Lecture 18: Neuropharmacology (Monoamine-modulating behavioral drugs & Behavior-modifying benzodiazepenes (BDZs)

What neurotransmitter is most commonly targeted by behavior-modifying drugs?

Serotonin (5HT); involved in depression, anxiety, appetite, and aggression.

What are the three pharmacologic intervention points for serotonin modulation?

Enzymatic degradation (MAOIs), reuptake inhibition (SSRIs/TCAs), receptor interaction (agonists/antagonists).

Why is combination therapy with behavior-modifying drugs discouraged?

Increased risk of serotonin syndrome and overlapping side effects; reserved for refractory cases.

What behavioral issues can be treated with drugs alone?

Uncontrollable situational anxieties, compulsive behaviors, cognitive dysfunction, and when owners refuse training.

What is the main drug used for cognitive dysfunction in dogs?

Selegiline (Anipryl); a selective MAO-B inhibitor that increases dopamine and mildly serotonin.

What are the side effects of selegiline?

GI upset, cardiovascular stimulation, tachypnea; contraindicated in dogs with CV issues or on other monoamine drugs.

What is the mechanism of TCAs (NSRIs)?

Block reuptake of serotonin and norepinephrine; less selective than SSRIs.

Which TCA is most selective for serotonin?

Clomipramine (Clomicalm); used for separation anxiety and compulsive disorders.

Why are TCAs contraindicated in geriatric or hepatic patients?

They are prodrugs requiring liver metabolism; increased risk of toxicity.

Which SSRI is veterinary-labeled and widely used?

Fluoxetine (Reconcile); used for separation anxiety, urine spraying, cribbing in horses.

What are the benefits of fluoxetine over TCAs?

Less cardiotoxicity, less sedation, safer in epileptics, once-daily dosing.

What is a caution when using fluoxetine?

May inhibit subservience and lead to aggression in some dogs.

Which SSRI is teratogenic and should not be used in pregnant animals?

Paroxetine; also more cardiotoxic than fluoxetine.

What is buspirone's mechanism and use?

Serotonin receptor agonist; used for mild chronic anxiety and feline urine spraying.

What is trazodone's mechanism and use?

Blocks serotonin autoreceptor, increasing release; used for situational anxiety and thunderstorm phobia.

What is mirtazapine's mechanism and use?

Serotonin receptor antagonist; increases dopamine, appetite stimulation in cats, least cardiotoxic.

What is serotonin syndrome?

Life-threatening condition from excess serotonin due to drug combinations or supplements.

What are signs of serotonin syndrome?

Restlessness, seizures, vomiting, diarrhea, hyperthermia, increased HR/RR, coma.

What is the treatment for serotonin syndrome?

Stop serotonergic drugs; cyproheptadine, diazepam/phenobarbital, fluids, cooling.

What nutraceuticals can contribute to serotonin syndrome?

St. John's wort, SAMe, tryptophan.

What foods can trigger serotonin syndrome with MAOIs?

Tyramine-rich foods: dried meats, cheese, bananas, pickles.

What non-serotonergic drugs can trigger serotonin syndrome?

Tramadol, linezolid, metoclopramide.

What is the GABA receptor subtype targeted by benzodiazepines?

GABAA; an ion channel allowing chloride influx for inhibitory effect.

Why is GABAA pharmacologically more important than GABAB?

GABAA is an ion channel with faster onset; targeted by BDZs, barbiturates, ethanol.

What is the role of GABA in behavior modulation?

Inhibits excitatory neurotransmitter release, especially glutamate; leads to calming effect.

What are the dose-dependent effects of BDZs?

Low = anxiolytic, moderate = sedative, high = hypnotic.

Which BDZ must be injected?

Midazolam; all others can be given orally, rectally, or transnasally.

What is the BDZ antagonist and when is it used?

Flumazenil; reverses BDZ overdose or CV complications, but may cause seizures if combined with TCAs/SSRIs.

Which BDZ is used for appetite stimulation in cats and aggression-prone dogs?

Oxazepam; short-acting and less likely to cause aggression.

Which BDZ is used for sleep disorders?

Triazolam; short-acting.

Which BDZ is most important for short-acting anxiety treatment?

Alprazolam; used for thunderstorm phobia, middle-of-night anxiety, fear/aggression.

Which BDZ is most important for long-acting anxiety treatment?

Diazepam; used for many behavioral issues and seizures, but not in cats.

Which BDZ is a metabolite of diazepam with longer duration?

Clorazepate.

Which BDZ is least hepatotoxic and suitable for cats?

Clonazepam; small pill size.

Why are BDZs not first-line behavior drugs?

Tolerance and dependence; risk of withdrawal and sedation.

What is the role of endogenous BDZs and neurosteroids?

Enhance GABAA receptor responsiveness; e.g., allopregnanolone and its analog ganaxalone.

Which benzodiazepine must be injected?

Midazolam; it's the only BDZ that must be administered via injection.

Which BDZs can be given orally, rectally, or transnasally?

All BDZs except midazolam; useful when animals can't swallow.

Why can't most BDZs be given in IV fluids?

They bind to soft plastics and are sensitive to storage conditions.

Which BDZ is short-acting and used for thunderstorm phobia and middle-of-night anxiety?

Alprazolam; also used for fear/aggression and anxiety in mares or orphaned foals.

Which BDZ is long-acting and used for anxiety and seizures?

Diazepam; broad behavioral use but contraindicated in cats.

Why should diazepam not be used in cats?

It causes fatal idiopathic hepatic necrosis.

What is the GABA receptor antagonist used to reverse BDZ effects?

Flumazenil; blocks BDZ binding site on GABAA receptor.

When is flumazenil used?

To reverse midazolam-induced CV complications or BDZ overdose; caution with TCAs/SSRIs due to seizure risk.

Which GABA-modulating drug is used as a swine sedative?

Alfaxalone; activates neurosteroid site on GABAA receptor to enhance GABA binding.

What is the mechanism of GABA in behavior modulation?

Inhibits excitatory NT release (especially glutamate), leading to calming effects.

What are the two GABA receptor subtypes?

GABAA (ion channel) and GABAB (GPCR); GABAA is pharmacologically more important.

Which receptor do BDZs bind to?

GABAA; they do not bind to GABAB.

Why is GABAA more pharmacologically relevant than GABAB?

GABAA is an ion channel with faster onset; targeted by BDZs, barbiturates, ethanol.

What is the major side effect of BDZs?

Sedation; motor issues are secondary.

Which BDZ is used for inter-cat aggression?

Lorazepam; short-acting.

Which BDZ is used for urine spraying in cats and stress colitis?

Chlordiazepoxide; often combined with clinidium.

What is the mechanism of action of alfaxalone?

Activates the neurosteroid site on GABAA receptor; enhances GABA binding.

What is the function of GABA at axoaxonic synapses?

Prevents NT release by inhibiting voltage-gated calcium channels.

What is the function of GABAA receptor activation?

Allows chloride influx, hyperpolarizing the cell and preventing NT release.

What is the function of GABAB receptor activation?

Activates GPCR pathway to inhibit calcium channels and NT release.

What are BDZs commonly used for in behavior?

Separation anxiety, noise phobias, inappropriate elimination, situational anxieties, sleep issues, appetite stimulation.

What is the BDZ binding site relative to GABA?

Different site; BDZs do not compete with endogenous GABA.

What is the role of allopregnanolone?

Endogenous neurosteroid that enhances GABAA responsiveness to GABA and BDZs.

What is ganaxalone?

Analog of allopregnanolone under development for anxiety and seizures.