New Developments in Behavioral Pharmacology

*Jonathan Cueto-Escobedo, Fabio García-García, Caio Maximino and Juan Francisco Rodríguez-Landa*

### **Abstract**

Behavioral pharmacology research has been a cornerstone in the understanding of the processes that underlie the behavior of living organisms as well as the biological basis of the behavioral, emotional, and cognitive disorders that affect humans. The findings in this area have helped to explore the potential therapeutic effects of several substances for the treatment of the mentioned disorders. The present chapter brings an extremely brief introduction to this vast area. First, we try to put in context behavioral pharmacology and its relevance and then show some brief examples of how this discipline has developed over the years. Second, we review the concept of a "research model" in preclinical behavioral pharmacology, given the importance of animal models and tests in this area, followed by a brief review of the recent advances using zebra fish as a valuable tool of research. Third, more specific examples are aborded, such as the findings on sleep disorders and those related to sexual hormones and menopause.

**Keywords:** behavioral pharmacology, psychopharmacology, psychoactive drugs, behavioral models

### **1. Introduction**

Every time academics talk about the evolution of human societies and the advance of humanity, language is always mentioned, followed by different pieces of technology that allowed us to change the world. Few times, medicine is mentioned, and within the same area of knowledge, pharmacology is even more frequently omitted. But without the development of pharmacology as a science founded in systematic research, the capacities of medical sciences and therapeutics would be very limited. Knowledge in pharmacology allows us to understand that there exist chemical substances with very specific structures and properties which, in controlled doses, can interact with the normal physiology of our organism in order to produce effects that improve our health, known as therapeutic effects; but if the doses are insufficient or excessive, the effects will be useless or harmful (toxic), respectively [1]. These substances responsible for the actions of medicines are named as active compounds.

Most of the active compounds used in medicine were consumed together with the organism which contained them, most frequently plants. As chemistry advanced, scientists succeed in isolating these compounds and described their chemical structure. In consequence, laboratories started to synthesize these

substances and others with a similar structure that should be tested in research laboratories before using them to treat diseases in humans [2].

Nowadays, pharmacological research has grown beyond treatments for infectious agents, covering diseases related to the alteration of the normal functioning of the central nervous system (CNS). There are medications to treat disorders such as depression, anxiety, chronic pain, attention deficit and hyperactivity disorder, epilepsy, and Parkinson's disease, and new drugs are desperately sought to stop Alzheimer's disease. On the other hand, one of the most important current health problems is related to the addictive behaviors triggered by the consumption of certain substances and the side effects of these addictions: respiratory and cardiovascular diseases in the case of tobacco, metabolic diseases in the case of alcoholism and addictive consumption of refined sugars, infectious diseases in the case of injected drugs, and many others that are not mentioned here. Without losing sight of the fact that addiction is itself a disease of the nervous system with devastating effects *per se* on the patient's quality of life. In several countries, prescription of different therapeutic agents acting on the CNS to treat psychiatric disorders, such as antidepressants, antipsychotics, and stimulants, has increased [3, 4] as in the case of methylphenidate and amphetamines in different countries such as United States [5] and the Netherlands [6]. The same way, antidepressant users have increased markedly around the world in countries such as Norway, Sweden, and Denmark [7], among others. Additionally, the use of different substances of abuse such as tobacco [8] and marijuana has increased in the population [9]. Also, the development of new technologies and products has a significant impact on mental health as the discovery of Internet addiction [10] and the addictive consumption of refining sugar [11, 12], which impacts on the behavior of subjects. All these make important the continuous development of behavioral pharmacology in order to cope with the challenges in mental health.

#### **2. Development of behavioral pharmacology**

Behavioral pharmacology, also known as psychopharmacology, has developed as an interdisciplinary science that comprises fields such as neuroethology, neurochemistry, pharmacology and neuropharmacology, psychophysiology, neurophysiology, experimental analysis of behavior, and several other fields related to neurosciences [13]. Behavioral pharmacology is founded on systematic research with precise methods for assessing and interpreting the effects of chemical, hormones, and drugs on the behavior in humans and experimental animals in order to establish its potential as therapeutic agents or pharmacologic tools to explore how the brain functions and the underlying neurobiological mechanism of cognition, emotions, and behavior. Behavioral pharmacology must thus be an integral component of many neuroscience research programs [14].

In this sense, the development of behavioral pharmacology comprises the development of areas as pharmacology and psychology, experimental analysis of behavior, and recently neuroscience. For a historical review, see [14–16]. However, research in behavioral pharmacology can be summarized in: (1) the development of procedures to screen pharmacological agents for potential clinical effectiveness. (2) Perfecting behavioral techniques to explore the mechanisms of action of behaviorally active drugs and using these chemicals and drugs as tools for the analysis of complex behaviors (i.e., when drugs reinforce behavior and when drugs serve as discriminative stimuli) [16] (see **Table 1**). Therefore, drugs are not only a subject of study, because of its behavioral effects but are also a piece of technology that helps to elucidate how behaviors are controlled by living organisms.

**9**

**3. Measuring behavior**

**Table 1.**

Behavior is a biological property of organisms, which remarks on the significance of the study of drug-behavior interactions [15]. Maybe, a great example of the impact of behavior beyond psychology is the research by ethologists K. Lorenz, N. Tinbergen, and K. von Frisch, which focused on the analysis of behavior in several species including fish, insects, and birds, and the importance of which made them worthy of the Nobel price of medicine in 1973 "*for their discoveries concerning* 

**Year Description Reference**

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

1936 Selye H. described the impact of several types of adverse stimuli on animal health, in the form of a syndrome characterized by three phases: alarm, adaptation, and exhaustion, which can lead to death if stimuli are maintained. This syndrome was later named as the stress response which has been intensively studied and strongly associated with the impairment of brain function in

animals or the development of mental disorders in humans

1972 The first study to administrate Delta-9-tetrahydrocannabinol in humans to test

1977 The forced swim test is proposed as a behavioral tool to explore the effects of

1986 Elevated plus maze is developed as a tool to measure anxiety-like behaviors of the rat and test substances with potential anxiolytic effects

1988 Modafinil was prescribed for the first time for the treatment of narcolepsy and

ovariectomized rats (OVX). These rats were more sensitive to stress, which was associated with a low concentration of steroid hormones. This effect was

12-week post-ovariectomy there is more anxiety-like behavior than a 3-week

condition that triggers despair behavior (immobility)

2005 This study explored the behavioral and neuronal response to stress in

sleep parameters, but some adverse effects were reported

experimental model of surgical post-menopause

2006 Anxiety-like behavior is dependent on the post-ovariectomy time frame. At

2016 The first systemic review and meta-analysis that discuss the effects of the orexin agonist Suvorexant for the treatment of insomnia. Suvorexant improved some

2019 In this study, it was identified that at 3-week post-ovariectomy appears anxietylike behavior, but from 6-week post-ovariectomy in addition to anxiety-like behavior, also increases depression-like behavior in rats, supporting an

the effects on sleep patterns is carried out. The results show a decrease in sleep onset latency. To date, there are controversial results about the positive effects

antidepressant drugs in rats and mice that are exposed to a stressful inescapable

The first step in all behavioral sciences has been to define what is behavior; it could seem an easy task, but historically many different definitions of behavior have been used by scientists over the time, and even the knowing of a unique definition is elusive and may be useless for every different area such as psychology, ethology, and experimental analysis of behavior, among others; for review see [26, 27]. As mentioned before, one of the directions of behavioral pharmacology was the development of procedures to screen the effects of pharmacological agents on specific behaviors under controlled environments. This approach allows scientists to work with operational definitions of specific behaviors, for example, exploration can be

*organization and elicitation of individual and social behaviour patterns*."

*New Developments in Behavioral Pharmacology DOI: http://dx.doi.org/10.5772/intechopen.93700*

the cannabis on sleep quality

idiopathic hypersomnia in patients

post-ovariectomy

*Emblematic research in behavioral pharmacology.*

prevented by restitution with 17-β estradiol

*New Developments in Behavioral Pharmacology DOI: http://dx.doi.org/10.5772/intechopen.93700*

*Behavioral Pharmacology - From Basic to Clinical Research*

challenges in mental health.

ence research programs [14].

**2. Development of behavioral pharmacology**

laboratories before using them to treat diseases in humans [2].

substances and others with a similar structure that should be tested in research

Nowadays, pharmacological research has grown beyond treatments for infectious agents, covering diseases related to the alteration of the normal functioning of the central nervous system (CNS). There are medications to treat disorders such as depression, anxiety, chronic pain, attention deficit and hyperactivity disorder, epilepsy, and Parkinson's disease, and new drugs are desperately sought to stop Alzheimer's disease. On the other hand, one of the most important current health problems is related to the addictive behaviors triggered by the consumption of certain substances and the side effects of these addictions: respiratory and cardiovascular diseases in the case of tobacco, metabolic diseases in the case of alcoholism and addictive consumption of refined sugars, infectious diseases in the case of injected drugs, and many others that are not mentioned here. Without losing sight of the fact that addiction is itself a disease of the nervous system with devastating effects *per se* on the patient's quality of life. In several countries, prescription of different therapeutic agents acting on the CNS to treat psychiatric disorders, such as antidepressants, antipsychotics, and stimulants, has increased [3, 4] as in the case of methylphenidate and amphetamines in different countries such as United States [5] and the Netherlands [6]. The same way, antidepressant users have increased markedly around the world in countries such as Norway, Sweden, and Denmark [7], among others. Additionally, the use of different substances of abuse such as tobacco [8] and marijuana has increased in the population [9]. Also, the development of new technologies and products has a significant impact on mental health as the discovery of Internet addiction [10] and the addictive consumption of refining sugar [11, 12], which impacts on the behavior of subjects. All these make important the continuous development of behavioral pharmacology in order to cope with the

Behavioral pharmacology, also known as psychopharmacology, has developed as an interdisciplinary science that comprises fields such as neuroethology, neurochemistry, pharmacology and neuropharmacology, psychophysiology, neurophysiology, experimental analysis of behavior, and several other fields related to neurosciences [13]. Behavioral pharmacology is founded on systematic research with precise methods for assessing and interpreting the effects of chemical, hormones, and drugs on the behavior in humans and experimental animals in order to establish its potential as therapeutic agents or pharmacologic tools to explore how the brain functions and the underlying neurobiological mechanism of cognition, emotions, and behavior. Behavioral pharmacology must thus be an integral component of many neurosci-

In this sense, the development of behavioral pharmacology comprises the development of areas as pharmacology and psychology, experimental analysis of behavior, and recently neuroscience. For a historical review, see [14–16]. However, research in behavioral pharmacology can be summarized in: (1) the development of procedures to screen pharmacological agents for potential clinical effectiveness. (2) Perfecting behavioral techniques to explore the mechanisms of action of behaviorally active drugs and using these chemicals and drugs as tools for the analysis of complex behaviors (i.e., when drugs reinforce behavior and when drugs serve as discriminative stimuli) [16] (see **Table 1**). Therefore, drugs are not only a subject of study, because of its behavioral effects but are also a piece of technology

that helps to elucidate how behaviors are controlled by living organisms.

**8**


#### **Table 1.**

*Emblematic research in behavioral pharmacology.*

## **3. Measuring behavior**

Behavior is a biological property of organisms, which remarks on the significance of the study of drug-behavior interactions [15]. Maybe, a great example of the impact of behavior beyond psychology is the research by ethologists K. Lorenz, N. Tinbergen, and K. von Frisch, which focused on the analysis of behavior in several species including fish, insects, and birds, and the importance of which made them worthy of the Nobel price of medicine in 1973 "*for their discoveries concerning organization and elicitation of individual and social behaviour patterns*."

The first step in all behavioral sciences has been to define what is behavior; it could seem an easy task, but historically many different definitions of behavior have been used by scientists over the time, and even the knowing of a unique definition is elusive and may be useless for every different area such as psychology, ethology, and experimental analysis of behavior, among others; for review see [26, 27]. As mentioned before, one of the directions of behavioral pharmacology was the development of procedures to screen the effects of pharmacological agents on specific behaviors under controlled environments. This approach allows scientists to work with operational definitions of specific behaviors, for example, exploration can be

*Behavioral Pharmacology - From Basic to Clinical Research*

measured by scoring ambulation, rearing or nose approaching to an object; sexual behavior can be measured by conditioned place preference, number of mounts, latency and number of ejaculations. All these behaviors are normally studied under controlled environments that are designed specifically to the required behavioral display and every feature of the environment; the experimental subjects or chemical agents with probed effects on humans have been studied in this environment with the purpose of establishing these manipulations as models of a specific behavior (see **Table 2**) as spatial learning and memory, or models of specific pathologies behaviorally expressed as is the case of anxiety [28], depression [29], obsessive compulsive disorder [30], Parkinson [31], epilepsy [32] or addictive behaviors [33], and sleep deprivation [34], among others.
