PHENOTYPIC PRESENTATIONS OF FEAR, AGGRESSION, AND ANXIETY

The extent to which learning and memory play roles in fear, anxiety, phobias, and obsessive-compulsive disorder (OCD) is incompletely understood. The systems involved are extremely complex.

Fear is best defined as arousal associated with impending threat, pain, danger, whether or not threat is real. Many canine and feline diagnoses presuppose some basis in fear. Anxiety is best defined as the apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria (in humans) and somatic symptoms of tension: vigilance and scanning, increased motor activity, increased autonomic hyperactivity, whether or not the focus of the anxiety is real. Many canine and feline behavioral disorders also presuppose some basis in anxiety, but the general nature of it makes anxiety tougher to target than fear as an underlying problem. Many behavioral conditions that have labels (e.g., “aggression”) that describe the abnormal behavior fail to indicate that the basis of much of that behavior may be anxiety. Aggression itself, in the broad sense, is best defined as an appropriate or inappropriate, inter- or intra-specific, threat, challenge, or contest resulting in combat or in deference and resolution. Note that some agonistic or aggressive behaviors can be normal and adaptive. In behavioral medicine we focus on the ones that are maladaptive and abnormal. The definition of aggression leaves room for the roles of uncertainty and anxiety, particularly when the aggression is a diagnosis and a manifestation of an abnormal response.

For example, dominance aggression, like other diagnoses involving aggression, is probably representative of a canine anxiety disorder. It’s about control or access to control in social situations involving humans (1) and is based in uncertainty about the interactions and the information involved in them. The behaviors of the two major groups of dogs with this condition support the anxiety hypothesis: 1) the explosive / impulsive dogs (formerly often called “rage”) react inappropriately to any discomfiting stimulus in a stereotypic manner because they cannot help it—they only have one response when uncertain and they are socially uncertain with humans; and 2) dogs who are unsure of their social role and use the aggressive behaviors to deform the social system to get much needed information about what is expected of them, defining their social and behavioral boundaries using the response to their aggression.(2)

NEUROANATOMY

We know that: 1) a functioning amygdala is required to learn fear; 2) a functioning forebrain is required to unlearn fear (i.e., to effect habituation); and 3) many human fears appear to be the result of the inability to inhibit a fear response. Accordingly, it has been hypothesized that fear is, in part, due to chronic amygdala over-reaction and/or failure of the amygdala to turn off after the threat has passed.

The central nucleus of the amygdala has direct projections to hypothalamic and brainstem areas possibly involved in the signs seen in fear and anxiety.(3)

 Direct projections from the central nucleus to the lateral hypothalamus appear to activate the sympathetic branch of the ANS during responses involving fear and anxiety.

 Direct projections to the dorsal motor nucleus of the vagus nerve may affect the signs that are measured as assessments of fear and anxiety since the vagus nerve is responsible for many autonomic functions.

 Projections of the central nucleus of the amygdala to the parabranchial nucleus may directly affect respiratory changes exhibited in fearful or anxious responses.

 Projections from the amygdala to the ventral tegmental area (VTA) may mediate stress-related effects of dopamine and its metabolites in the prefrontal region.

 Direct amygdala projections to the locus coeruleus (LC), the principal norepinerphrinergic (noradrenergic) [NE/NA] nucleus in the brain, in addition to some indirect loops through the VTA, are thought to mediate the response of cells within the LC to any conditioned fear stimulus, including those produced through repeated exposure to the object of fear (e.g., thunderstorms). Dysregulation of the LC appears to lead to panic and phobias in humans.(4) The LC directly supplies the limbic systems and may be responsible for many correlated “limbic” signs. Patients with true panic and phobic responses are more sensitive to pharmacologic stimulation and suppression of the LC than are controls.(4-6)

 Direct projections from the amygdala to the lateral dorsal tegmental nucleus may increase synaptic transmission in thalamic sensory neurons during fearful reactions. Combined with increased thalamic stimulation due to activation by the LC, this stimulation may lead to increased vigilance and superior signal awareness in fearful and anxious states. There may also be a synergistic interaction between the amygdala and LC that affects serotonergic [5-HT] neurons in the raphé: both NE and 5-HT facilitate excitations of motor neurons, which could lead to enhanced performance during a fearful state.

 Projections from the amygdala to the nucleus reticularis pontis caudalis appear to potentiate the startle reflex in fear states.

 The central nucleus of the amygdala projects to the central gray—a region with complex responses thought to be part of the general defense system. In part, this system is responsible for freezing and the cessation of behaviors.

 Direct amygdala projections to the trigeminal and facial motor nuclei may mediate some facial expressions of fear.

 Indirect projections, via the hypothalamus and other routes, of the amygdala’s central nucleus to the paraventricular nucleus of the hypothalamus may mediate neuroendocrine responses

Areas of the brain involved in aggression are diffuse. Much of what we know about these areas is from ablation experiments which do not mirror the complexity of the intact system; however, such data serve to set boundaries for responses.

 The amygdala activates or suppresses the hypothalamus and has efferents to the extrapyramidal system. This network has the function of associating sensory experiences with behavior. Bilateral lesions of the amygdala can ablate aggression, perhaps because of this “association” function, while stimulation leads to outburst aggression.

 In its role of regulating neuroendocrine responses, the hypothalamus is also involved in aggression but in very complex ways. In cats, stimulation of the anterior hypothalamus induces predatory attack, stimulation of the dorsomedial hypothalamus induces (DMH) active attack, and stimulation of the ventromedial hypothalamus (VMH) and posterolateral hypothalamus (PLH), respectively, lengthens and shorten the latency of attack. Destruction of the VMH produces permanently aggressive rats and cats.

 The prefrontal cortex acts to modulate and integrate all limbic and hypothalamic activity. This integration is associated with social aspects of interaction and aggression, and judgment affecting them. The prefrontal cortex also co-ordinates timing of social cues. Lesions in the prefrontal cortex result in disinhibited aggression although the actual effect depends on the discrete area involved.

Central to the above discussion is that the effects discussed vary greatly depending on the individual’s underlying “temperament.” The phenotype seen will depend on the boundaries set by genomic plasticity at each of the molecular, neurochemical, and neuroanatomical levels. This is why inbred mice and knockout genes are used to study these questions and why they are so inadequate to describe the entire complex involving fear, anxiety, and aggression.

 Fear and anxiety are particularly interesting because they are so complexly intertwined. In clinical situations, fear is considered more specific than anxiety. This observation is supported experimentally: spontaneous activation of the central nucleus of the amygdala produces a state resembling fear in the absence of an eliciting stimulus. In addition, fear and anxiety often preceded temporal lobe epileptic seizures (7) that appear to be associated with abnormal electrical activity in the amygdala. Lesioning and imaging studies have supported a partially overlapping, but distinct role for regions and tracts involved in a primarily fearful response compared with a primarily aggressive response that might be involved in anxiety. Accordingly, drugs or techniques that block conditioned or learned fear may not block anxiety unless they are directly targeted specifically to the amygdala. Drugs that block or affect aggression have a number of more diffuse regions at which they can interact. The most successful drugs—primarily anti-anxiety agents—are those that treat the aggression while leaving other “normal” behaviors intact.

NEUROTRANSMITTERS AND NEUROCHEMICAL TRACTS

The neurotransmitters primarily involved in anxiety and fear are 5-HT, NE, dopamine, gamma amino butyric acid (GABA), and excitatory amino acids (EEAs).

 5-HT: The 5-HT₁ receptors are linked to the inhibition of adenylate cyclase and affect mood and behavior. Presynaptic 5-HT_1A-receptors predominate in dorsal and median raphé nuclei; post-synaptic 5-HT_1A-receptors predominant in limbic regions (hippocampus and septum) and some cortical layers. The overall effect depends on regulation of second messengers (cAMP, Ca²⁺, cGMP, IP₃) and their effects on protein kinases that then alter neuronal metabolism and receptor protein transcription. Urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid) is a measure of 5-HT turnover and has been used to assess neurochemical abnormalities in human psychiatric patients, and has potential in this regard for veterinary behavioral medicine.

 NE: NE neurons are clustered in the LC and medulla. NE has been postulated to affect 1) mood [NE decreases in depression and increases in mania]; 2) functional reward systems; and 3) arousal.

 Dopamine: Dopaminergic nuclei are found primarily in: 1) the substantia nigra pars compacta which projects to the striatum and is largely concerned with coordinated movement; 2) the ventral tegmental area which projects to the frontal and cingulate cortex, nucleus acumbens, and other limbic structures; and 3) the arcuate nucleus of the hypothalamus which projects to the pituitary. A large proportion of the brain's dopamine is found in the corpus striatum, the part of the extrapyramidal system concerned with coordinated movement. The D₂, D₃, and D₄ receptors are all affected in mood disorders and stereotypies. Excess dopamine, as produced by dopamine releasing agents (amphetamines and dopamine agonists, like apomorphine) is associated with the development of stereotypies.

 GABA: GABA, the inhibitory neurotransmitter found in short interneurons, is produced in large amounts only in the brain and serves as a neurotransmitter in ~30% of the synapses in the human CNS. GABA is formed from the EEA glutamate via glutamic acid decarboxylase (GAD), catalyzed by GABA-transaminase (GABA-T) and destroyed by transamination. There are two main groupings of GABA receptors—GABA_A and GABA_B. Barbiturates and benzodiazepines are potentiators of GABA_A. GABA_B receptors are involved in the fine-tuning of inhibitory synaptic transmission.(7)  GABA also has a variety of tropic effects on developing brain cells.(9) During ontogeny GABAergic axons move through areas where other neurotransmitter phenotypes are being produced, and so may be related to later monoaminergic imbalances.(8) The extent to which such ontogenic effects are relevant for behavioral conditions is unknown but bears investigation.

 EAAs: EEAs have a role as central neurotransmitters and are produced in abnormal levels in aggressive, impulse, and schizophrenic disorders. The main fast excitatory transmitters in the CNS are EEAs. Both barbiturates and progesterone suppress excitatory responses to glutamate.(10) Pre-synaptic barbiturates inhibit calcium uptake and decrease synaptosomal release of neurotransmitters, including GABA and glutamate.(11,12)

ROLES FOR NEURONAL STIMULATION, SYNAPTIC PLASTICITY, AND RECEPTOR PROTEIN TRANSCRIPTION AND TRANSLATION

What makes TCAs and SSRIs special and why are they so useful for anxiety disorders? The key to the success of these drugs is that they utilize the same second messenger systems and transcription pathways that are used to develop cellular memory or to “learn” something. This pathway involves cAMP, cytosolic response element binding protein (CREB), brain derived neurotrophic factor (BDNF), NMDA receptors and protein tyrosine kinases (PTK)—particularly Src—which regulate activity of NMDA receptors and other ion channels and mediates the induction of LTP (long-term potentiation = synaptic plasticity) in the CA1 region of the hippocampus.(13-15)

There are two phases of TCA and SSRI treatment: short-term effects and long-term effects. Short-term effects result in a synaptic increase of the relevant monoamine associated with re-uptake inhibition. The somatodendric autoreceptor of the pre-synaptic neuron decreases the firing rate of that cell as a thermostatic response. Regardless, there is increased saturation of the post-synaptic receptors resulting in stimulation of the ß-adrenergic coupled cAMP system. cAMP leads to an increase in PTK as the first step in the long-term effects. PTK translocates into the nucleus of the post-synaptic cell where it increases CREB, which has been postulated to be the post-receptor target for these drugs. Increases in CREB lead to increases in BDNF and tyrosine kinases (e.g., trkB), which then stimulate mRNA transcription of new receptor proteins. The altered conformation of the post-synaptic receptors renders serotonin stimulation and signal transduction more efficient.(16,17)

Knowledge of neurochemical pathways, regional brain involvement, and their effects on phenotypes involved in anxiety, fear, and aggression permit very successful treatment. This approach also allows us to stop blaming the animal or the owner, which leads only to abuse or relinquishment, and to start helping our patients and clients.

Psychopharmacological Agents Useful in Disorders Involving Fear, Aggression and Anxiety

These notes are in part adapted from: Overall, K.L., Clinical Behavioral Medicine for Small Animals,
Mosby, St. Louis, 1997.

REFERENCES ARE AVAILABLE ON REQUEST