Anhedonia, avolition, and anticipatory deficits: assessments in animals with relevance to the negative symptoms of schizophrenia

Abstract

Schizophrenia represents a complex, heterogeneous disorder characterized by several symptomatic domains that include positive and negative symptoms and cognitive deficits. Negative symptoms reflect a cluster of symptoms that remains therapeutically unresponsive to currently available medications. Therefore, the development of animal models that may contribute to the discovery of novel and efficacious treatment strategies is essential. An animal model consists of both an inducing condition or manipulation (i.e., independent variable) and an observable measure(s) (i.e., dependent variables) that are used to assess the construct(s) under investigation. The objective of this review is to describe currently available experimental procedures that can be used to characterize constructs relevant to the negative symptoms of schizophrenia in experimental animals. While negative symptoms can encompass aspects of social withdrawal and emotional blunting, this review focuses on the assessment of reward deficits that result in anhedonia, avolition, and abnormal reward anticipation. The development and utilization of animal procedures that accurately assess reward-based constructs related to negative symptomatology in schizophrenia will provide an improved understanding of the neural substrates involved in these processes.

Keywords: Animal models; Brain reward; Contrast effects; Effort-related choice; ICSS; Sucrose preference.

Figure 1

Impairments relating to various components of reward processing are evident after withdrawal from chronic amphetamine administration. (A) Rats displayed an elevation of ICSS thresholds, reflecting a reward deficit, after withdrawal from chronic amphetamine administration (closed circles), compared to saline-treated controls (open circles). B: Baseline [Modified with permission from Paterson et al., 2000]. (B) Withdrawal from chronic amphetamine treatment significantly reduced the breakpoint for a sucrose pellet in a progressive-ratio schedule task, reflecting a motivational deficit, an effect that persisted for up to 29 days. B: Baseline [Modified with permission from Der-Avakian and Markou, 2010]. (C) Rats trained to anticipate the introduction of a sexually receptive female displayed fewer anticipatory side changes during amphetamine withdrawal, compared to saline-treated controls, reflecting an anticipatory deficit [Taken with permission from Barr and Markou, 2005, and originally from Barr et al., 1999]. (D) Amphetamine withdrawal was also associated with an increased post-ejaculatory interval, reflecting a reduction in an additional component of motivated sexual behavior [Taken with permission from Barr and Markou, 2005, and originally from Barr et al., 1999]. (E) Withdrawal from an escalating amphetamine treatment schedule produced alterations in a successive negative contrast procedure in rats, reflecting an increased negative reaction to reward devaluation. Amphetamine withdrawal significantly reduced consumption of a sucrose solution when the concentration was unexpectedly downshifted (from 32% to 4%) compared to saline-treated rats, and significantly increased the time to return to the consumption levels of control rats [Taken with permission from Barr and Markou, 2005, and originally from Barr and Phillips, 2002].

Figure 2

Overexpression of the dopamine D2 receptor (D2R-OE) in the striatum of mice resulted in reduced willingness to work for a desirable reward as the workload was increased compared with a less desirable, yet freely accessable, reward. (A) As the workload increased from Ratio Requirement 5 (RR-5) to RR-20, the number of preferred rewards earned by the control mice (open circles) remained relatively constant. However, the D2R-OE mice (closed circles) earned fewer rewards with increasing workload. (B) When the transgene was turned off, no differences were observed between groups of mice in the number of rewards earned, confirming that the reduction in the willingness to work was due to overexpression of striatal dopamine D2 receptors. (C) Performance during the RR-20 session was significantly decreased in D2R-OE mice, exemplified by the decrease in lever presses during this high workload session. (D) D2R-OE mice consumed more chow during the RR-20 session compared to control mice, confirming that the impaired performance of D2R-OE mice was not due to decreased appetite or hedonic capacity for food. Figures modified with permission from Ward et al., 2012.