To understand how behavioral medications work in veterinary medicine, one must start with a general understanding of how the central nervous system (CNS) functions. The CNS consists of physical anatomic connections, similar to a complex electric circuit, and biochemical connections. The biochemical connections involve neurotransmitters. We can think of behavior changes as a result of any malfunction in the CNS, which can be physical or biochemical. “When neurons malfunction, behavioral symptoms may occur.” Thus, whenever we use drugs to alter neuronal function, “we can observe behavioral symptoms being relieved, worsened, or produced (1).”
The neuron consists of dendrites, soma (or cell body), and the axon. Neurons are designed to receive information via dendrites and transmit information via axons, typically in one direction (Figure 1). Neurons are also equipped to send information to other neurons through synapses (synaptic cleft). In classical synaptic transmission, dendrites receive various signals, such as light, hormones, drugs, electrical impulses, or neurotransmitters. These signals are electrically encoded and propagated down the neuron. At the axon terminal, the electrical impulses are converted into biochemical messages that can be delivered to the next neuron. Messages within a neuron are electrical, whereas messages between neurons are chemical, and neurotransmitters are the biochemical messengers.
Neurotransmitters are stored in vesicles (small packages) at the axon terminal. When the presynaptic neuron fires, the neurotransmitters in the vesicles are released into the synaptic space, the space between the axon terminal and the next neuron. Once in the synapse, the neurotransmitter can do several things: bind with the appropriate receptor on the postsynaptic neuron; diffuse to receptors on nearby neurons; or travel backward to the presynaptic neuron, providing negative feedback (Figure 2).
Basically, communication between neurons is “turned on” when the electrical signal in the presynaptic neuron causes the release of neurotransmitters from the vesicle into the synapse. Communication occurs when the neurotransmitter binds to the appropriate receptor on the postsynaptic neuron. Communication is “turned off” when the neurotransmitters are removed from the synapse and returned to the presynaptic neuron, primarily via specific transport pumps.
Signal transduction cascades are more complex than a simple exchange of messages between two neurons. Neurotransmission can also communicate from the genome of the presynaptic neuron to the genome of the post synaptic neuron and then back to the presynaptic neuron. This cascade involves multiple chemical messengers that Stahl (1) refers to as the “molecular pony express.” Specialized molecules act as a sequence of riders, passing the message to the next specialized molecule until the message reaches its functional destination, such as gene expression or the activation of otherwise “sleeping” or inactive molecules. While most behavior-modifying medications affect the release or reuptake of neurotransmitters, each step in the signal transduction cascade can potentially influence long-term changes. “The neuron is dynamically modifying its synaptic connections throughout its life, in response to learning, life experiences, genetic programming, epigenetic changes, drugs, and diseases, with chemical neurotransmission being the key aspect underlying the regulation of all these important processes” (1).
Neurotransmitter receptors are very specific; for example, dopamine will not/does not/cannot bind to a serotonin receptor, and vice versa. In general, there are multiple slightly different receptor subtypes for each neurotransmitter, and often these subtypes have additional subtypes. So, for example, there are seven serotonin receptor subtypes (5-HT1 through 5HT7).
Behavioral drugs used in veterinary medicine, and a variety of other compounds like LSD and marijuana, bind to specific receptors or block the reuptake of specific neurotransmitters by inhibiting the function of the transport pump. The end result is an increased concentration of neurotransmitter in the synapse. Although the change in neurotransmitter concentration is almost immediate, many behavioral medications take weeks or more to show an effect. The exact mechanisms of these behavioral medications remain a mystery.
Drug-receptor interactions are reversible and depend on the drug’s affinity for the receptor. A drug that is considered an “agonist” binds to the receptor and increases its effects, while an “antagonist” blocks the agonist from binding. This is a mutually exclusive relationship – if the agonist is bound to the receptor, the antagonist cannot bind, and vice versa. Drugs can also be “partial agonists,” resulting in an increased effect but not as much as the full “agonist” (Figure 3).
Drugs often mimic the brain’s neurotransmitters. For example, the brain produces its own morphine (β-endorphin) and marijuana (endocannabinoids). “Morphine was used in clinical practice before the discovery of β-endorphin; marijuana was smoked before the discovery of cannabinoid receptors and endocannabinoids; the benzodiazepines Valium (diazepam) and Xanax (alprazolam) were prescribed before the discovery of benzodiazepine receptors; and the antidepressants Elavil (amitriptyline) and Prozac (fluoxetine) entered clinical practice before molecular clarification of the serotonin transporter site. This underscores the point that the great majority of drugs that act in the central nervous system act upon the process of neurotransmission” (1).
Interest in the role of biogenic amines in mental health emerged in the 1950s (1, 2). The biogenic amine hypothesis stated that depression in humans was a result of a deficiency of monoamine neurotransmitters and mania was an excess of monoamine neurotransmitters. Despite extensive research, direct evidence to support the “chemical imbalance theory” of mood disorders is lacking. The focus then shifted to the “neurotransmitter receptor hypothesis,” where decreased neurotransmitters lead to an upregulation (increased number of receptors). However, drugs that increase synaptic neurotransmitters do so immediately, yet behavioral effects take weeks to months to become evident. The latest theory for mood disorders is the “neuroplasticity and neuroprogression hypothesis of depression,” which is beyond the scope of this blog and outside my area of expertise. Suffice it to say that while we may understand the physiological effect of changing the concentration of neurotransmitters at the synapse, we have yet to understand how these changes relate to mood disorders in humans and other animals.
The monoamine neurotransmitters are dopamine (DA), serotonin (5-HT), and norepinephrine (NE) (1, 2). The enzyme monoamine oxidase (MAO) is involved in the degradation of monoamine neurotransmitters, so it makes sense that the inhibition of the enzyme MAO elevates the levels of these neurotransmitters. Anipryl (selegiline), an irreversible inhibitor of MAO, is used to treat cognitive dysfunction in dogs. This is a drug that should be used with caution when combined with other medications, and the combination of selegiline and blue cheese can lead to a hypertensive crisis in humans (3).
The six key neurotransmitters in the brain that are targets of psychotropic medications are dopamine, serotonin, norepinephrine, acetylcholine, glutamate, and γ-aminobutyric acid (GABA).
Dopamine is a catecholamine neurotransmitter originally thought to function as a precursor for epinephrine and norepinephrine. Fifty percent of catecholamine neurotransmitters in the brain are dopamine. Dopaminergic cell bodies are located in the mesencephalon (substantia nigra), with axons projecting to the striatum – this pathway contains most of the total brain dopamine. Dopaminergic cell bodies are also located in the ventral tegmental area (VTA) with connections to limbic structures (nucleus accumbens, aka mesolimbic) and cerebral cortex (prefrontal cortex, aka mesocortical dopamine systems). The VTA regulates the reward system, and transmission is increased by rewards such as food, sex, water, but also by drugs of abuse like amphetamines, cocaine, opioids, and nicotine. Pleasure, reward, and motivation are decreased in canine cognitive dysfunction and Parkinson’s disease.
Serotonin (5-hydroxytryptamine, aka 5-HT) is found in many cells in the body, with only 1-2% of the total serotonin found in the brain. Serotonergic neurons are located in the pons and brainstem (raphe nuclei) with projections to the CNS and spinal cord. Serotonin activates the forebrain (cerebral cortex, striatum, hippocampus). The biological function of 5-HT is complex and includes mood, reward, learning and memory, and various physiological functions. Disturbances of serotonin are postulated to play a role in depression, aggression, anxiety, migraine, locomotor activity, and obsessive behavior.
Norepinephrine is involved in alertness, concentration, arousal, mood, attention, restlessness, anxiety, memory formation (especially stress memories), and cardiovascular function (i.e., heart rate, blood pressure, etc.). Noradrenergic neurons arise from cell bodies in the pons (locus ceruleus). Selective norepinephrine alpha 2 receptor agonists produce sedation, analgesia, and muscle relaxation in animals.
Acetylcholine (ACh) is a cholinergic neurotransmitter, the first neurotransmitter identified in the peripheral nervous system, and is the neurotransmitter of all autonomic ganglia, post-ganglionic parasympathetic synapses, neuromuscular junctions, and cholinergic neurons in the CNS. Unlike other neurotransmitters, which are removed from synapses primarily by reuptake channels, ACh is removed from synapses by a powerful enzyme, acetylcholinesterase. Mechanisms to increase ACh in diseases like dementia involve inhibiting this enzyme.
Glutamate is a prominent excitatory amino acid neurotransmitter in the brain, and glutamate receptors mediate most of the excitatory transmission in the brain, making these receptors potential targets for therapeutic intervention. Major glutamatergic pathways are cortico-cortical; between the thalamus and cortex; and the extrapyramidal system (projections between the cortex and striatum). Estimates of the number of neurons that use glutamate as a neurotransmitter range from 70 to 85%.
Gamma-aminobutyric acid (g aminobutyric acid aka GABA) is the primary inhibitory neurotransmitter in the mammalian brain. As an inhibitory neurotransmitter, GABA hyperpolarizes the neuron. In the cerebral cortex and hippocampus, GABAergic neurons are primarily interneurons situated between other neurons. GABA has a regulatory function in vigilance, anxiety, muscle tension, memory, and epileptogenic focus.
Neurotransmission is a complex process involving a variety of neurotransmitters, receptors, messengers, channels, and molecules. Neurotransmission is influenced by our genes, our learning history, our environment, our medications, and many other factors many things currently unknown.
2) Crowell-Davis SL, Murray TF, de Souza Dantas LM. Veterinary Psychopharmacology. Wiley & Sons, Inc. 2019
3) Shorter E. The rise and fall in the age of psychopharmacology. Oxford Press 2021
Thanks to Rene Smith and Mike Shikashio for suggestions and review of the ma
Glossary of Terms:
AGONIST = drug that bonds to a receptor and increases the effect
ANTAGONIST = binds a receptor and prevents agonist to bind leading to decreased effect
AXON TERMINAL = the end of the neuron that contains and releases neurotransmitters
BIOGENIC AMINES = nitrogen compounds with biological activity
DENDRITE = the end of the neuron that receives the stimulus
NEURON = nerve cell
NEUROTRANSMITTER = biochemical compound stored in vesicles in the presynaptic axon that binds to specific receptors on the dendrite and results in a biological effect
SOMA = the neuron cell body
SYNAPSE = the space between the axon of one neuron and the dendrites of the next neuron; where neurotransmitters are released
RECEPTOR = protein on a cell surface that binds specific compounds or medications and results in an effect
VESICLE = storage container for neurotransmitters