Elsevier

Biological Psychiatry

Volume 73, Issue 3, 1 February 2013, Pages 263-270
Biological Psychiatry

Archival Report
Novelty-Seeking Behaviors and the Escalation of Alcohol Drinking After Abstinence in Mice Are Controlled by Metabotropic Glutamate Receptor 5 on Neurons Expressing Dopamine D1 Receptors

https://doi.org/10.1016/j.biopsych.2012.07.019Get rights and content

Background

Novel experiences activate the brain's reward system in a manner similar to drugs of abuse, and high levels of novelty-seeking and sensation-seeking behavior have been associated with increased susceptibility to alcohol and drug abuse. Here, we show that metabotropic glutamate receptor 5 (mGluR5) signaling on dopaminoceptive neurons is necessary for both novelty-seeking behavior and the abstinence-induced escalation of alcohol drinking.

Methods

Mice harboring a transgene expressing microRNA hairpins against mGluR5 messenger RNA under the control of the D1 dopamine receptor gene promoter (mGluR5KD-D1) were tested in a battery of behavioral tests measuring learning abilities, anxiety levels, reactions to novelty, operant sensation seeking, and alcohol sensitivity. In addition, we have developed a method to assess long-term patterns of alcohol drinking in mice housed in groups using the IntelliCage system.

Results

mGluR5KD-D1 mice showed no behavioral deficits and exhibited normal anxiety-like behaviors and learning abilities. However, mGluR5KD-D1 animals showed reduced locomotor activity when placed in a novel environment, and exhibited decreased interaction with a novel object. Moreover, unlike control animals, mutant mice did not perform instrumental responses under the operant sensation-seeking paradigm, although they learned to respond for food normally. When mGluR5KD-D1 mice were provided access to alcohol, they showed similar patterns of consumption as wild-type animals. However, mutant mice did not escalate their alcohol consumption after a period of forced abstinence, but control mice almost doubled their intake.

Conclusions

These data identify mGluR5 receptors on D1-expressing neurons as a common molecular substrate of novelty-seeking behaviors and behaviors associated with alcohol abuse.

Section snippets

Animals

The mGluR5KD-D1 strain has been described previously (24). Animals were 8 to 16 weeks of age at the beginning of experimental procedures and were housed in Plexiglas home cages (30 × 40 × 20 cm) with two to six animals per cage in a room with controlled temperature (22°C ± 1°C) and humidity (55% to 65%). Mice had access to standard lab chow (Labofeed H, WPiK, Kcynia, Poland) and water ad libitum. Experiments were conducted in accordance with the European Union guidelines regarding the care and

Generation and Characterization of mGluR5KD-D1 Mice

Mice with selective knockdown of mGluR5 messenger RNA in D1-expressing neurons (mGluR5KD-D1 mice) were bred as congenic with the C57BL/6N strain (24). To confirm the cell-type specificity of transgene expression, we used immunohistochemical staining of the green fluorescent protein, which is expressed by the transgene. The strongest signal was observed in the striatum, but green fluorescent protein-expressing cells were also detected in the lower layers of the cortex, the basolateral amygdala,

Discussion

The loss of mGluR5 from neurons expressing dopamine D1 receptors abolishes sensation-seeking behavior, which extends the previous observation from mGluR5 KO mice (21). We found that all novelty-seeking behaviors were attenuated in mGluR5KD-D1 mice, which also displayed mildly decreased locomotor activity across all tests performed, except for the water maze. In contrast, mice with complete mGluR5 KO have been reported to exhibit enhanced activity in a novel environment (22), which could be due

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    Authors JRP and MS contributed equally to this work.

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