**2.3 Animal models in bipolar disorder (BD)**

Bipolar disorder (BD) is a chronic mood disorder, characterized by fluctuations between mania and depressive episodes, which affects approximately 1% of the global population irrespective of nationality, ethnic origin, or socioeconomic status [78]. Due to the complex mood alterations, misdiagnosis in BD is very common, as other mental illnesses as depression and SCZ share several common symptoms, in addition to the specific and common endophenotypes and brain structural changes [79, 80]. The search for advances in diagnosis is important for these disorders, since early diagnosis would be essential to foster earlier suited pharmacological treatment in BD, which was proved to be beneficial to prevent the cognitive deficits and disabilities in these BD patients [81], as also demonstrated for SCZ patients [82]. The major limitation in evaluating a model for BD is the difficulty in reproducing the phases of mania and depression observed in the clinic. Many of these models present only one of these parameters, and they are often developed by genetic alterations in genes known to be involved in this disorder or stressors, mainly involved in the circadian cycle as also demonstrated for other PDs. Another interesting approach used for the development of animal models for BD is the one induced by psychostimulant sensitization (which causes mania-like behavior), as withdrawal from psychostimulants is accompanied by depressivelike behavior, which together leads to changes and compulsory behaviors. Some of these models are exemplified in **Table 4**. A more detailed review of BD models can be found elsewhere [93].


BDNF = brain-derived neurotrophic factor; ERK1 = Extracellular signal-regulated kinase 1; DAT = dopamine transporter.

#### **Table 4.**

*Examples of models for BD induced by genetic manipulation, environmental stressors, and induced by sensitization, which lead to some aspects of molecular and behavioral changes related to BD.*

**65**

**3. Conclusion**

*and by prenatal insults.*

**Table 5.**

**Genetic manipulation** Spontaneously hypertensive rats

**Neonatal insults**

Coloboma mouse mutant ↑ Locomotion; ↑

6-hydroxydopamine ↓ Working memory;

Neonatal anoxia ↑ Locomotion;

*Animal Models in Psychiatric Disorder Studies DOI: http://dx.doi.org/10.5772/intechopen.89034*

**2.4 Animal models in attention-deficit/hyperactivity disorder (ADHD)**

on ADHD animal models can be found elsewhere [100] (**Table 5**).

↓ Attention; ↑ motor impulsiveness ↑ Locomotion; ↑ exploratory behavior

exploratory behavior; ↑ amphetamine sensibility

↑ exploratory behavior; ↓ spatial memory

*DOPAC = 3,4-Dihydroxyphenylacetic acid; HVA = Homovanillic acid; 5-HIIA = 5-Hydroxyindoleacetic acid.*

↑ locomotion; ↑ Exploratory behavior

**Model Endophenotype Molecular alterations References**

↑ Dopamine

1 expression ↓ Brain volume

↓ Dopamine ↑ Dopamine receptor 4 ↓ Serotonin transporter binding in striatum

5-HIAA ↓ CA1 cell density

Transient changes in neurotransmitters ↑ Dopamine turnover ↓ Noraepinephrine and

↑ Noraedrenergic function ↓ Dopamine ↓ DOPAC and HVA

↓ Dopamine transporter

[101–104]

[105–108]

[109–111]

[112–114]

There is a consensus about the critical role of animal models for the advance and understanding the functioning of brain and brain disorders, as well as for the development of new treatments. However, it is important to use them judiciously and avoid the over interpretations derived for the findings, as it is noticeable that the results obtained on experimental animals are not necessarily confirmed in clinical studies.

*Examples of models for ADHD induced by genetic manipulation in susceptibility genes and selective inbreeding* 

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, affecting approximately 2.2–2.8% of worldwide, with multifactorial inducement, as reflected by the heterogeneity found in this disorder, and as indicated by the diversity in its psychiatric comorbidities [97]. This disorder is defined by inappropriate levels of attention deficits and/or hyperactivity behavior, which directly interfere with the normal life and functioning of an individual [98]. While there is no cure for ADHD, currently available treatments can help reducing the symptoms and improving the general functioning, although with a peculiar wide variability due to the clinically and scientifically difficulties to exactly determine the specificity and the origin of the symptoms [99]. As for other PDs, due to the high heritability, animal models for ADHD are mostly derived from genetic alterations or breeding selection or from neonatal insults that can lead to neurodevelopmental changes. Models related to dopaminergic neurotransmission are also important to evaluate ADHD, as also listed in **Table 2**, and which includes the administration of psychostimulants as amphetamine. A more detailed review

*Animal Models in Medicine and Biology*

be found elsewhere [93].

**Genetic manipulation**

**Environmental stress**

**Sensitization model** Chronic amphetamine administration followed by withdrawal

kinase 1; DAT = dopamine transporter.

BDNF haploinsufficient ↑ Locomotion; ↑ agressive

DAT Knock-down ↑ Locomotion; ↓ anxiety;

Sleep deprivation ↑ Locomotion; ↑ agressive

↑ rearing

behavior

ERK1 Knock-out ↑ Amphetamine

**2.3 Animal models in bipolar disorder (BD)**

Bipolar disorder (BD) is a chronic mood disorder, characterized by fluctuations between mania and depressive episodes, which affects approximately 1% of the global population irrespective of nationality, ethnic origin, or socioeconomic status [78]. Due to the complex mood alterations, misdiagnosis in BD is very common, as other mental illnesses as depression and SCZ share several common symptoms, in addition to the specific and common endophenotypes and brain structural changes [79, 80]. The search for advances in diagnosis is important for these disorders, since early diagnosis would be essential to foster earlier suited pharmacological treatment in BD, which was proved to be beneficial to prevent the cognitive deficits and disabilities in these BD patients [81], as also demonstrated for SCZ patients [82]. The major limitation in evaluating a model for BD is the difficulty in reproducing the phases of mania and depression observed in the clinic. Many of these models present only one of these parameters, and they are often developed by genetic alterations in genes known to be involved in this disorder or stressors, mainly involved in the circadian cycle as also demonstrated for other PDs. Another interesting approach used for the development of animal models for BD is the one induced by psychostimulant sensitization (which causes mania-like behavior), as withdrawal from psychostimulants is accompanied by depressivelike behavior, which together leads to changes and compulsory behaviors. Some of these models are exemplified in **Table 4**. A more detailed review of BD models can

BDNF = brain-derived neurotrophic factor; ERK1 = Extracellular signal-regulated

**Model Endophenotype Molecular alterations References**

↓ Brain volume; ↓ BDNF;

↑ Dopamine [87–89]

— [90, 91]

↓ Phospho-RSK1/3 in PFC and striatum; shift of activity rhythm

neurotransmission to somatostatin

↓ Dopamine responsiveness ↑ serotonin sensitivty [83, 84]

[85–86]

[92]

[94–96]

↓ dopamine

behavior; ↑ food intake

sensibility; ↓ learing in fear conditioning; ↑ locomotion; ↓ immobility in forced swim

behavior; ↑ exploratory

Photoperiod lenghts ↑ Anxiety; ↑ helplessness Switch in dopamine

↑ Locomotion; ↑ anxiety; ↑ anhedonia; ↓ motivation; ↓ working memory

*BDNF = brain-derived neurotrophic factor; ERK1 = Extracellular signal-regulated kinase 1; DAT = dopamine* 

*Examples of models for BD induced by genetic manipulation, environmental stressors, and induced by sensitization, which lead to some aspects of molecular and behavioral changes related to BD.*

**64**

*transporter.*

**Table 4.**
