Changes in Sensitivity of Reward and Motor Behavior to Dopaminergic, Glutamatergic, and Cholinergic Drugs in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1-/Y) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function

Antibody Inhibition of a Viral Type 1 Interferon Decoy Receptor Cures a Viral Disease by Restoring Interferon Signaling in the Liver

Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1-IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy

Different Contributions of Dopamine D1 and D2 Receptor Activity to Alcohol Potentiation of Brain Stimulation Reward in C57BL/6J and DBA/2J Mice

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1–0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003–0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1–3.0 mg/kg) and antagonist raclopride (0.01–0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6–2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains

Changes in Sensitivity of Reward and Motor Behavior to Dopaminergic, Glutamatergic, and Cholinergic Drugs in a Mouse Model of Fragile X Syndrome

<div><p>Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which <i>Fmr1</i> has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (<i>Fmr1</i>^-/Y) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. <i>Fmr1</i>^-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in <i>Fmr1</i>^-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in <i>Fmr1</i>^-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in <i>Fmr1</i>^-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of <i>Fmr1</i>^-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the <i>Fmr1</i>^-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.</p> </div

Effects of the partially M1-selective antagonist trihexyphenidyl on ICSS and locomotor behavior in wild type (WT, <i>white</i><i>circles</i>) and <i>Fmr1</i>^-/Y mice (red circles).

<p>Changes in BSR threshold (<b>A</b>) and maximum operant response rate (MAX, <b>B</b>) 31-45 minutes after i.p. trihexyphenidyl injections are shown. Values are expressed as mean percentages of pre-injection baselines ± SEM. Asterisks (*) indicate <i>p</i> < 0.05 vs. vehicle (V); daggers (†) indicate <i>p</i> < 0.05 vs. WT (dose x genotype interaction <i>post </i><i>hoc</i>). <b>C</b>. Mean distance traveled (± SEM) before and after injection of dH₂O (VEH) or trihexyphenidyl (THX, 10.0 mg/kg i.p.) in 15-minute intervals. Shading indicates post-injection time points. Daggers (†) indicate <i>p</i> < 0.05 vs. WT (time x genotype interaction <i>post </i><i>hoc</i>). <b>D</b>. Mean change in locomotion (± SEM) as a percentage of pre-injection baseline for 60 minutes after injection of dH₂O (VEH) or trihexyphenidyl (THX, 10.0 mg/kg i.p.).</p

Effects of the atypical neuroleptic aripiprazole on ICSS and locomotor behavior in wild type (WT, <i>white</i><i>circles</i>) and <i>Fmr1</i>^-/Y mice (red circles).

<div><p>Changes in BSR threshold (<b>A</b>) and maximum operant response rate (MAX, <b>B</b>) 46-60 minutes after i.p. aripiprazole injections are shown. Values are expressed as mean percentages of pre-injection baselines ± SEM. </p> <p>Asterisks (*) indicate <i>p</i> < 0.05 vs. vehicle (V). <b>C</b>. Mean distance traveled (± SEM) before and after injection of vehicle (VEH) or aripiprazole (ARI, 0.1 mg/kg i.p.) in 15-minute intervals. Shading indicates post-injection time points. <b>D</b>. Mean change in locomotion (± SEM) as a percentage of pre-injection baseline activity for 60 minutes after injection of vehicle (VEH) or aripiprazole (ARI, 0.1 mg/kg i.p.).</p></div

Comparison of ICSS and locomotor behavior in wild type (WT, <i>white</i><i>circles</i>) and <i>Fmr1</i>^-/Y mice (red circles).

<p><b>A</b>. Both <i>Fmr1</i>^-/Y and WT mice responded for BSR in a frequency-dependent manner. Values are mean number of responses per 50 sec access to BSR at each stimulus frequency ± SEM. <b>B</b>. BSR sensitivity expressed as electrical charge delivery at baseline BSR threshold frequency (θ₀) did not differ between WT (white bars) and <i>Fmr1</i>^-/Y mice (red bars). Values are mean charge in Coulombs ± SEM. <b>C</b>. Baseline maximum operant response rates were lower in <i>Fmr1</i>^-/Y mice than WT mice. Values are mean maximum number of responses ± SEM. * = <i>p</i> < 0.05 vs. WT. <b>D</b>-<b>F</b>. Habituation to the novel locomotor apparatus and handling in WT and <i>Fmr1</i>^-/Y mice. On Day 1 (D) <i>Fmr1</i>^-/Y mice were less active at all time points before (15-45 min) and after handling (60-105 min), and had lower cumulative total locomotion before and after handling (inset). On Day 2 (E) <i>Fmr1</i>^-/Y mice were less active prior to (inset) and for 30 min following handling. By Day 3 (F), total locomotion remained lower in <i>Fmr1</i>^-/Y mice prior to handling but no difference in locomotion was seen after handling (inset). Dashed lines indicate handling time points. Values are mean distance traveled ± SEM. Asterisks (*) indicate <i>p</i> < 0.05 vs. WT.</p

Effects of cocaine on ICSS and locomotor behavior in wild type (WT, <i>white</i><i>circles</i>) and <i>Fmr1</i>^-/Y mice (red circles).

<p>Changes in BSR threshold (<b>A</b>) and maximum operant response rate (MAX, <b>B</b>) in the first 15 minute series after i.p. cocaine injections are shown. Values are expressed as mean percentages of pre-injection baselines ± SEM. <b>C</b>. Mean change in locomotion (± SEM) as a percentage of pre-injection baseline activity after injection of saline (V) or cocaine (1.0, 3.0, or 10.0 mg/kg i.p.) in the first 15 minutes after injection. For A-C, asterisks (*) indicate <i>p</i> < 0.05 vs. vehicle (V); daggers (†) indicate <i>p</i> < 0.05 vs. WT (dose x genotype interaction <i>post </i><i>hoc</i>). <b>D</b>. Mean distance traveled (± SEM) before and after injection of saline (VEH) or cocaine (COC, 1.0, 3.0, or 10.0 mg/kg i.p.) in 15-minute intervals. Shading indicates post-injection time points. Daggers (†) indicate <i>p</i> < 0.05 vs. WT (time x genotype interaction <i>post </i><i>hoc</i>).</p

Effects of the mGluR5-selective antagonist MPEP on ICSS and locomotor behavior in wild type (WT, <i>white</i><i>circles</i>) and <i>Fmr1</i>^-/Y mice (red circles).

<div><p>Changes in BSR threshold (<b>A</b>) and maximum operant response rate (MAX, <b>B</b>) 31-45 minutes after i.p. MPEP injections are shown. Values are expressed as mean percentages of pre-injection baselines ± SEM. </p> <p>Asterisks (*) indicate <i>p</i> < 0.05 vs. vehicle (V); daggers (†) indicate <i>p</i> < 0.05 vs. WT (dose x genotype interaction <i>post </i><i>hoc</i>). <b>C</b>. Mean distance traveled (± SEM) before and after injection of saline (VEH) or MPEP (5.6 mg/kg i.p.) in 15-minute intervals. Shading indicates post-injection time points. Daggers (†) indicate <i>p</i> < 0.05 vs. WT (time x genotype interaction <i>post </i><i>hoc</i>). <b>D</b>. Mean change in locomotion (± SEM) as a percentage of pre-injection baseline for 60 minutes after injection of saline (VEH) or MPEP (5.6 mg/kg i.p.).</p></div