Animal Models in Psychiatry: Types, Validity & Research Uses

What are Animal Models?

• Animal models are experimental efforts to reproduce the essential features of various human disorders in non-human subjects.
• Animal model experiments date back to the beginning of the 20th century.
• Some examples include:
  • Pavlov's study of experimental neurosis
  • Harry Harlow's experiment on the rhesus monkey.

Why Are Animal Models Required?

 Animal models are required for the following reasons:

• Limitations on range and amount of data characterize any disorder that can be collected from one patient.
• Poor understanding of the etiology of psychiatric disorders is reflected by the unmet clinical needs of pharmacological agents.
• Difficulty in assessing the long-term effects of any planned intervention or treatment because of the following reasons:
  • Confounding treatment-related factors.
  • Lack of appropriate controls.
  • Practical difficulties and expenses.
• It allows for manipulations and measurements with animals that are simple and not possible with humans.
• Animals can be selectively bred or genetically manipulative.
• Various therapeutic interventions can be systematically administered.
• Effects can be objectively determined.

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Similarities between Humans and Experimental Animals

• Similarities exist at both functional and biological levels.
• The following similarities are present between humans and experimental animals:
  • Common brain design and substantial homologies for most neural structures.
  • Subcortical structures are similar.
  • Basic psychological processes such as stress, panic, anxiety, motivation, attention, and reward are present in rodents and non-human primates.

Challenges to Modeling Psychiatric Disorders in Animals

1. Symptoms of psychiatric disorders, in some ways, are uniquely expressed in humans. Hence, it is difficult to replicate them authentically in animals. The substantial differences between humans and nonhuman primates and rodents:
   • Abstract thought
   • Self-reflection
   • Language
   • Insights

The differences between animal models and humans exist due to the biological differences, including a more developed cortex and prefrontal cortex in humans as compared to nonhuman primates and rodents. At genetic levels, most human genes have homologous versions in non-human primates or rodents. There are substantial differences at the level of gene regulation.

2. Lack of objective measures to unequivocally diagnose mental illness.
3. There exists a gap between basic scientific and clinical research.

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Categorization of Animal Research in Psychiatry

Animal research in psychiatry falls into two categories listed below:

• To improve current understanding of psychological & neurobiological processes
• To model human psychiatry:
  • To help identify novel targets for therapeutic drug development.
  • To provide a preclinical test of the effectiveness of a compound on a behavior

Animal Research in Psychiatry

• It should focus on well-defined phenotypes that
  • Have a known biological basis
  • Can be measured to facilitate experimentation
• Brain substrates with homology between human and animal models.
• In genetic models, focusing on highly penetrant genetic variants is useful to ensure relevance to human diseases.

Criterion for Animal Models

• Face validity: It is the extent to which a behavior studied in animals resembles the behavior in humans intended to model.
• Construct validity: It is the extent to which an animal model reproduces the etiology of the human psychiatric disorder.
• Predictive validity: It is the extent to which drug effects in animal models predict clinical effectiveness in psychiatric patients. It is assessed by how the model responds to treatment or factors known to improve or exacerbate reluctant symptoms.
• In practice, no animal models fully meet these 3 criteria of validity.
• Other validities:
  • Convergent validity: It is the degree to which a test correlates with the results of another test attempting to measure the same construct. It can be seen with a demonstration of equivalent effects of that drug on different models of the disorders.
  • Discriminant validity: It is indicated by the lack of correlation between two different tests.

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Types of Animal Models

Homologous models

It includes symptoms shown by animals, and the cause of the condition is identical to humans. A few models fulfill requirements. For example: well-defined lesion syndrome. These models display face validity.

Isomorphic models

In these animals, symptoms are similar, but the cause differs for humans. Spontaneous models are often isomorphic.

Predictive models

 It is based on its ability to characterize the therapeutic activity of a drug for a disorder. These models display predictive validity.

Second Classification of Animal Models

The second classification of animal models includes the following:

• Experimental models: They are the most common types
• of animal models. They resemble the human condition, including the phenotype and response to the treatment. They are induced artificially in the laboratory.
• Spontaneous models: They are analogous to the human condition but occur naturally in animals studied.
• Negative models: Negative models are control animals used in research validation and experimental results.
• Orphan models: Orphan models are the diseases occurring in animals, but human analogs is not available.

Approaches to Construct Animal Models for Psychiatric Disorders

• Genetic manipulations: Genetic disruptions of NMDA receptors and NR1 B4 knockout in mice have been done to study diseases like schizophrenia.
• Modulation of neurotransmitters: The example includes the administration of amphetamine in schizophrenia.
• Environmental factors: These include stress-induced behavioral abnormalities.
• Immune activation during pregnancy: It is done to understand abnormalities in neurodevelopment.
• Selective breeding.
• Electrical stimulation and lesions: Abnormalities in brain circuits.
• Instead of an entire human psychiatric disorder, animals can be used to model particular symptoms.

Symptoms

Classification (DSM, ICD)

• Symptom-based
• Heterogenous
• Difficult to construct disorders in animal models

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Endophenotypes

• According to Gottesman and Gould, 2003 - Endophenotypes are heritable traits that underpin a mental disorder and are more closely associated with genetic factors than the disorder's symptoms.
• It is possible to assess endophenotypes through lab-based methods rather than by clinical observation.
• Research domain criteria have been introduced as an alternative categorization system.
• It supports endophenotype-based comparison of animals and humans on an objective neurobiological basis across all behavioral domains.

Animal Models in Schizophrenia 

• Drug-induced models
  • Psychostimulants like amphetamine increase the mesolimbic dopamine response
  • Glutaminergic manipulation (PCP, Ketamine): decrease the parvalbumin-immunoreactive neurons in PFC, hippocampus
• Genetic manipulation
  • DISC-1 mutation
    • Missense mutation models
    • Knockdown
    • Overexpression
  • Neuregulin, ErbB4 knockout
  • DAT knockout mice
  • ComT knockout mice
• Developmental models
  • Neonatal excitotoxic damage to the hippocampus
  • MAM (methylazomethanol)
• Environmental manipulations (including social impairment)
  • Prenatal stress
  • Postnatal stress
  • Early handling
  • Maternal separation
  • Early social isolation

Animal Models in Major Depressive Disorders 

Stress-induced models

• Learned helplessness
• Forced swim test
• Tail suspension test
• Early life stress models
• Unpredictable chronic mild stress

Genetic models

• Genetic manipulation
• For example: Cognitive deficits induced by single gene disruption in mice (mutation of αCaMKII in Ca1 region)
• Selective inbreeding

Brain lesion models

• Olfactory bulbectomy (leads to dysfunction in the HPA axis)

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Animal Models in Bipolar Disorders

Genetic manipulation

BDNF haploinsufficient

ERK1 knockout

DAT knockdown

Environmental stress

Sleep deprivation

Sensitization model

Chronic amphetamine administration followed by withdrawal

Animal Models in Anxiety Disorders 

• Conditioned models.
  • Conflict tests
    • Geller-seifter test
    • Vogel's conflict test
• Ethologically based models.
  • Elevated plus maze
  • Defensive withdrawal test
  • Defensive burying test
  • Ultrasonic distress vocalization
  • Social interaction test
  • Quinpirole-induced compulsive checking
• Genetic models.
  • Selective breed (Maudsley reactive and nonreactive strain)
  • Natural variants ('uptight' and 'laid back' rhesus monkey)
  • Genetic manipulation (5HT1a knockout)
• Environmental stress.
  • Maternal deprivation of rats
  • Adversely reared primates

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Animal Models in Addiction

Laboratory models

• Drug self-administration paradigm
• Conditioned place preference paradigm
• Conditioned reinforcement paradigm
• Reinstatement paradigm
• Brain stimulation reward paradigm

Theoretical models

• Positive reinforcement models
• Negative reinforcement models

Hope you found this blog helpful for your Psychiatry Residency Basic Sciences Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.