PSYCHOPHARMACOLOGY: BEHAVIOR THE DARK AND DIRTY SECRETS Sophia Yin, DVM, MS

Definition Psychopharmacology is the study of drugs that affect the mind and emotions.

Drugs Are Known to Cause Psychological Changes We have known for centuries that drugs can cause major psychological changes in people and that these changes are dose dependent. For instance, marijuana causes people to initially feel lightheaded or slightly dizzy and then euphoric. They then become stoned, a state in which they are calm, relaxed, and in a dream-like state. They may experience a sense of disinhibition, which often manifests as increased laughter.

The poppy, Papaver somniferum, generates a white fluid that leaks out when the skin is scored. This latex is called opium. About 14% of opium is morphine. Opium, along with cocaine, or extract of the coca leaf, has been found to have many positive effects in terms of pain relief and also causes euphoria. In earlier times, opium was used as a cough suppressant, and both opium and cocaine were used in many medicinal elixers.

Probably the most famous drug elixir of all was developed by a pharmacist and marketed as a medicinal drink that tasted good. The drink was Coca Cola, and it contained extract of both the coca plant and the cola nut. By 1906, the medical community had figured out that these products had serious addictive side effects, and the U.S. Food and Drug Administration (FDA) was set up as a result. The Coca Cola company then started removing cocaine from its coca leaf extract.

Marijuana, cocaine, and opium are some historical natural products known to cause major changes in behavior and emotions in humans and other animals. However, we do not use these drugs to treat psychological issues in humans or in pets. The drugs we will be talking about are:

• Antianxiety drugs: Benzodiazepines • Antidepressants: Tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin reuptake inhibitors • Antinorepinephrine drugs (my term for them): Propranolol and clonidine. • Other drugs that affect serotonin: Azapirone (buspirone, trazadone)

Neurology Overview: How Psychotropic Drugs Affect the Brain If drugs cause changes in behavior and emotional states, they must be affecting the brain. To understand what they are doing, we have to know a little bit about the central nervous system (CNS).

The CNS is comprised of the brain and spinal cord and the cells that transmit signals are neurons. Each neuron contains dendrites that receive signals, a cell body, an axon, and an axon terminal. Signals flow only one way within a neuron. They start at the dendrite or cell body and travel down the axon to the axon terminal. The axon terminal generally abuts dendrites of other neurons. Once the signal travels down the first neuron, it somehow sends a signal to the second neuron. That signal can activate the second neuron or it can inactivate (decrease likelihood of activation). So the signal can be excitatory or inhibitory. But how does the signal get from one neuron to the next?

Signals go from one neuron to the other via neurotransmitters (NTs). When the signal travels down the neuron and reaches the axon terminal, it causes calcium channels to open and calcium flows in. This causes vesicles holding an NT to fuse with the synaptic membrane and release the NT into the synapse. Some of the NT makes it to the postsynaptic membrane binding to specific receptors, which then triggers ion channels to open. Ion channels regulate the flow of ions and can be either opened or closed. If the neuron is an activating neuron, then the ions are Na and we get activation of the second neuron. If the neuron is an inhibitory neuron, then we get Cl– and hyperpolarization or deactivation.

Each neuron has only one type of NT. The most common excitatory NT is glutamate, with 50% to 75% of the neurons of the brain using glutamate as their NT. The most common inhibitory NT in the brain is GABA, with 30% to 45% of brain neurons releasing GABA.

Benzodiazepines Work at the GABA Receptor Benzodiazepines are anxiolytic drugs that target GABA receptors to potentiate the action of GABA. That means they do not look like GABA, but they make the receptor more sensitive to GABA and prolong the action each time GABA binds. They in effect turn the neurons off and as a result decrease anxiety and seizures, increase muscle relaxation, and cause sedation. Here are some common ones:

• Chlordiazepoxide was the first one discovered. • Diazepam is the cheapest • Alprazolam (conjugation-only, no metabolites) • Oxazepam (conjugation-only, no metabolites) • Lorazepam (conjugation-only, no metabolites) • Triazolam

Which benzodiazepine should we use? It depends on how quickly we want it to act and how long it lasts, and this is based on its metabolism. We often use those where the onset of action is fastest, such as: diazepam, lorazepam, alprazolam, or triazolam.

How long they last depends on how they are metabolized by the liver. Benzodiazepines are metabolized by the liver and excreted into the urine. The goal of metabolizing them is to make them more water-soluble so that they can be excreted by the kidneys. The first phase of liver metabolism is to oxidize the compound (Cytochrome P450). The second phase is conjugation, where a hydrophilic chemical arm is added to make it more soluble in water. Lorazepam, oxazepam, and alprazolam only go through phase two—conjugation—and then are quickly excreted. They are quick acting and short in duration (two to four hours).

Diazepam, chlordiazepoxide, and triazolam have to be oxidized first, and the metabolites formed are also active, thus extending the effect of the product on some animals and building up in the bloodstream with repeated dosing. This can in particular be a problem.

Side Effects of Benzodiazepines Fulminant hepatic failure was associated with oral administration of diazepam in eleven cats (sick within 96 hours of initial treatment—they were given three to six doses). So, for cats, we must do blood work first to check liver values. Choose benzodiazepines without metabolites if you are planning to give multiple doses.

Other nuances and nuisances to know about include: • Some behaviorists avoid benzodiazepines altogether except for fractious cats coming into the hospital, because they causes a great amount of ataxia so that owners are noncompliant. • They can cause disinhibition, so fearful animals could become more aggressive, or the ones that raid trash, for example, may not be disinhibited from doing so. • It may take longer for pets to learn when they are on benzodiazepines. • They can have a paradoxical excitatory effect.

Other Important Neurotransmitters So far we have only talked about glutamate and GABA. But when we think of mind-altering NTs, what are the big three? • Serotonin • Norepinephrine • Dopamine

Although these are the big three, really they are only a tiny fraction of all NTs in the brain. They belong to a class called the biogenic amines and are all formed from amino acids.

Norepinephrine Norepinephrine is a biogenic amine derived from the amino acid and is released by the adrenal gland and by neurons in the brainstem during the fight-or-flight response. The overall response of the animal is hypervigilance, hyperarousal, and increased heart rate and blood pressure during the fight or flight response. It is possible in some cases that if we mitigate the physiological flight-or-fight response, we can decrease the pet’s behavioral response, too. In behavioral medicine, we have several drugs that reverse the effects of norepinephrine—propranolol and clonidine. Two drugs used in veterinary medicine that work in an antinorepinephrine fashion include propanolol and clonidine. Both are fast-acting and work by decreasing the physiological response associated with norepinephrine release.

Propranolol is a ß blocker. It works by blocking the ß receptors on the postsynaptic membrane. That is, it prevents norepinephrine from binding to the postsynaptic receptors and consequently blocks norepinephrine’s response.

Clonidine, on the other hand, is an alpha-2 agonist. The alpha-2 receptor is an autoreceptor. That is, it is located on the presynaptic membrane, and when norepinephrine binds to it, it provides negative feedback, which causes the presynaptic neuron to release less norepinephrine. Clonidine binding to the alpha-2 receptor has the same negative feedback effect. The end results is less norepinephrine in the synapse.

Both propranolol and clonidine decrease the effects of norepinephrine. One does it by decreasing the amount of norepinerphrine released. The other decreases the effect of norepinephrine by blocking NE receptors.

Serotonin Like norepinephrine, serotonin-releasing neurons have their cell bodies in the brainstem. There are at least fourteen subtypes of serotonin receptors. For instance, the 5-HT2c receptor is important in obesity and seizures. Mice that have a deficiency of this receptor are obese and have increased seizures. The 5-HT3 receptor is found in the GI tract and in the chemoreptor trigger zone of the brain and is important in regulating vomiting. The 5-HT4 receptor is important in peristalsis. The 5-HT1B receptor is related to aggression. Mice lacking a functional receptor have increased aggression. 5HT2A,2C receptors are in the limbic cortex, and increased binding results in increased agitation and anxiety. 5-HT1A in the raphe may help depression.

Many drugs work by blocking serotonin reuptake. Some are very selective just for serotonin receptors (fluoxetine, sertraline, paroxetine), while others affect a number of other receptors (amitryptilline).

Drugs by Class

Anxiolytics We have already covered the benzodiazepines, which work at the GABA receptor, and both clonidine and propranolol, which block the effects of norepinephrine, consequently blocking the physiologic effects associated with the fight-or-flight response.

Antidepressants Antidepressants are so named because they were initially used in human medicine to treat depression. They are now used for a number of behavioral issues, including general anxiety and compulsive disorders. There is no way to determine which drug or class of drugs will work for which patient or issues. Rather, the use is trial and error.

There are three classes of antidepressants: monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Monoamine oxidase inhibitors (MAOI) work by preventing the breakdown of monoamines such as serotonin, epinephrine, and dopamine. As such they should not be used with other MAOIs or with the SSRIs or TCAs (described next). The only MAOI approved for use in dogs is selegiline (Anipryl), which is used for cognitive dysfunction in dogs. A second classes of antidepressants is the tricyclic antidepressants (TCA), so named because the chemicals have three cyclic rings in their structure. Some TCAs include amitryptilline, clomipramine, and imipramine. TCAs block the reuptake of norepinephrine, dopamine, and serotonin into the presynaptic terminal. So they effectively increase the level of neurotransmitter in the synapse. Clomipramine is the most specific for serotonin and is approved for use in dogs with separation anxiety when treatment is combined with behavior modification. Selective serotonin reuptake inhibitors (SSRIs) selectively block the reuptake of serotonin back into the presynaptic neuron. Consequently, they increase the levels of serotonin in the synapse.

Buspirone also works at the serotonin synapse and increases serotonin levels. Trazodone, a serotonin agonist, reuptake inhibitor (SARI), is a weak reuptake inhibitor and a strong blocker of the serotonin 5-HT2A receptor. By blocking the 2A receptor, serotonin preferentially binds to the 1A receptor, which may have more antidepressant activity. So it helps to block the side effects that can be caused by 5-HT2A binding and increases the activity at the 1A receptor. Trazodone is generally used in conjunction with a TCA or an SSRI.

Antinorepinephrines (my term) include propranolol and clonidine, which were described earlier in these notes.

Fast Action Slow Action (3+ weeks) • Benzodiazepines (diazepam, alprazolam) Antidepressants • Propranolol • Monoamine oxidase inhibitors (selegiline) • Clonidine • Tricyclic antidepressants (amitryptilline, • Trazodone (serotonin antagonist, reuptake clomipramine) inhibitor); used in conjunction with an • Serotonin reuptake inhibitors (fluoxetine, SSRI or TCA sertraline, paroxetine) Azapirone (buspirone)

References and Suggested Reading Crowell-Davis SL, Murray T. Veterinary psychopharmacology. Ames, IO: Blackwell, 2006. Meyer JS, Quenzer LF. Psychopharmacology: drugs: the brain and behavior. Sunderland, MA: Sinauer, 2005. Presti D. Psychology 119: drug and behavior. Berkeley: Itunes University. Stahl, SM. Essential pharmacology: neuroscientific basis and practical applications. Cambridge: Cambridge University Press, 2000.