Single dose of H3 receptor antagonist - ciproxifan - abolishes negative effects of chronic stress on cognitive processes in rats

Rationale

The role of histamine neurons in stress evoked cognitive impairments remains unclear. Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in naïve rodents.

Objectives

The purpose of this study was to determine if ciproxifan, (cyclopropyl-(4-(3-1H-imidazol-4-yl) propyloxy) phenyl) ketone, an H(3) receptor antagonist, could alleviate cognitive deficits observed in chronically stressed rats.

Methods

Specifically, we attempted to characterize the preventive action of single dose of ciproxifan (3 mg/kg, i.p.) against an impairment caused by chronic restraint stress (2 h daily for 21 days) on recognition memory tested in an object recognition task and on the long-term memory tested in a passive avoidance test.

Results

We found that administration of ciproxifan potently prevented deleterious effects of chronic restraint stress, when administered prior to learning, or immediately after learning, or before retrieval on both the recognition (p<0.001) and the passive avoidance behavior (p<0.001).

Conclusions

These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of stress evoked cognitive impairments.     

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory

Rationale

The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.

Objectives

To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D₂ receptor occupancy and changes in working memory.

Methods

Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [¹¹C]raclopride and [¹⁸?F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [¹⁸?F]FDG scan.

Results

The mean (±SD) D₂ receptor occupancies were 22.2?±?16.0 % in the 2 mg group, 35.5?±?3.6 % in the 5 mg group, 63.2?±?9.9 % in the 10 mg group and 72.8?±?2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t?=?2.705, df?=?14, p?=?0.017). Greater striatal D₂ receptor occupancy was related to greater decrease in frontal metabolism (r?=??0.659, p?=?0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r?=??0.597, p?=?0.019) under the greatest task load.

Conclusions

Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D₂ receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.     

Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons

Rationale

The various α subtypes of GABA_A receptors have been strongly implicated in alcohol reinforcement and consumption.

Objectives

The effects of the GABA_A α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on seeking and self-administration responses were evaluated in two groups of baboons trained under a 3-component chained schedule of reinforcement (CSR).

Methods

Alcohol (4 %?w/v; n?=?5; alcohol group) or a preferred nonalcoholic beverage (n?=?4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). 3-PBC (1.0–30.0 mg/kg) and saline were administered before drinking sessions under both acute and 5-day dosing conditions.

Results

Repeated, and not acute, doses of 3-PBC significantly decreased total self-administration responses (p?<?0.05), volume consumed (p?<?0.05), and gram per kilogram of alcohol (p?<?0.05) in the alcohol group. In the control group, 5-day administration of 3-PBC significantly decreased total self-administration responses (p?<?0.05) but produced nonsignificant decreases in volume consumed. Within-session pattern of drinking was characterized by a high level of drinking in the first 20 min of the session for both groups, which was significantly (p?<?0.05) decreased by all doses of 3-PBC (1.0–18.0 mg/kg) only in the alcohol group. In contrast, the first drinking bout in the control group was only reduced at the highest doses of 3-PBC (10.0 and 18.0 mg/kg).

Conclusions

The results support the involvement of the GABA_A α1 subtype receptor in alcohol reinforcement and consumption.     

The CRF1 receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and d-cycloserine

Rationale

The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus.

Objectives

The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD.

Methods

Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study.

Results

Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and d-cycloserine.

Conclusions

These findings confirm that the CRF₁ receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress.     

The effects of BMY-14802 against l-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat

Rationale

l-DOPA continues to be the primary treatment for patients with Parkinson’s disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT_1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce l-DOPA induced dyskinesia in a 5-HT_1A receptor dependent manner.

Objective

In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against l-DOPA, the D₁ receptor agonist SKF81297 and the D₂ receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802’s effects was evaluated using WAY-100635, a 5-HT_1A receptor antagonist.

Results

Results confirmed the dose-dependent (20?>?10?>?5 mg/kg) anti-dyskinetic effects of BMY-14802 against l-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D₁ and D₂ receptor agonists. Additionally, BMY-14802’s anti-dyskinetic effects against l-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5 mg/kg).

Conclusion

Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against l-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD.     

Discriminative stimulus effects of pregnanolone in rats: role of training dose in determining mechanism of action

Rationale

Positive γ-aminobutyric acid_A (GABA_A) modulators acting at different binding sites often produce similar behavioral effects; however, their effects are not identical. Actions of neuroactive steroids at other receptors, in addition to GABA_A receptors, might account for some differences between neuroactive steroids and other positive modulators, like benzodiazepines.

Objective

Multiple mechanisms of other drugs (e.g., ethanol) have been elucidated by comparing their discriminative stimulus effects across different training doses; the current study used that approach to examine the mechanisms of action of the neuroactive steroid pregnanolone.

Methods

Separate groups of rats (n?=?6–8/group) discriminated pregnanolone from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Two groups initially discriminated 3.2 mg/kg; once stimulus control was established, the training dose was systematically decreased to 1.33 mg/kg in one group and increased to 7.5 mg/kg in the other group. Other rats discriminated either 1.33 or 7.5 mg/kg without training at another dose.

Results

Stimulus control was established in 24–28 sessions in all groups. Positive GABA_A modulators produced ≥80 % pregnanolone-lever responding, regardless of training dose; rank-order potency was flunitrazepam?>?midazolam?>?pregnanolone?=?pentobarbital. Ethanol produced some drug-lever responding (42 %) only in rats discriminating 1.33 mg/kg, whereas the N-methyl-d-aspartate receptor antagonist ketamine and the serotonin receptor agonist 1-(m-chlorophenyl)-biguanide occasioned predominantly vehicle-lever responding in all rats.

Conclusions

There was little difference in discriminative stimulus effects of pregnanolone across different training conditions, confirming a predominant, if not exclusive, role of GABA_A receptors in these effects of pregnanolone.     

Synthesis and anticonvulsant activity of novel quinazolin-4(3H)-one derived pyrazole analogs

Eighteen novel 6,8-(dibromo/unsubstituted)-2-(methyl/phenyl)-3-(4-(5-(substitutedphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl)phenyl)-quinazolin-4(3H)-ones 4a–4r were designed and synthesized in good yield. Antiepileptic screening of the title compounds was performed using MES and scPTZ seizures tests while the neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 4d, 4e, 4p, 4q, and 4r were found active in MES model, while 4a, 4d, 4f, 4m, and 4p showed significant antiepileptic activity in scPTZ model. Further, all these eight compounds were administered to rats and compounds 4e, 4p, and 4q showed better activity than Phenytoin in oral route. Among these compounds 4p revealed protection in MES after i.p. administration at a dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h). The compound 4p also provided protection in the scPTZ at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h).     

Candesartan prevents impairment of recall caused by repeated stress in rats

Rationale

Deleterious effects of psychological stress on memory are increasingly important. Overexpression of the AT₁ angiotensin receptors in brain has been found to participate in several negative effects of chronic stress including hypertension and a cognitive impairment.

Objective

In this study, we searched for the protective effects the AT₁ angiotensin receptor blockade with candesartan against the adverse effects of repeated stress on recall of aversively and appetitively motivated behaviours in rats.

Methods

Two groups of male Wistar rats were repeatedly stressed by keeping them daily (2 h/21 days) in tight plastic tubes. The subjects of the group 1 received candesartan (0.1 mg/kg, orally) each day before the stressing procedure. The rats of the group 2 received vehicle. Another two groups of rats (3 and 4) receiving candesartan and vehicle, respectively, were appropriately handled but not stressed. Next day, after ending the repeated stress procedure, all rats were tested in two cognitive paradigms: inhibitory avoidance (IA) and object recognition (OR).

Results

Stressed animals displayed decreased recall of the IA behaviour (p?<?0.01) and decreased OR (p?<?0.05). These effects were not seen in the animals stressed and concomitantly treated with candesartan. The auxiliary tests designed to control for the possible unspecific contribution of motor (open field) and emotional (elevated “plus” maze) effects of the experimental procedures to results of the cognitive tests showed no such contribution.

Conclusion

These data strongly suggest that the AT₁ angiotensin receptor blockade effectively counteracts deleterious effects of stress on recall of aversively and appetitively motivated memories in rats.     

Serotonergic hallucinogens differentially modify gamma and high frequency oscillations in the rat nucleus accumbens

Rationale

The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse. Psychoactive compounds, such as N-methyl-d-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130–180 Hz) in local field potentials (LFPs) recorded in the NAc. Lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT_2A receptors likely underlies their hallucinogenic effects. Whether these compounds can also modulate LFP oscillations in the NAc is unclear.

Objective

This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT_2A receptors mediate the effects observed.

Methods

LFPs were recorded from the NAc of freely moving rats. Drugs were administered intraperitoneally.

Results

LSD (0.03–0.3 mg/kg) and DOI (0.5–2.0 mg/kg) increased the power and reduced the frequency of HFO. In contrast, the hallucinogens produced a robust reduction in the power of low (40–60 Hz), but not high gamma oscillations (70–90 Hz). MDL 11939 (1.0 mg/kg), a 5HT_2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band. Equivalent increases in HFO power were observed after TCB-2 (5HT_2A receptor agonist, 0.1–1.5 mg/kg), but not CP 809101 (5H_2C receptor agonist, 0.1–3 mg/kg). Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg).

Conclusions

Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT_2A receptors. Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed.     

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

Rationale

Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABA_A receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence.

Objective

The present study used this approach to investigate the role of GABA_A receptor subtypes in mediating dependence-like effects following benzodiazepine administration.

Methods

Squirrel monkeys (n?=?6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1–10 mg/kg; nonselective GABA_A receptor agonist), zolpidem (0.032–1.0 mg/kg; α1 subunit-containing GABA_A subtype-preferring agonist), and HZ-166 (0.1–10 mg/kg; functionally selective α2 and α3 subunit-containing GABA_A receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1–3.2 mg/kg; nonselective GABA_A receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1–3.2 mg/kg and 0.32–10 mg/kg, respectively; α1 subunit-containing GABA_A receptor antagonists).

Results

Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem.

Conclusions

These data raise the possibility that α1 subunit-containing GABA_A receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.     

Comparison of the D1 dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease

Rationale

Preclinical evidence indicates that D₁ dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D₁ dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine (DOX), an oxygen bioisostere of DHX that has even greater selectivity for the D₁ dopamine receptor.

Objectives

Using the unilateral 6-hydroxydopamine-lesioned rat model of PD, DOX and DHX were compared at several doses (0.625, 1.25, 2.5, or 5.0?mg/kg) for their ability to elicit contralateral rotation by either intraperitoneal injection or oral gavage.

Results

After intraperitoneal administration, both DOX and DHX showed robust contralateral rotation at doses of 2.5 and 5.0?mg/kg compared to vehicle. In addition, after intraperitoneal administration at doses of 2.5 and 5.0?mg/kg, DHX had a significantly longer duration of action than DOX (p?p?Conclusion These results demonstrate that although DHX and DOX have similar activity after intraperitoneal administration, DOX demonstrated greater activity after oral administration compared to DHX. Despite its catechol functionality, DOX may possess sufficient oral availability for development as a human therapeutic agent.     

Influence of the novel histamine H3 receptor antagonist ST1283 on voluntary alcohol consumption and ethanol-induced place preference in mice

Rationale

Growing evidence supports a role for the central histaminergic system to have a modulatory influence on drug addiction in general and alcohol-use disorders in particular through histamine H₃ receptors (H₃R).

Objective

In the present study, the effects of systemic injection of the newly synthesized H₃R antagonist ST1283 on ethanol (EtOH) voluntary intake and EtOH-conditioned reward in mice have been investigated.

Methods

Oral EtOH, saccharin, and quinine intake was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol or tastant solutions. EtOH-induced place preference (CPP), EtOH-induced locomotor activity, and blood ethanol concentration (BEC) were also measured.

Results

Following administration of the H₃R antagonist (2.5, 5, and 10 mg/kg, i.p.), there was a significant dose-dependent decrease in alcohol consumption and preference. Importantly, vehicle- and ST1283 (5 mg/kg)-treated mice showed similar consumption and preference to increasing concentration of both sweet and bitter tastes. More interestingly, systemic administration of ST1283 inhibited EtOH-CPP and EtOH-enhanced locomotion. This inhibition was blocked when mice were pretreated with the selective H₃R agonist R-(alpha)-methyl-histamine (10 mg/kg). Finally, vehicle- and ST1283-treated mice had similar BECs.

Conclusion

Our results show that ST1283 may decrease voluntary EtOH consumption and EtOH-CPP by altering its reinforcing effects, suggesting a novel role for histamine signaling in regulation of alcoholism. Lastly, the results add to the growing literature on H₃R modulation in the pharmacotherapy of EtOH addiction.     

Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats

Background and rationale

Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at ??4??2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).

Methods

Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control.

Results

Dizocilpine caused a significant (p?p?p?Conclusions AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.     

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

Rationale

Serotonin 1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson’s disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.

Objective

To further delineate the relationship between 5-HT_1A receptors and glutamate, the current study examined the effects of the 5-HT_1AR agonist, ±8-OH-DPAT and the N-methyl-d-aspartic acid receptor (NMDAR) antagonist, MK-801, on l-DOPA-induced motor behavior.

Materials and methods

Unilateral 6-hydroxydopamine lesioned male Sprague–Dawley rats were rendered dyskinetic with 1 week of daily l-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: ±8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined ±8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by l-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of ±8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.

Results

Individually, both ±8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of ±8-OH-DPAT+MK-801 reduced l-DOPA-induced AIMs and potently enhanced contralateral rotations without altering l-DOPA-induced motor improvements.

Conclusions

The current results indicate a functional interaction between 5-HT_1AR and NMDAR that may improve pharmacological treatment of PD patients.     

Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors

Rationale

Cognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated.

Objectives

In this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly.

Materials and methods

Mice were repeatedly administered PCP at a dose of 10mg/kg for 14days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01–1.0mg/kg) and haloperidol (0.3 and 1.0mg/kg) on cognitive impairment in mice treated with PCP repeatedly.

Results

Single (1.0mg/kg) and repeated (0.03 and 0.1mg/kg, for 7days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D₁ receptor antagonist, SCH23390, and a serotonin 5-HT_1A receptor antagonist, WAY100635; however, co-treatment with a D₂ receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole.

Conclusions

These results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D₁ and serotonin 5-HT_1A receptors.     

Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [11C]GSK189254 in anesthetized baboon

Rationale

The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone) as a high-affinity histamine H₃ receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors.

Objective

This study measured brain histamine H₃ receptor blockade by JNJ-39220675 (1?mg/kg) in the female baboon.

Methods

Positron emission tomography imaging and [¹¹C]GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H₃ receptor, was used to measure histamine H₃ receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1?mg/kg) in the anesthetized baboon. Histamine H₃ receptor availability was estimated as the total distribution volume (V _T) in brain regions. The sensitivity of [¹¹C]GSK189254 binding to injected mass and carryover effects was determined.

Results

JNJ-39220675 produces robust (ca. 90?%) blockade of [¹¹C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1?mg/kg), the fractional receptor occupancy was >0.9 at 90?min with a slight increase from 90 to 240?min. Similar to prior studies in humans, V _T was highly sensitive to the mass of GSK189254 with ED₅₀ estimated to be 0.16?μg/kg.

Conclusions

The robust blockade of binding of [¹¹C]GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood–brain barrier and occupies the histamine H₃ receptor after oral administration at low plasma concentrations (～1?ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [¹¹C]GSK189254 to injected mass at doses >0.1?μg/kg.     

Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist

Rationale and objective

Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT₃ receptor (5-HT₃R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects.

Results

EVP-5141 bound to α7 nAChRs in rat brain membranes (K _i ?=?270 nM) and to recombinant human serotonin 5-HT₃Rs (K _i ?=?880 nM) but had low affinity for α4β2 nAChRs (K _i ?>?100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT₃R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3–30 mg kg^?1, p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3–3 mg kg^?1) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg^?1, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg^?1, i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg^?1, p.o.).

Conclusions

EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.     

Crocins,the active constituents of Crocus Sativus L., counteracted ketamine–induced behavioural deficits in rats

Rationale

Experimental evidence indicates that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders including anxiety and depression.

Objectives

The present study was designed to investigate the ability of crocins to counteract schizophrenia-like behavioural deficits produced by ketamine in rats.

Methods

Crocin’s ability to counteract hypermotility, stereotypies and ataxia induced by ketamine was evaluated in a motor activity cage. The ability of crocins to reverse ketamine-induced memory deficits was assessed using the novel object recognition task (NORT). The social interaction test was used in order to examine the effects of crocins on ketamine-induced social withdrawal.

Results

Crocins (50 but not 30 mg/kg, i.p.) attenuated ketamine (25 mg/kg, i.p.)-induced hypermotility, stereotypies and ataxia. In a subsequent study, post-training administration of crocins (15 and 30 mg/kg, i.p.) reversed ketamine (3 mg/kg, i.p.)-induced performance deficits in the NORT. Finally, crocins (50 but not 30 mg/kg, i.p.) counteracted the ketamine (8 mg/kg, i.p.)-induced social isolation in the social interaction test.

Conclusions

Our findings show that crocins attenuated schizophrenia-like behavioural deficits induced by the non-competitive NMDA receptor antagonist ketamine in rats.     

On the behavioural specificity of hypophagia induced in male rats by mCPP,naltrexone, and their combination

Rationale

Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation.

Objectives

In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT_2C/1B receptor agonist mCPP and their combination.

Methods

Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose–response profile of mCPP (0.1–3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg).

Results

Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone.

Conclusions

In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT_2C/1B receptor mechanisms.     

Effect of a single-dose rifampin on the pharmacokinetics of pitavastatin in healthy volunteers

Purpose

As an inhibitor of HMG-CoA reductase that catalyses the first step of cholesterol synthesis, pitavastatin undergoes little hepatic metabolism; however, it is a substrate of uptake and efflux transporters. Since pitavastatin is potentially co-administered with agents that affect transporter activities, the pharmacokinetics of pitavastatin was investigated on the effects of a single-dose rifampin in healthy volunteers.

Methods

Twelve Chinese healthy male volunteers took 4 mg pitavastatin orally with 150 ml water or with a single dose of 600 mg rifampin on separate occasions and the plasma concentrations of pitavastatin were measured over 48 h by HPLC-MS/MS.

Results

A single dose of rifampin significantly increased the mean area under the plasma concentration-time curve(AUC)_(0-48h) and C_max of pitavastatin by 573.5 %(95%CI, 373.3–773.7 %, p?<?0.001) and 819.2 %(95 % CI, 515.4–1123.0 %, p?<?0.001) respectively, while significantly decreased the t_1/2 and CL/F of pitavastatin by 38.8 % (95 % CI, 18.2–59.4 %, p?<?0.001) and 81.4 % (95 % CI, 75.0–87.7 %, p?<?0.001) respectively.

Conclusions

Co-administration of pitavastatin with a single dose of rifampin resulted in a significant increase in plasma levels of pitavastatin in Chinese healthy subjects.