Elsevier

Biological Psychiatry

Volume 69, Issue 10, 15 May 2011, Pages 928-935
Biological Psychiatry

Archival Report
Pharmacologic Rescue of Motivational Deficit in an Animal Model of the Negative Symptoms of Schizophrenia

https://doi.org/10.1016/j.biopsych.2011.01.012Get rights and content

Background

Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits.

Methods

Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry.

Results

The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice.

Conclusions

We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness.

Section snippets

Mice

The generation of D2R-OE mice, temporal regulation of the transgene, and food restriction protocol have been previously described (6) and are detailed in Supplement 1.

Behavior Testing

Behavioral testing was carried out as previously described for progressive ratio (8, 10), with some adjustments. For a detailed description of the apparatus and procedures used, please see outline and text in Supplement 1.

Drug Treatments

The 5-HT2C receptor antagonist SB24280 (Sigma Aldrich, St. Louis, Missouri) was dissolved in .9% saline and

Selective Overexpression of Dopamine D2 Receptors in Striatum Results in a Reversible Impairment in Incentive Motivation Across a Range of Work Requirements and Is Not Due to a Difference in Sensitivity to Satiety or Fatigue

We previously determined that mice with striatal specific overexpression of D2Rs display a reversible impairment in incentive motivation (8, 10). Using a doubling operant progressive ratio schedule (PR X2), we found that D2R-OE mice earned significantly fewer rewards than control littermates. This phenotypic difference was reversible; it was eliminated by doxycycline, which switched off the expression of the transgene. To determine if this genotypic difference was consistent for less onerous

Discussion

Two characteristic features of schizophrenia are deficits in incentive motivation and in cognition, each of which negatively impacts the other (22). Both of these features are evident in D2R-OE mice. We find that the transient motivational deficit observed in the D2R-OE mice is due to a reluctance to work for food, rather than a decrease in satiation threshold, a decreased tolerance for low rates of reward, or a difference in reactivity to reward itself. Systemic pharmacologic blockade of D2Rs

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      Motivational impairments could arise due to an inability to experience pleasure (anhedonia) or an inability or unwillingness to work purposefully to obtain a rewarding outcome (avolition) (Barnes et al., 2014; Gard et al., 2007). Research in both human participants (Cohen and Minor, 2010; Gold et al., 2008) and with animal models of schizophrenia favours the latter idea (Simpson et al., 2011). For example, Ward et al. (2012) used a transgenic animal model of the negative symptoms of schizophrenia in which mice over-express striatal dopamine (DA) D2 receptors (D2R-OE mice).

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    Authors EHS and CK contributed equally to this work.

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