Preliminary Data Regarding the Alleviating Effects of Haloperidol and Risperidone on the Short-Term Memory and Associative Learning in a Zebrafish Model of Schizophrenia

Abstract

Background: Schizophrenia (SCZ) is a psychiatric disorder that negatively impacts patients' quality of life, frequently inducing difficulties in managing day-to-day tasks. Current research is persistently working on finding therapeutic methods to alleviate the positive and negative symptoms, as well as the associated cognitive dysfunctions. Since the main therapeutic approach in SCZ is antipsychotics, the current study aimed to explore the effects of typical (haloperidol, HAL) vs. atypical (risperidone, RIS) antipsychotics on the cognitive functions in an animal model (Danio rerio) of SCZ, obtained by ketamine (KET) administration. Methods: The cognitive evaluation of the zebrafish was performed using memory and learning tests based on two stimuli: food and colours (i.e., T memory test and novel object recognition (NOR) test, respectively). Results: According to the behavioural analyses, HAL significantly enhanced the cognitive performances of the SCZ model, as compared to RIS. Nonetheless, HAL and RIS exhibited comparable effects on social behaviour in the SCZ model. Interestingly, both HAL and RIS enhanced the interest for the novel object in the NOR test in control individuals, but significantly decreased it in the SCZ model. The interaction between KET and RIS could exhibit sedative properties. Conclusions: Both typical (HAL) and atypical (RIS) antipsychotics alleviated cognitive, socio-affective, and decision-making impairments in a ketamine-based adult zebrafish model of schizophrenia. HAL was more effective, particularly in food-stimulated decision-making compared to novel object or social stimuli. Colour influenced behavioural responses, with silver linked to prey/feeding effects and red perceived as aversive. The KET-RIS combination induced exploratory impairments, possibly due to sedative effects. These findings highlight differential pharmacological and ethological modulation of schizophrenia-like behaviours.

Keywords: anxiety; cognitive performance; haloperidol; ketamine; learning and memory; risperidone; schizophrenia; social behaviour.

Figure 1

Behavioural assessment of memory and learning, as evaluated by the T-maze test (HAL = 0.13 mg/L; RIS = 0.08 mg/L; KET = 0.1 mg/mL). During a 5 min test trial, locomotion and anxiety-like behavioural parameters, such as (A) total swimming distance (cm), (B) freezing behaviour duration (s), (C) total movement time (s), and (D) swimming velocity (cm/s), were recorded and analysed. The results are presented as means ± SEM (n = 5 animals/group; a–c, Tukey’s HSD test).

Figure 2

Behavioural assessment of memory and learning, as evaluated by the T-maze test (HAL = 0.13 mg/L; RIS = 0.08 mg/L; KET = 0.1 mg/mL). During a 5 min test trial, specific behavioural parameters, such as (A) latency to movement towards the decision point (s), (B) counter-clockwise rotation frequency (#), (C) time spent in the right arm (s), and (D) time spent in the left arm (s), were also recorded and analysed. The results are presented as means ± SEM (n = 5 animals/group; a–c, Tukey’s HSD test).

Figure 3

Behavioural assessment of memory and learning, as evaluated by NOR test (HAL = 0.13 mg/L; RIS = 0.08 mg/L; KET = 0.1 mg/mL). During the 5 min test trial, locomotion and anxiety-like behaviour parameters, such as (A) total swimming distance (cm), (B) swimming velocity (cm/s), and (C) tank zones alternation frequency (#), were recorded and analysed. The results are presented as means ± SEM (n = 5 animals/group; a–e, Tukey’s HSD test).

Figure 4

Behavioural assessment of memory and learning, as evaluated by the NOR test (HAL = 0.13 mg/L; RIS = 0.08 mg/L; KET = 0.1 mg/mL). During the 5 min test trial, specific behavioural parameters, such as (A) body contact duration (s), (B) object interaction time (s), (C) object interaction frequency (#), and (D) latency to the first interaction with objects (s), were recorded and analysed. The results are presented as means ± SEM (n = 5 animals/group; (A) a–e, Tukey’s HSD test; (B–D) a–e, Šídák’s multiple comparisons test).

Figure 5

Behavioural assessment of sociability, as evaluated by the social interaction test (HAL = 0.13 mg/L; RIS = 0.08 mg/L; KET = 0.1 mg/mL). During the 5 min test trial, locomotion and anxiety-like behavioural parameters, such as (A) total swimming distance (cm), (B) total swimming time (s), (C) swimming velocity (cm/s), (D) cumulative acceleration (cm/s²), were recorded and analysed. The results are presented as means ± SEM (n = 5 animals/group; a–c, Tukey’s HSD test).

Figure 6

Behavioural assessment of sociability, as evaluated by social interaction test (HAL = 0.13 mg/L; RIS = 0.08 mg/L; KET = 0.1 mg/mL). During the 5 min test trial, specific behavioural parameters, such as (A) time spent in the decision point (s), (B) time spent in the left arm (s), (C) clockwise and (D) counter-clockwise rotation frequencies (#), were recorded and analysed. The results are presented as means ± SEM (n = 5 animals/group; a–c, Tukey’s HSD test).

Figure 7

Experimental design representation.

Figure 8

Graphical representation of the training phase in the novel object recognition (NOR) test.