Abstract
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.
Highlights
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common singlegene defect identified in autism [1]
Throughout all intracranial self-stimulation (ICSS) experiments, mice showed frequency-dependent responding for brain stimulation reward (BSR; Figure 1A)
The present study investigated reward and motor function in the Fmr1-/Y mouse model of fragile X syndrome (FXS) by measuring the sensitivity of brain stimulation reward (BSR) and locomotor activity, respectively, to drugs that affect dopamine, muscarinic acetylcholine, and metabotropic glutamate receptors
Summary
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common singlegene defect identified in autism [1]. Mice lacking the Fmr gene model aspects of the pathophysiology and many of the abnormal behaviors seen in FXS and autism, including cognitive impairments [10,11,12,13], increased spontaneous motor activity [14,15,16] (but see 17,18), increased seizure susceptibility [19,20]; and altered social behaviors [17,21,22,23]. Activity at these receptors in response to stimuli facilitates local synaptic protein translation; and lack of FMRP leads to abnormally exaggerated experience and protein synthesis-dependent synaptic plasticity [25,26,27,28]. Heterodimeric D1/D2 dopamine receptors activate PLC through Gq [33,34], but whether this signaling mechanism is affected in Fmr1-null mice is not yet known
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