Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome

• Published in: PloS one 2013-10, Vol.8 (10), p.e77896-e77896
• Main Authors: Fish, Eric W, Krouse, Michael C, Stringfield, Sierra J, Diberto, Jeffrey F, Robinson, J Elliott, Malanga, C J
• Format: Article
• Language: English
• Subjects: Amphetamines; Animal behavior; Animals; Antipsychotic Agents - pharmacology; Aripiprazole; Behavior; Behavior, Animal - drug effects; Biosynthesis; Blotting, Western; Brain; Cocaine; Cocaine - pharmacology; Disease Models, Animal; Dopamine; Dopamine receptors; Dopamine Uptake Inhibitors - pharmacology; Drug abuse; Drugs; Enzymes; Excitatory Amino Acid Antagonists - pharmacology; FMR1 protein; Forebrain; Fragile X mental retardation protein; Fragile X Mental Retardation Protein - physiology; Fragile X syndrome; Fragile X Syndrome - drug therapy; Fragile X Syndrome - metabolism; Glutamatergic transmission; Glutamic acid receptors (metabotropic); House mouse; Hydroxylase; Immunoenzyme Techniques; Intellectual disabilities; Intracranial self-stimulation; Locomotor activity; Male; Mesencephalon; Mice; Mice, Knockout; Motor Activity - drug effects; Motor systems; Muscarinic Antagonists - pharmacology; Neurosciences; Pharmacology; Physiological aspects; Piperazines - pharmacology; Pyridines; Pyridines - pharmacology; Quinolones - pharmacology; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Receptor, Metabotropic Glutamate 5 - metabolism; Reinforcement; Reward; Rodents; Self-stimulation; Stimulation; Substantia nigra; Trihexyphenidyl; Trihexyphenidyl - pharmacology; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism; Ventral tegmentum
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0077896

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.