Freezing behavior, also called the freeze response or being petrified, is a reaction to specific stimuli, most commonly observed in prey animals. When a prey animal has been caught and completely overcome by the predator, it may respond by "freezing up/petrification" or in other words by uncontrollably becoming rigid or limp. Studies typically assess a conditioned freezing behavior response to stimuli that typically or innately do not cause fear, such as a tone or shock. Freezing behavior is most easily characterized by changes in blood pressure and lengths of time in crouching position, but it also is known to cause changes such as shortness of breath, increased heart rate, sweating, or choking sensation. [1] However, since it is difficult to measure these sympathetic responses to fear stimuli, studies are typically confined to simple crouching times. A response to stimuli typically is said to be a "fight or flight", but is more completely described as "fight, flight, or freeze". In addition, freezing is observed to occur before or after a fight or flight response.
Studies suggest that specific areas of the brain are known to either elicit or inhibit (in the case of lesions) freezing behavior in subjects. The regions include the basolateral amygdala and the hippocampus.
One such study, conducted by Ann E. Power et al., investigated the effects of lesions in the basolateral amygdala. [2] Rats were placed in a chamber containing cat hair. Two groups of rats were tested: rats that had been lesioned in the basolateral amygdala and rats that were the control group (which were sham-operated). All rats at first froze briefly then retreated away from the stimulus upon initial contact. The results showed that the lesioned rats froze much less to the cat hair than the rats of the control group. These data infer a connection between the basolateral amygdala and freezing behavior.
Another study, conducted by Gisquet-Verrier et al., tested the effects of the hippocampus, in three experiments, on both the freezing behavior and avoidance. [3] The rats were lesioned with ibotenic acid, and were tested against a control group. They first investigated changes from conditioned fear, and results showed that lesions to the hippocampus did not alter freezing behavior and marginally affected avoidance. Next, they tested single conditioning sessions, and it was found that freezing behavior remained unchanged while avoidance was disrupted. Finally, they tested conditioning with a larger stimulus (footshock intensity). It was found that avoidance was unaltered while freezing behavior decreased. Not only did these investigations show that the hippocampus is involved with freezing behavior, but avoidance and freezing behavior do not seem to have similar ways of being quantified when it comes to fear conditioning.
It has been experimentally tested that particular areas of the brain are involved with freezing behavior. As mentioned before, Ann E. Power investigated the effect of basolateral amygdala on freezing behavior. It was also found that muscarinic cholinergic activation plays a role in the behavior. [2] That suggests that neurotransmitters, in general, play a role in freezing behavior. Several investigations show that freezing behavior is influenced by the following:
Hashimoto et al. investigated the effects of conditioned fear on serotonin and freezing behavior in rats. [4] Through in vivo microdialysis, certain concentrations of extracellular serotonin in the rat brain were able to be measured. It was found that conditioned fear stress increased the levels of the serotonin in the medial prefrontal cortex. This increase was correlated with an increased freezing behavior that was observed. The rats were then given an inhibitor for the extracellular serotonin, which resulted in a reduced freezing behavior. It can be suggested from these results that inhibition of serotonin can decrease freezing behavior and, also, anxiety.
Not only does serotonin influence freezing behavior, but it has been shown that antipsychotic drugs (APDs), such as clozapine, ORG5222, and olanzapine, affect freezing behavior as well. [8] Drugs were administered subcutaneously to rats 30 minutes before footshock stress. It was observed that, 24 hours following the footshock, freezing behavior was present without shocks. This is interesting to note, since there was a sympathetic response to no stimuli at all. This suggests that antipsychotic drugs alter freezing behavior, making the rats more sensitive to fear stimulus, for example.
Methamphetamine has also been shown to potentially affect freezing behavior. [9] Tsuchiya et al. conducted a study investigating the effect of methamphetamine pretreatment on freezing behavior. Rats were given the drug over a week, ramping up the doses. After that, there was a five-day period without any drugs administered. The rats were then subjected to conditioned fear stress. Repeated but not single methamphetamine pretreatment resulted in a significantly increased freezing behavior. This evidence suggests that previous exposure to chronic methamphetamine results in an increased sensitivity to subsequent stress than a control group.
Just as neurotransmitters influence freezing behavior, inhibitors, as expected, interrupt neurotransmitters and influence freezing behavior. [10] This study examined the effects of monoamine oxidase inhibitors on freezing behavior. Rats were treated with specific inhibitors that target either monoamine oxidase A or B. The results showed that acute inhibition of both monoamine oxidase A and B reduce anxiety or freezing behavior. However, inhibition of monoamine oxidase A or B alone failed to do so.
It has been shown that parts of the brain are involved in freezing behavior and that neurotransmitters and similar chemicals influence freezing behavior, as well. In a related manner, hormones, progestogens and estrogen, also play a role in freezing behavior. [11] First, the authors tested the rats in marble burying and conditioned fear when they were in behavioral estrous or diestrous. Female rats in behavioral estrous have elevated levels of these steroid hormones and also elicit more approach and less freezing behavior than diestrous rats. Results demonstrate that rats in this behavioral estrous show less impulsive burying and also less freezing behavior than diestrous rats. The authors then administered progesterone and estrogen in ovariectomized rats and tested them in marble burying and conditioned fear. The results for this experiment demonstrate that administration of progesterone or both estrogen and progesterone decreases impulsive burying. Both demonstrate a decrease in freezing behavior. The study concludes that "progesterone and/or estrogen may mediate impulsive and/or avoidant behavior." Freezing behavior in a female's cycle is seen to be greatly impacted by levels of hormones. However, there may be future studies on whether testosterone influences freezing behavior as well.
An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.
Fear is an intensely unpleasant primal emotion in response to perceiving or recognizing a danger or threat. Fear causes psychological changes that may produce behavioral reactions such as mounting an aggressive response or fleeing the threat. Fear in human beings may occur in response to a certain stimulus occurring in the present, or in anticipation or expectation of a future threat perceived as a risk to oneself. The fear response arises from the perception of danger leading to confrontation with or escape from/avoiding the threat, which in extreme cases of fear can be a freeze response.
A phobia is an anxiety disorder, defined by an irrational, unrealistic, persistent and excessive fear of an object or situation. Phobias typically result in a rapid onset of fear and are usually present for more than six months. Those affected go to great lengths to avoid the situation or object, to a degree greater than the actual danger posed. If the object or situation cannot be avoided, they experience significant distress. Other symptoms can include fainting, which may occur in blood or injury phobia, and panic attacks, often found in agoraphobia and emetophobia. Around 75% of those with phobias have multiple phobias.
The hypothalamus is a small part of the brain that contains a number of nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. It forms the ventral part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is the size of an almond.
The amygdala is a paired nuclear complex present in the cerebral hemispheres of vertebrates. It is considered part of the limbic system. In primates, it is located medially within the temporal lobes. It consists of many nuclei, each made up of further subnuclei. The subdivision most commonly made is into the basolateral, central, cortical, and medial nuclei together with the intercalated cell clusters. The amygdala has a primary role in the processing of memory, decision-making, and emotional responses. The amygdala was first identified and named by Karl Friedrich Burdach in 1822.
Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus, resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus. Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).
Biological psychiatry or biopsychiatry is an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system. It is interdisciplinary in its approach and draws on sciences such as neuroscience, psychopharmacology, biochemistry, genetics, epigenetics and physiology to investigate the biological bases of behavior and psychopathology. Biopsychiatry is the branch of medicine which deals with the study of the biological function of the nervous system in mental disorders.
An avoidance response is a natural adaptive behavior performed in response to danger. Excessive avoidance has been suggested to contribute to anxiety disorders, leading psychologists and neuroscientists to study how avoidance behaviors are learned using rat or mouse models. Avoidance learning is a type of operant conditioning.
Lobeline is a piperidine alkaloid found in a variety of plants, particularly those in the genus Lobelia, including Indian tobacco, Devil's tobacco, great lobelia, Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder which is freely soluble in water.
A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.
5-Fluoro-α-methyltryptamine, also known as PAL-544, is a putative stimulant, entactogen, and psychedelic tryptamine derivative related to α-methyltryptamine (αMT). It has been found to act as a well-balanced serotonin-norepinephrine-dopamine releasing agent, a 5-HT2A receptor agonist, and a potent and specific MAO-A inhibitor. which suggests that 5-fluoro-αMT could be an active psychedelic in humans, although it is not known to have been tested in humans and could be dangerous due to its strong inhibition of MAO-A.
The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.
An adrenergic storm is a sudden and dramatic increase in serum levels of the catecholamines adrenaline and noradrenaline, with a less significant increase in dopamine transmission. It is a life-threatening condition because of extreme tachycardia and hypertension, and is especially dire for those with prior heart problems. If treatment is prompt, prognosis is good; typically large amounts of diazepam or other benzodiazepines are administered alongside beta blockers. Beta blockers are contraindicated in some patients, so other anti-hypertensive medication such as clonidine may be used. Antipsychotics are also used to treat the most severe psychiatric reactions such as psychosis, paranoia or terror, after their use was formerly discouraged because of their potential to prolong the QT interval; however, more recent research performed since 2019 has revealed that this and other severe side effects are rare and their occurrence does not warrant banning antipsychotics from the treatment of adrenergic crises for which they can be extremely useful.
A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.
The biology of obsessive–compulsive disorder (OCD) refers biologically based theories about the mechanism of OCD. Cognitive models generally fall into the category of executive dysfunction or modulatory control. Neuroanatomically, functional and structural neuroimaging studies implicate the prefrontal cortex (PFC), basal ganglia (BG), insula, and posterior cingulate cortex (PCC). Genetic and neurochemical studies implicate glutamate and monoamine neurotransmitters, especially serotonin and dopamine.
3-Fluoroamphetamine is a stimulant drug from the amphetamine family which acts as a monoamine releaser with similar potency to methamphetamine but more selectivity for dopamine and norepinephrine release over serotonin. It is self-administered by mice to a similar extent to related drugs such as 4-fluoroamphetamine and 3-methylamphetamine.
The management of traumatic memories is important when treating mental health disorders such as post traumatic stress disorder. Traumatic memories can cause life problems even to individuals who do not meet the diagnostic criteria for a mental health disorder. They result from traumatic experiences, including natural disasters such as earthquakes and tsunamis; violent events such as kidnapping, terrorist attacks, war, domestic abuse and rape. Traumatic memories are naturally stressful in nature and emotionally overwhelm people's existing coping mechanisms.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
Many experiments have been done to find out how the brain interprets stimuli and how animals develop fear responses. The emotion, fear, has been hard-wired into almost every individual, due to its vital role in the survival of the individual. Researchers have found that fear is established unconsciously and that the amygdala is involved with fear conditioning.
The pharmacology of antidepressants is not entirely clear. The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis, which states that depression is due to an imbalance of the monoamine neurotransmitters. It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway. Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid, robust and sustained antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases.
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