1 Chapter 1: Introduction CHAPTER 1: INTRODUCTION Anxiety and fear 1.1 Definition Fear is usually defined as a state of the organism elicited by a threatening and clearly identifiable stimulus that prepares the organism to cope with the danger, and subsides shortly after its offset Anxiety is defined as a state of the organism that is characterized by many of the same signs and symptoms of fear However, it usually is not clearly associated with a single eliciting stimulus, and may last for longer periods of time once activated (Charney and Deutch, 1996) Some authors argue that external stimuli are insufficient to distinguish fear and anxiety According to them fear is related to action, and particularly to escape and avoidance When the action is blocked, fear is turned into anxiety Therefore fear is an avoidance motive If there were no restraints, internal or external, fear would support the action of fight or flight Anxiety can be defined as unresolved fear, or, alternatively, as a state of undirected arousal following the perception of threat The alarm or primary anxiety may be channelled or resolved into fear, if escape is selected as the action option after completely controlled processing of stimulus situation (Lang et al., 2000) In this work, anxiety will be differentiated from “fear” on the basis of two above cited characteristics First, the two are differentiated by the presence (in fear) or the absence (in anxiety) of a specific stimulus that elicits the affective response Second, fear is conceptualized as the motivator of a set of coping responses to events Chapter 1: Introduction that provide more or less direct threats to the survival or well-being of the organism, whereas anxiety occurs when the situation is too uncontrollable to permit active coping behaviors (Ohman and Mineka, 2001) However, it must be emphasized that anxiety and fear are normal reactions to danger When anxiety and fear are more recurrent and persistent than what is reasonable under the circumstances, and when they impend normal life, an anxiety/fear disorder exists (LeDoux, 1995) 1.2 Anxiety disorders According to the estimation of ADAS (Anxiety Disorders Association of America, 2002), anxiety disorders are the most common mental illness in the U.S with 19.1 million (13.3%) of the adult U.S population (ages 18-54) affected Characteristics that distinguish abnormal from adaptive anxiety include: (1) Anxiety out of proportion to the level of threat (2) Persistence or deterioration without intervention (> weeks) (3) Symptoms that are unacceptable regardless of the level of threat, including recurrent panic attacks, severe physical symptoms and abnormal beliefs such as thoughts of sudden death (4) Disruption of usual or desirable functioning The five anxiety disorders are identified as: Panic Disorder, ObsessiveCompulsive Disorder, Post-Traumatic Stress Disorder, Generalized Anxiety Disorder and Phobias (including Social Phobia, also called Social Anxiety Disorder) The significance of anxiety/fear in health and disease is well recognized today, but its underlying molecular and neurobiological mechanisms are not well Chapter 1: Introduction understood Anxiety/fear is a complex emotional state that cannot be reduced to imbalances of a single neurotransmitter; however, preclinical and clinical evidence has suggested the involvement of noradrenaline (NA), benzodiazepine, serotonin (5hydroxytryptamine, 5-HT), dopamine neuronal systems in anxiety and fear development And a lot of neurotransmitters are responsible for this process as well Among them, a prominent participation of cholecystokinin (CCK) (Griebel, 1999; Woodruff et al., 1991), 5-HT (Blanchard et al., 1988; Graeff et al., 1996) and corticotropin-releasing factor (CRF) (Eckart et al., 1999; Takahashi, 2001) in anxiety and fear is generally acknowledged today Cholecystokinin (CCK) and its receptors 2.1 CCK: a neurotransmitter 2.1.1 Discovery of CCK and its molecular forms CCK was first identified and characterized in the gastrointestinal tract as a hormone with a major role in regulating the control of gut motility, pancreatic secretion, and gall bladder contractions In the brain, CCK is also one of the most widely distributed peptides, where it acts as a neurotransmitter CCK fulfills the criteria for a neurotransmitter in the CNS: it is synthesized and stored in nerve terminals and cell bodies, it is released by depolarization, specific receptors and antagonists exist, and it influences the firing rate of other central neurons This peptide, initially characterized as a 33-amino-acid sequence, is present in a variety of biologically active molecular forms derived from a 115-amino-acid precursor molecule (prepro-CCK) (Deschenes et al., 1984), such as CCK-58, CCK- Chapter 1: Introduction 39, CCK-33, CCK-22, sulfated CCK-8 [Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-PheNH2] and CCK-7, unsulfated CCK-8 and CCK-7, CCK-5, and CCK-4 (Trp-MetAsp-Phe-NH2) (Fig 1-1) Several molecular CCK forms, ranging from to 58 amino acids, are found in the brain and peripheral organs The most abundant fragment in the brain is the sulfated octapeptide CCK-8S The tetrapeptide CCK-4 is an important and the shortest biologically active form occurring in the brain as well 2.1.2 Distribution of CCK-related peptides in the central nervous system CCK is very abundant in the brain, more than in the gut CCK levels are very high (> ng CCK/mg protein) in cerebral cortex, caudate-putamen, hippocampus, and amygdala, while thalamus, hypothalamus and olfactory bulb are lower (1–2 ng/mg protein) The pons, medulla and spinal cord have even lower levels (