DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all ...rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.
•The dopamine D1 potentiator DETQ was tested in humanized D1 mice and rhesus monkeys.•Actions of DETQ were dependent on endogenous dopaminergic tone.•DETQ displayed a behavioral profile consistent with central D1 receptor activation.•Neurochemical actions of DETQ support potential pro-cognitive effects.•D1 potentiators show promise for Parkinson's disease and other CNS disorders.
The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). ...We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (Ki) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HTEX levels. Atomoxetine also increased DAEX concentrations in PFC 3-fold, but did not alter DAEX in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NEEX and DAEX equally in PFC, but also increased DAEX in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DAEX. We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.
Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. In ...nonclinical assessments, 1 was mainly eliminated by CYP3A4-mediated metabolism, therefore at the risk of being a victim of drug–drug interactions (DDI) with CYP3A4 inhibitors and inducers. An effort was initiated to identify a new D1 PAM with an improved DDI risk profile. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic.
Background
The nociceptin/orphanin‐FQ (or opioid receptor‐like ORL1) receptor (NOP) is localized in the mesolimbic reward pathway and has been suggested to play a role in feeding, mood, stress, and ...addiction. Since its deorphanization in 1995, there has been a clear dichotomy in the literature regarding whether an agonist or antagonist would provide therapeutic benefit. Specifically, the literature reports indicate that NOP receptor antagonists produce efficacy in animal models of hyperphagia and antidepressant‐like activity, whereas NOP agonists produce anxiolytic‐like effects and dampen reward/addiction behaviors including ethanol consumption.
Methods
We characterize here the potent, orally bioavailable NOP antagonist, LY2940094, in rodent models of ethanol consumption, including ethanol self‐administration, progressive ratio operant self‐administration, stress‐induced reinstatement of ethanol seeking, and in vivo microdialysis in the nucleus accumbens.
Results
LY2940094 dose dependently reduced homecage ethanol self‐administration in Indiana alcohol‐preferring (P) and Marchigian Sardinian alcohol‐preferring (msP) rats, without affecting food/water intake or locomotor activity. Reduced ethanol intake in P rats did not show significant tolerance over 4 days of subchronic dosing. LY2940094 attenuated progressive ratio operant responding and break points for ethanol in P rats. Moreover, stress‐induced reinstatement of ethanol seeking in msP rats was completely blocked by LY2940094. Furthermore, LY2940094 blocked ethanol‐stimulated dopamine release in response to ethanol challenge (1.1 g/kg, intraperitoneally).
Conclusions
Our findings demonstrate for the first time that blockade of NOP receptors attenuates ethanol self‐administration and ethanol‐motivated behaviors, stress‐induced ethanol seeking, and ethanol‐induced stimulation of brain reward pathways in lines of rats that exhibit excessive ethanol consumption. Results suggest that LY2940094 may have potential therapeutic utility in treating alcohol addiction.
Evidence suggests that NOP receptor antagonists might be useful for treating depression and obesity, whereas NOP agonists might be useful for treating anxiety and addiction. Upregulation of NOP signaling has been reported in alcohol‐preferring rat lines, suggesting a causative role in high ethanol intake. We demonstrate for the first time that NOP antagonists are efficacious in animal models of ethanol self‐administration and provide a working hypothesis to explain how NOP agonists and antagonists could produce similar results in the models.
The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric ...disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.
In the present study we demonstrated that ketamine, an NMDA antagonist and possible psychotomimetic, increases extracellular histamine (HA) in the rat brain. We then examined the ability of the group ...II mGlu receptor agonist LY379268 to modulate the ketamine evoked increases in HA release in three limbic brain regions. Ketamine (25 mg/kg) increased HA in the medial prefrontal cortex (mPFC), ventral hippocampus (vHipp) and the nucleus accumbens (NAc) shell. LY379268 administered alone was without effect on basal HA efflux in the mPFC or vHipp but modestly decreased HA efflux in the NAc shell. Administration of LY379268 (3 and 10 mg/kg) prior to ketamine significantly attenuated the HA response in the mPFC, vHipp and the NAc shell. The inhibitory effects of LY379268 in the mPFC were mimicked by the systemic administration of the mGlu2 receptor positive allosteric modulator CBiPES (60 mg/kg). Finally, local perfusion experiments revealed that the effects of LY379268 on ketamine evoked HA efflux appear to be mediated by mGlu2 receptors outside the PFC as the intra-mPFC perfusion of LY379268 (100 μM or 300 μM) failed to attenuate ketamine evoked increases in HA efflux. Together, these novel observations reveal an effect of ketamine on histaminergic transmission in limbic brain areas and provide further insight into the possible antipsychotic mechanism of action of mGlu2/3 receptor agonists.
Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile ...compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA) efflux in the mPFC of the rat by means of
in vivo
microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine, and perphenazine treatment. We found no effect of the selective 5-HT
2A
antagonist MDL100907, 5-HT
2c
antagonist SB242084, or the 5-HT
6
antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H
1
receptor antagonists pyrilamine, diphenhydramine, and triprolidine, the H
3
receptor antagonist ciproxifan and the mixed 5-HT
2A
/H
1
receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H
1
receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H
1
receptor affinity (risperidone, aripiprazole, and haloperidol) were also without effect on HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H
1
receptors whereas nine other receptors, including 5-HT
2A
, were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H
1
receptors.
Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile ...compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA) efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine, and perphenazine treatment. We found no effect of the selective 5-HT(2A) antagonist MDL100907, 5-HT(2c) antagonist SB242084, or the 5-HT(6) antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H(1) receptor antagonists pyrilamine, diphenhydramine, and triprolidine, the H(3) receptor antagonist ciproxifan and the mixed 5-HT(2A)/H(1) receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H(1) receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H(1) receptor affinity (risperidone, aripiprazole, and haloperidol) were also without effect on HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H(1) receptors whereas nine other receptors, including 5-HT(2A), were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H(1) receptors.
1.
1. Adult male Sprague-Dawley rats were subjected to the fear-potentiated startle, elevated plus-maze and social interaction tests and the levels of norepinephrine, dopamine and serotonin in the ...dorsomedial hypothalamus were determined by high-performance liquid chromatography.
2.
2. Only rats subjected to the full fear potentiated startle test and not the other tests of anxiety or components (foot shocks or acoustic startle) of fear-potentiated startle showed significant increases in norepinephrine and dopamine levels after 24 hours.
3.
3. A time course experiment specific for the norepinephrine changes in the dorsomedial hypothalamus of fear-potentiated startle rats revealed a significant increase in tissue content as compared to controls at both the 12 and 24 hour post-test time points.
4.
4. Tyrosine hydroxylase activity in the dorsomedial hypothalamus of the fear-potentiated startle rats did not show a significant change from controls.
5.
5. An in vitro release study found a significant decrease in potassium-stimulated release of norepinephrine in the dorsomedial hypothalamus as compared to controls at 24 hours posttest.
6.
6. These results suggest that animals exposed to fear-potentiated startle and not other tests of “anxiety” have a change in tissue catecholamine levels and that the norepinephrine change may be the result of a decrease in release and not an increase in synthesis.
After flooding events, well users are encouraged to disinfect their private wells. However, well disinfection strategies are not consistently applied or proven effective. This study examines the ...science-based evidence that disinfection procedures reduce microbial loading in well water; reviews inclusion of disinfection principles in state-level emergency protocols; and explores research gaps potentially hindering disinfection efficacy. Emergency well disinfection protocols from 34 states were reviewed based on instructions for creating chlorine solutions; circulating chlorine solutions throughout the distribution system; achieving effective CT disinfection (chlorine dose*contact time); and post-disinfection guidance. Many protocols were missing key information about fundamentals of disinfection. Only two protocols instructed well users to verify chlorine residuals and three protocols instructed users to measure water pH. Most protocols recommended that high chlorine doses be introduced into the well, circulated throughout the system, and stagnated for several hours. A CT value estimated to inactivate at least 99.9% (3-log removal) of Cryptosporidium (255 mg-hr/L) was predicted to be achieved by 72.7% of protocols, and estimated CT values ranged from 35 to 16,327 mg-hr/L. Two research gaps identified were determining whether chlorine doses should differ based on well water chemistries and evaluating the appropriate chlorine dose that should be recommended for inactivating pathogens. This effort underscores a need for consistent, evidence-based messaging in emergency well disinfection protocols.
Display omitted
•Evidence-based emergency well disinfection protocols are critically needed.•Of the 8 identified disinfection steps, most protocols (64.5%) included 4–5 steps.•It is unknown how differences in well water chemistry impact chlorine residuals.•Research on a chlorine dose for inactivating well water pathogens is needed.
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