VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

Abstract

The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP ؉ ) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP ؉ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP ؉ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

“…The high level of metab olites suggests an increase of both the time spent in the cytoplasm and the exposure to enzymes, such as monoamine oxidase (MAO), 29 as demonstrated by the increased 5-HT levels observed following MAO-A inhibition in VMAT2-KO mice. 11 The deletion of VMAT2 in DA neurons is solely responsible for postnatal death Whereas the constitutive deletion of VMAT2 is lethal 2-3 days after birth, [11][12][13] only its specific deletion in DA neurons reproduces this phenotype. Mice with a conditional deletion of VMAT2 in NE or 5-HT neurons are viable and reach adulthood, although retarded growth has previously been observed in VMAT2 SERTcre -KO mice.…”

“…This increased locomotor response to drugs is associated with a decreased sensitization to cocaine and a reduction in amphetamine-conditioned place preference (CPP). 12,13 The behavioural characterization of VMAT2-HET and WT animals did not indicate any difference in anxiety levels, although a sucrose preference test revealed that HET mice are less responsive to sucrose. 14 In conjunction with the decreased CPP in HET mice, these data suggest the presence of anhedonia in VMAT2-HET mice.…”

“…[11][12][13] The constitutive removal of the VMAT2 gene results in death within a few days of birth. VMAT2-KO mice display massive growth deficiency, little movement and poor feeding.…”

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

“…Mice lacking both copies of the VMAT2 gene die during development, but heterozygotes survive and show reduced amphetamineconditioned reward, enhanced amphetamine and cocaineinduced locomotion, and enhanced MPTP toxicity (Takahashi et al, 1997;Wang et al, 1997). We hypothesized that sequence variants in the regions of the mouse genes encoding VMAT2, the alpha 2A adrenergic receptor, and/or beta-1 adrenergic receptor might explain the QTL and thus the differential effects of citalopram in the parental strains.…”

The ethical implications of genetic testing in the classroom

“…A paper by Silveira discusses a multidisciplinary approach to teaching students about the interplay of genes and the environment using a polymorphism that students were interested in but conveyed no risk for disease [9]. Following the submission of the paper, however, the author noted two recent reports that correlated VMAT2 variations with schizophrenia [30,31]. This raises a number of issues about how to deal with new developments after students have completed a genetic testing exercise.…”