analysis , Dopaminergic Neurons/enzymology , Drug Evaluation, Preclinical , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Intracellular Signaling Peptides and Proteins/administration & dosage , Ion Channels/biosynthesis , Ion Channels/genetics , Male , Microinjections , Mitochondrial Membrane Transport Proteins/biosynthesis , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Proteins/biosynthesis , Mitochondrial Proteins/genetics , Mitochondrial Uncoupling Proteins , Motor Activity/drug effects , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuroprotective Agents/administration & dosage , Oncogene Proteins/administration & dosage , Oxidative Stress/drug effects , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Protein Deglycase DJ-1 , Rats , Rats, Sprague-Dawley , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Substantia Nigra/pathology , Superoxide Dismutase/biosynthesis , Superoxide Dismutase/genetics , Tyrosine 3-Monooxygenase/analysis , alpha-Synuclein/biosynthesis , alpha-Synuclein/geneticsABSTRACT
All marketed antipsychotics act by blocking dopamine D(2) receptors. Fast dissociation from D(2) receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D(2) receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D(2) ligand. Its D(2) receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [α(1), α(2), H(1), muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D(2) antagonism (D(1), D(3), and 5-HT(2A)). JNJ-37822681 occupied D(2) receptors in rat brain at relatively low doses (ED(50) 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED(50) (0.17 mg/kg, peripheral D(2) receptors) close to the ED(50) required for apomorphine antagonism (0.19 mg/kg, central D(2) receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D(2) antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D(2) antagonism for the treatment of schizophrenia and bipolar disorder.
Subject(s)
Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Piperidines/pharmacology , Pyridazines/pharmacology , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/pharmacology , Apomorphine/antagonists & inhibitors , Apomorphine/metabolism , Behavior, Animal/drug effects , Benzodiazepines/adverse effects , Brain/drug effects , Brain/metabolism , CHO Cells , Catalepsy/chemically induced , Catalepsy/drug therapy , Catalepsy/metabolism , Cells, Cultured , Cricetinae , Female , Haloperidol/adverse effects , Haloperidol/metabolism , Humans , Ligands , Locomotion/drug effects , Male , Olanzapine , Prolactin/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Dopamine D2/metabolism , Schizophrenia/metabolism , Serotonin/metabolismABSTRACT
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterizing by degeneration of dopaminergic neurons in the nigrostriatal pathway. The discovery of levodopa revolutionized the treatment of PD however, after several years of treatment most patients develop involuntary movements which significantly impair the quality of life. 4-Aminopyridine (4-AP) and tetraethylammonium (TEA) are wide-spectrum potassium channel blockers which based on the animal model studies and clinical trials have beneficial effects in treatment of several neurological disorders such as ataxia, Alzheimer disease and multiple sclerosis. Current study investigates effect of these blockers in the treatment of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. After surgical injection of 6-OHDA into medial forebrain bundle, behavioral tests were performed in the 2nd and 3rd weeks post-surgery. Only animals which showed more than 100 apomorphine-induced rotations/1h in the 3rd week were selected for evaluation of the blocker effects. Statistical analysis of results from rotational test shows that application of high dose of 4-AP (1mg/kg) and moderate dose of TEA (2mg/kg) attenuate behavioral symptoms of the Parkinsonism while high dose of TEA (5mg/kg) and application both 4-AP and TEA exacerbates these symptoms. Results from elevated body swing test confirmed the effects of TEA but not 4-AP on the rotational test. However, experiments performed on the partial Parkinsonian rats show that application of high dose of TEA attenuates apomorphine-induced rotational asymmetry significantly. Our findings indicating TEA and 4-AP could have significant effects in attenuation of PD symptoms but these effects are sensitive to dose and degree of severity of PD.
Subject(s)
4-Aminopyridine/therapeutic use , Behavior, Animal/drug effects , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Potassium Channel Blockers/therapeutic use , Tetraethylammonium/therapeutic use , 4-Aminopyridine/pharmacology , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Disease Models, Animal , Drug Interactions , Male , Medial Forebrain Bundle/drug effects , Microinjections , Potassium Channel Blockers/pharmacology , Rats , Rats, Wistar , Tetraethylammonium/pharmacologyABSTRACT
Apomorphine, a dopamine D1/D2 agonist is effective in the treatment of Parkinson's disease; but its long term use is often associated with the dependence and addiction. The development of locomotor sensitization to psychostimulants including apomorphine is considered to be an important contributor to psychostimulant drug abuse. Previous studies have shown that long term administration of drugs of abuse increases the effectiveness of somatodendritic 5-hydroxytryptamine (5-HT)-1A receptors. Repeated administration of buspirone attenuates the effectiveness of somatodendritic 5-HT(1A) receptors. The present study was designed to test the hypothesis that coadministration of buspirone may attenuate apomorphine induced sensitization. Administration of apomorphine at a dose of 1.0, 2.0 & 4.0mg/kg increased motor activity in an activity box in a dose dependent manner. Locomotor enhancing effects of a low dose of apomorphine were augmented upon repeated administration suggesting drug-induced sensitization. The sensitization effects were significant in an activity box as well as in an open field. Coadministration of buspirone at a dose of 1.0mg/kg reversed apomorphine-induced sensitization. Repeated administration of buspirone at a dose of 2.0 mg/kg but not 1.0 mg/kg also elicited sensitization in motor behavior. It is suggested that buspirone may oppose the development of sensitization to apomorphine by decreasing the sensitivity of somatodendritic 5-HT(1A) receptors. Findings may help in extending therapeutics in Parkinson's disease.
Subject(s)
Apomorphine/administration & dosage , Apomorphine/antagonists & inhibitors , Buspirone/administration & dosage , Motor Activity/drug effects , Animals , Dose-Response Relationship, Drug , Male , Motor Activity/physiology , Random Allocation , Rats , Rats, WistarABSTRACT
The partial agonist profile of novel antipsychotics such as aripiprazole has hardly been demonstrated in biochemical assays on animal tissues. As it is established that responses induced by dopamine D2 receptor agonists are increased in models of dopaminergic sensitization, this paradigm was used in order to facilitate the detection of the partial agonist properties of aripiprazole. At variance with all other partial and full agonists tested, the partial agonist properties of aripiprazole were not revealed in guanosine 5'-O-(γ-[³5S]thiotriphosphate ([³5S]GTPγS) binding assays on striatal membranes from haloperidol-treated rats. Hence,aripiprazole behaved as an antagonist, efficiently inhibiting the functional response to dopamine. Similarly, in behavioural assays, aripiprazole dose-dependently inhibited the stereotypies elicited by apomorphine. However, at variance with haloperidol, repeated administrations of aripiprazole(3 weeks) at the doses of 10 and 30 mg/kg did not induce any up-regulation or hyperfunctionality of the dopamine D2 receptors in the striatum. These data highlight the putative involvement of other pharmacological targets for aripiprazole that would support in the prevention of secondary effects commonly associated with the blockade of striatal dopamine D2 receptors. Hence, in additional experiments, aripiprazole was found to efficiently promote [³5S]GTPγS binding in hippocampal membranes through the activation of 5-HT(1A) receptors. Further experiments investigating the second messenger cascades should be performed so as to establish the functional properties of aripiprazole and understand the mechanism underlying the prevention of dopamine receptor regulation in spite of the observed antagonism.
Subject(s)
Corpus Striatum/metabolism , Dopamine D2 Receptor Antagonists , Piperazines/pharmacology , Quinolones/pharmacology , Receptors, Dopamine D2/metabolism , Up-Regulation/drug effects , Animals , Apomorphine/analogs & derivatives , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Aripiprazole , Buffers , Catalepsy/chemically induced , Catalepsy/diagnosis , Cell Membrane/drug effects , Cell Membrane/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Corpus Striatum/drug effects , Domperidone/pharmacology , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Drug Antagonism , Drug Partial Agonism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Haloperidol/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Male , Piperidines/pharmacology , Pyridines/pharmacology , Rats , Rats, Wistar , Receptors, Dopamine D2/agonists , Receptors, Serotonin, 5-HT1/metabolism , Serotonin/pharmacology , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Stereotyped Behavior/drug effectsABSTRACT
RATIONALE: H(3)-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated. OBJECTIVES: We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H(3)-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine. RESULTS: Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine. CONCLUSIONS: Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.
Subject(s)
Antipsychotic Agents/antagonists & inhibitors , Apomorphine/antagonists & inhibitors , Dizocilpine Maleate/antagonists & inhibitors , Drug Inverse Agonism , Inhibition, Psychological , Phencyclidine/antagonists & inhibitors , Stereotyped Behavior/drug effects , Animals , Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Benzofurans/antagonists & inhibitors , Dizocilpine Maleate/pharmacokinetics , Haloperidol/pharmacology , Histamine Antagonists/pharmacology , Imidazoles/antagonists & inhibitors , Male , Methamphetamine/antagonists & inhibitors , Methamphetamine/pharmacology , Mice , Phencyclidine/pharmacology , Piperidines/antagonists & inhibitors , Pyrrolidines/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effectsABSTRACT
Dopamine D(2)-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D(4) and D(3) receptors, respectively. The current studies were aimed at characterizing a series of D(2), D(3), and D(4) agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D(4) receptor (R) knockout (KO) mice. All D(3) agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D(4) agonists. Likewise, D(2), D(3), and D(4) antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D(3) antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D(2) antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D(4) antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D(3) receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D(4)RKO mice, effects that were inhibited by the D(3) antagonist, PG01037, in both wild-type and D(4)R KO mice. Together, these studies provide strong support that D(2)-like agonist-induced PE and yawning are differentially mediated by the D(3) (induction) and D(2) (inhibition) receptors. These studies fail to support a role for the D(4) receptor in the regulation of PE or yawning by D(2)-like agonists.
Subject(s)
Dopamine Agonists/pharmacology , Penile Erection/drug effects , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/agonists , Animals , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Behavior, Animal/drug effects , Benzothiazoles/antagonists & inhibitors , Benzothiazoles/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Dose-Response Relationship, Drug , Male , Mice , Mice, Knockout , Pramipexole , Rats , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Dopamine D4/agonists , Receptors, Dopamine D4/antagonists & inhibitors , Receptors, Dopamine D4/genetics , Yawning/drug effectsABSTRACT
INTRODUCTION: 5-HT(2C) agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT(2C) agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics). OBJECTIVES: The objectives of these studies were to combine WAY-163909, a selective 5-HT(2C) agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur. RESULTS AND DISCUSSION: In mice, co-administration of either haloperidol, or clozapine, produced a significant leftward shift in the ability of WAY-163909 to block apomorphine-induced climbing behavior, without any affect on apomorphine-induced stereotypy or an increased propensity for catalepsy. In the rat-conditioned avoidance model, WAY-163909 was combined with either haloperidol or clozapine at doses that individually produced reductions in avoidance response on the order of 10%, while the combination of WAY-163909 and either of the antipsychotics resulted in a greater than 70% reduction in avoidance, with no evidence of response failures, or pharmacokinetic interaction. CONCLUSION: Doses of either haloperidol or clozapine, that failed to antagonize an MK-801 induced deficit in prepulse inhibition, significantly attenuated the sensory gating deficit when combined with WAY-163909. Data support the notion that 5-HT(2C) receptor agonists, co-administered with other marketed antipsychotics, allow for dose sparing with a more favorable side-effect profile.
Subject(s)
Antipsychotic Agents/pharmacology , Avoidance Learning/drug effects , Azepines/pharmacology , Indoles/pharmacology , Serotonin 5-HT2 Receptor Agonists , Animals , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Apomorphine/antagonists & inhibitors , Azepines/adverse effects , Azepines/therapeutic use , Catalepsy/chemically induced , Catalepsy/drug therapy , Clozapine/adverse effects , Clozapine/pharmacology , Clozapine/therapeutic use , Dizocilpine Maleate/pharmacology , Drug Synergism , Drug Therapy, Combination , Haloperidol/adverse effects , Haloperidol/pharmacology , Haloperidol/therapeutic use , Indoles/adverse effects , Indoles/therapeutic use , Male , Mice , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Stereotyped Behavior/drug effectsABSTRACT
Analogues of the pyridine based PLG (Pro-Leu-Gly-NH(2)) peptidomimetic were synthesized and evaluated as dopamine modulating agents. Modifications in the position corresponding to the leucine side chain in PLG afforded derivatives , and , substituted with H, Me and Bn instead of the isobutyl group, respectively. Changes in the proline residue produced derivative , substituted with a symmetrical piperidine ring instead of the pyrrolidine ring and , in which the pyrrolidine ring is connected to the pyridine ring via a hydroxymethyl group instead of a keto function. The peptidomimetics were tested for their ability to enhance the maximal effect of N-propylapomorphine (NPA) at dopamine D2 receptors in the functional cell-based R-SAT assay. Compounds , , and , produced a statistically significant increase in the maximal NPA response at 10 nM (117 +/- 6%, 118 +/- 6%, and 116 +/- 3%, respectively), which is similar to the effect of PLG in this assay, whereas was able to potentiate the response to a similar extent at 1 nM concentration (115 +/- 5%). All derivatives produced a bell-shaped dose-response curve and none of the compounds were active at the D2 receptor alone, which indicates that the mechanism behind the activity of both the pyridine based mimetics and PLG is the same. Interestingly, l-Pro-d-Leu-Gly-NH(2) was found to be more potent than PLG and produced a 119 +/- 1% increase in the NPA response at 1 nM.
Subject(s)
Iodide Peroxidase/drug effects , MSH Release-Inhibiting Hormone/chemical synthesis , MSH Release-Inhibiting Hormone/pharmacology , Molecular Mimicry , Pyridines/chemistry , Animals , Apomorphine/analogs & derivatives , Apomorphine/antagonists & inhibitors , Apomorphine/pharmacology , Dose-Response Relationship, Drug , Humans , Ligands , MSH Release-Inhibiting Hormone/chemistry , Mice , Molecular Structure , NIH 3T3 Cells , Stereoisomerism , Structure-Activity Relationship , Iodothyronine Deiodinase Type IIABSTRACT
5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped Fos induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased Fos expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders.