Chapter 10 Dietary composition has long been a focus for improving performance in working dogs, such as sled dogs, where fats have been used to provide sources of both calories and water. Diet continues to play a large role in the treatment of many medical conditions, including diabetes, cardiac disease, and renal disease, by helping to control substances that may exacerbate disease. For behavioral concerns, commercial dietary and dietary supplement strategies have largely focused on the role that anti-oxidants and related compounds can have for behavioral changes that occur with age. Substances that have been used as either supplements or additives include, but may not be restricted to, the substances listed alphabetically in Table 10-1. TABLE 10-1 Putative Dietary Substances with Behavioral Effects and Presumptive Effects The most common roles for compounds found in, or added to, diets fall into a few classes: 2. anti-oxidants, most of which should be neuroprotective, 3. reactive oxygen species (ROS)/free radical scavengers, most of which should be neuroprotective, 4. precursor neurochemicals, which are postulated to affect the behaviors associated with the neurochemical of interest with the intent to enhance cognition or decrease reactivity, 5. enzymes, co-enzymes, or co-factors for some aspect of Kreb’s cycle function or neurochemical production, and 6. sources of energy for brain metabolism for enhanced cognition and neuroprotection. These compounds are united by their contributions to the maintenance of cellular metabolism and to efficient neuron-to-neuron communication, processes essential to keeping brain neurons plump, healthy, and functional. Our understanding of dietary effects on behavior is nascent. One of the most controversial dietary supplements is tryptophan, which is a precursor to serotonin (tryptophan → 5-hydroxy-l-tryptophan [5-HTP] → serotonin/5-hydroxytryptamine [5-HT]) and an essential amino acid (AA) in humans. Of the essential AAs—arginine, histidine, methionine, threonine, valine, isoleucine, phenylalanine, tryptophan, leucine, and lysine—arginine and histidine have also received a lot of attention because they are thought to be essential during growth, a period of high anabolic activity (Bosch et al., 2007). Studies in rodents, humans, and pigs suggest tryptophan may affect behavior but not always in the desired direction. Pigs fed diets supplemented with tryptophan have been reported to experience better recovery from stressful situations (Koopmans et al., 2005). Horses fed diets supplemented with tryptophan and then isolated showed increases in motor activity and heart rates compared with horses not receiving supplements (Bagshaw et al., 1994). Rats fed diets high in tryptophan have been reported to decrease killing of mice (Chamberlain et al., 1987) and to recover better from stressors (Dunn, 1988), but increased tryptophan has been associated with increased aggression in male mice who are territorial (Lasley and Thurmond, 1985). The finding that humans who are depressed have lower tryptophan concentrations compared with humans who are not depressed led to the hypothesis that because stressors initially decrease serotonin turnover, precursor AA may be depleted, which could contribute further to decreases in serotonin (Branchey et al., 1984). Were this true, supplementation with tryptophan may be beneficial. Tryptophan is one of three members of a group of aromatic AAs—tryptophan, tyrosine, and phenylalanine—that are precursors in the biosynthetic pathway for the neurotransmitters serotonin, dopamine, and norepinephrine (NE) (Table 10-2). The amount and timing of food intake, composition of diet, and overall digestibility of the diet all affect availability of these AAs (Bosch et al., 2007). Aromatic AAs are postulated to affect brain function, which requires that the food ingested alters the level of these AAs in the brain, but not all tryptophan is equally available. TABLE 10-2 Precursor Amino Acids and Neurotransmitter Pathways That They Affect DOPA, Dihydroxyphenylalanine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTP, 5-hydroxy-l-tryptophan. Only very small molecules cross the blood-brain barrier (BBB), and for any AA to have an effect on behavior it must cross the BBB. Tryptophan is a relatively small molecule, but whether it crosses the BBB depends on the relative availability, the availability of the appropriate carrier, and the extent to which the tryptophan remains protein bound in the serum. To make matters more complex, factors pertaining to the patient including, but likely not restricted to, breed, sex, age, activity level, social status, and arousal level all affect metabolism and transport of tryptophan across the BBB, whereas composition of the diet is responsible for availability of dietary tryptophan (Bosch et al., 2007). As noted, the extent to which tryptophan is available depends on the diet. Tryptophan is found in most protein-containing foods, but its relative availability depends on the other AAs present. Large neutral AAs that may affect accessibility of tryptophan include phenylalanine (an AA and neurotransmitter thought to affect affiliative social behavior), leucine, isoleucine, valine, and tyrosine (a precursor in the synthesis of dopamine and NE [tyrosine → dihydroxyphenylalanine → dopamine → NE]). High-protein meals generally increase tyrosine concentrations in the brain but decrease concentrations of tryptophan (Bosch et al., 2007; Leathwood, 1987). Whether increased protein—or supplementation using tryptophan itself—has an effect on the amount of serotonin produced in the neurons depends on how efficient the regulation of the synthesis and recycling components of central nervous system neurons is. Studies show that in normal/unstressed animals, tryptophan supplementation appears not to make a difference in behavior. Even in some forms of stress-related behavior, no effect of supplementation has been seen (Bosch et al., 2007). When some effects of tryptophan supplementation are found, they tend to be non-specific (e.g., less exploratory behavior). If exploratory behavior decreases, but activity does not (as has been the case in many studies), there may have been a change in the form of anxiety measured, without affecting the amount of anxiety measured (Janczak et al., 2003). Clients attempting supplementation should be aware of this finding because a change in the way the anxiety is shown or conveyed may not be an improvement from the dog’s or cat’s perspective. In the published studies focusing on combined tryptophan and protein supplementation in dogs, the effects noted may be non-specific effects of changes in locomotor behavior and not qualitative shifts in the behaviors about which people are usually concerned (DeNapoli et al., 2000; Dodman et al., 1996). For example, if an aggressive dog moves around more on one diet than another, we may have altered the probability that he will encounter a stimulus that will encourage his aggression, rather than altering the aggressive response itself. Clients should be aware that although altering the probability of encountering provocative situations may be helpful, supplementation does not seem to affect the actual behaviors once the dog reacts. One rigorous study that demonstrated an increase in plasma tryptophan by 2.6 times with supplementation failed to show behavioral changes attributable to this treatment in privately owned, mildly anxious pet dogs over the 8 weeks of the study (Bosch et al., 2009). In this study, plasma tryptophan levels were increased by 37.4%, and the tryptophan ratio with large neutral AAs was increased by 32.2%, levels theoretically sufficient to engender a possible effect. The best evidence for the effect of tryptophan for modulating non-specific aggressive responses via serotonin metabolism may come from experimentally induced tryptophan depletion. In studies where tryptophan is “depleted” (an artificial and incredibly difficult situation to produce), rodents and humans become “aggressive” in situations in which they otherwise would have been non-reactive (Bell et al., 2011). This extreme laboratory result may have limited application to the real world. Metabolism of tryptophan is also informative when considering supplementation. Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) degrade tryptophan. IDO is responsible for converting tryptophan into kynurenine. TDO is specific to the liver and regulates circulating levels of tryptophan (Turner et al., 2006). Both IDO and TDO are stimulated by pro-inflammatory cytokines, which make less tryptophan available for conversion into 5-HTP and serotonin. Corticoids also induce TDO (Salter and Pogson, 1985), lowering tryptophan levels, which is one possible mechanism for the adverse changes in behavior (e.g., greater reactivity) that can occur when some patients are treated with corticosteroids (Notari and Mills, 2011). Depressed human patients often can have increased cortisol levels (Porter et al., 2004) and so may have lowered serotonin levels as a result of the effect cortisol has on increasing TDO, which then lowers tryptophan, 5-HTP, and serotonin. Finally, at concentrations in excess of those found in normal physiology, tryptophan itself induces TDO and/or IDO, so increased dietary intake may not cause increases in either tryptophan or its derivative neurochemicals (Turner et al., 2006). Arachidonic acid (ARA), docosahexaenoic acid (DHA), and eicosahexaenoic acid (EHA) are long-chain polyunsaturated fatty acids (PUFAs) that are essential for developing and maintaining the integrity of cells of the brain’s membranes. These PUFAs are related by their synthetic sequence: linoleic acid (18 : 2n-6) < ARA (20 : 4n-6) < docosapentaenoic acid (22 : 5n-6). Elongation of alpha-linoleic acid produces eicosapentaenoic acid (EPA) (20 : 5n-3) < DHA (22 : 6n-3) (Bosch et al., 2007). DHA may encourage development stage–specific associational learning, although the data are mixed (Fahey et al., 2008). Supplementation with DHA and EPA affects concentration of these substances in rat brains, and their distribution is not uniform. Diets deficient in alpha-linoleic acid especially cause decreases of DHA in the frontal cortex—the part of the brain responsible for complex learning and integration of information and executive function. In dogs, low concentrations of DHA during gestation and/or lactation depress the retinal sensitivity of puppies, which can have profound and complex behavioral outcomes. The current data support the need for DHA for optimal neurological development in puppies, and there are hints that it may improve both early and long-term cognitive abilities, but the data are scant. It has been suggested that PUFAs are also important in some canine behavioral conditions. In one study of German shepherd dogs with a history of aggressive behavior, aggressive dogs showed a significantly lower concentration of DHA (22 : 6n-3) and a higher omega-6/omega-3 ratio compared with unaffected dogs (Re et al., 2008). Plasma concentrations of ARA (20 : 4 n-6) and EPA (20 : 5 n-3) did not differ. These same animals showed reduced levels of cholesterol compared with control dogs. Similar, non-specific findings regarding cholesterol have been reported for aggressive dogs (Sentürk and Yalçin, 2003). It is important to realize that the characterization of “aggression” in these studies is variable and that such correlations say nothing about cause. Such findings could be the outcome of aberrant neurochemical function. However, one of the main roles for PUFAs appears to be maintenance of membrane fluidity and protection from oxidative stress, especially in the part of the brain essential to associational learning, the hippocampus. Finally, in humans, the brain contains 600 g lipid/kg, with approximately equal amounts of ARA and DHA. It’s been postulated that a dietary intake of Rift Valley lake fish and shellfish comprising 6% to 12% protein provided sufficient DHA and ARA that allowed the early hominoid cerebral cortex to grow disproportionately larger without requiring an increase in body mass (Broadhurst et al., 1998). Any putative effects of these PUFAs on cognitive abilities are likely routed in this evolutionary history. PUFA levels in brains of young versus geriatric dogs, when measured, have not been shown to be different (Swanson et al., 2009), but effects of varying amounts in different regions of the brain (e.g., the hippocampus, which is key to learning, and the frontal cortex, which is involved in learning and is essential for executive function or application of that learning) in older animals have not been studied, the beneficial effects of ARA on membrane fluidity in the hippocampus notwithstanding. One of the major foci of age-related and illness-related changes is the effect of a cumulative burden of oxidative stress over time. Increased oxidative stress is one of the most common topics examined in brain aging, and it appears to affect all major classes of molecules involved in neurotransmission. Development of oxidative stress may not be independent of energy source or use (see section on energy sources, p. 464). Effects for enhancement are pronounced in the regions of the brain associated with making and consolidating associational memories—the hippocampus and the cerebral cortex. Anti-oxidants improve cognitive performance on memory tests for old dogs, but not young dogs (Cotman et al., 2002; Siwak et al., 2005). Data from the brains of both old dogs and old rodents show that dietary enhancements using anti-oxidants appear to work best when they are accompanied by cognitive enhancement that is an intensive part of the daily routine (Milgram et al., 2002, 2004; Nippak et al., 2007; Opii et al., 2008; Roudebush et al., 2005; Siwak et al., 2005; Wedekind et al., 2002). For young dogs, such enhancement may be ongoing because of their activity levels. As activity levels wane, old dogs may be more at risk for cognitive degeneration associated with a lack of stimulation of complex social tasks and problem solving. We overlook such effects all the time in patients, and part of routine exams should be to assess the cognitive stimulation and exercise available to the patient. Astrocytes are responsible for de novo synthesis of two neurotransmitters: glutamate and d-serine (Dienel and Cruz, 2006). Glutamate, the excitatory neurotransmitter that is responsible for an estimated 85% of synaptic activity, appears also to be essential in metabolic activity of the brain. Glutamate may be responsible for energy regulation by affecting neurovascular exchange (Magistretti, 2009). Glutamate has as its signaling targets the synapse, astrocytes, and intra-parenchymal capillaries. Glutamate also affects astrocytes, which are non-neuronal cells (Magistretti, 2009). Glutamate transporters appear to use the sodium gradient to facilitate glutamate uptake by astrocytes. More recent anatomical studies show that astrocytic processes ensheath intra-parenchymal capillaries and synapses and that many of these processes have receptors and reuptake sites for neurotransmitters. It is these findings that allow glutamate to act as a metabolic intermediary. In short, glutamate stimulates the conversion of glucose into lactate in astrocytes. Many pathways that affect glycolysis for brain energy are also adversely affected at some point by oxidative change. Many of these effects may be modulated by anti-oxidant or co-factor treatment, coupled with active behavioral interventions/enrichment. Alpha-enolase inter-converts 2-phosphoglycerate and phosphoenolpyruvate. Alpha-enolase has been shown to be altered in canine models of neurodegenerative disorders and responds to treatment with anti-oxidants, mitochondrial co-factors (lipoic acid), and behavioral/social/cognitive enrichment (Opii et al., 2008). Decreased oxidation of alpha-enolase and glyceraldehyde-3-phosphate dehydrogenase could improve glycolytic function, with a resultant increase in adenosine triphosphate (ATP) production. Together, these alterations appear to lead to neuronal recovery and improved cognitive function in the canine model of human brain aging (Opii et al., 2008). In a study of gene expression in brains of old dogs, the expression of genes involved in neurochemical signaling and synaptic transmission was decreased (Swanson et al., 2009). Particularly affected were levels of growth and transmission factors already discussed, including BDNF and trkB. These factors did not respond to anti-oxidant diet supplementation. In the same study, compounds such as glutathione S-transferase—responders to oxidative stress—were also decreased in geriatric dogs. Such findings show the ultimate inter-relatedness of available brain energy, neurotransmission, and neuroregulator function and structural changes in aging dogs. Glucose is considered the common brain energy currency, but it is not stored. The stored form of glucose is glycogen. Glycogen is found mainly in astrocytes, and the amount of glycogen available is affected by glucose concentration and neurotransmitter presence and function (Brown and Ransom, 2007; Pellerin et al., 2007). During hypoglycemia, glycogen is converted to lactate via pyruvate (glucose → pyruvate → lactate). The lactate is transferred to adjacent neurons. This conversion and transfer allow the neurons to use a source of aerobic fuel. Glycolysis can also be anaerobic and is faster at producing energy than oxidative phosphorylation (Raichle and Minton, 2006). In fact, glycolysis makes pyruvate faster than it can be oxidized: by converting glucose to lactate, ATP is made twice as fast than would be the case were glucose oxidized completely. The use of lactate in hypoglycemic events can extend axon functions for 20 minutes or longer (Pellerin et al., 2007). This conversion of astrocyte glycogen to lactate also occurs during periods of intense neural activity, demonstrating the role of astrocytes as bankers of energy-conversion compounds. After glucose, lactate is the preferred energy source for the human brain (van Hall et al., 2009), and there is no reason to assume that this may not also be an important pattern in dogs. Most lactate used as an energy source is thought to come from glycogenic processes because most lactate is too large a molecule to pass through the BBB. However, blood lactate has been measured in oxidized form and may be a source of some energy for brain tissue. Some astrocytes appear to “prefer” to process glucose glycolytically into lactate (Magistretti, 2009). Lactate can then be converted into pyruvate and enter the tricarboxylic acid cycle, providing energy in the form of ATP. Ketone bodies and fatty acids have been proposed as alternative energy sources because of their modulating effects on hypoglycemia. 8-Hydroxybutyrate (8-OHB), in particular, may be useful for protecting hippocampal neurons from toxicity (Reger et al., 2004). A placebo-controlled, double-blind study found that patients with Alzheimer disease with mild impairment who were supplemented with medium-chain triglycerides (MCT) showed improvement in a number of pre-treatment versus post-treatment cognitive test measures and that such improvement correlated with 8-OHB increases. It should be noted that this result depended on the apolipoprotein E (APOE) genotype: only patients without an APOE-epsilon4 allele responded to acute elevation of 8-OHB. Assessment of genetic risk factors has not been pursued in dogs, which, because of the presence of breeds, may be rich sources for such information. Fatty acid oxidation in the brain has been studied in rats using nuclear magnetic resonance spectroscopy (NMRS). One of the MCTs, octanoate, is thought to constitute up to 13% of the free fatty acid pool in humans. Because it readily crosses the BBB, it has been studied in a variety of clinical and experimental settings. In a labeling study in rats subjected to NMRS, octanoate could contribute 20% of brain energy in an intact, physiological system (Ebert et al., 2003). The mechanism for this change in brain energy balance was likely incorporation into both glucose and ketones and secondary effects on the metabolism of the excitatory neurotransmitter, glutamate. In a study of eight beagles (four in a control group and four in a treatment group) 9 to 11 years of age, supplementation with MCT at a dosage of 2 g/kg/day resulted in improved mitochondrial function, which was most pronounced in the parietal lobe (Studzinski et al., 2008). Steady-state levels of amyloid precursor protein also decreased in the parietal lobe after short-term supplementation leading the authors to conclude that short-term MCT supplementation can improve brain energy metabolism and decrease amyloid precursor protein levels in old dogs. The nutritional supplement Aktivait (VetPlus Ltd; available online but not in the United States) contains a number of anti-oxidants and free radical scavengers. The listed components are N-acetyl cysteine, alpha-lipoic acid, vitamins C and E, l-carnitine, co-enzyme Q10, phosphatidylserine, selenium, DHA, and EPA. The supplement Senilife (CEVA/Sanofe) contains phosphatidylserine and Ginkgo biloba. Phosphatidylserine appears to be important for neuronal membrane stability and function (Osella et al., 2008) and has been shown to improve learning and memory test outcomes in rodents in a dose-dependent manner (Suzuki et al., 2001) and in aged beagles (Araujo et al., 2008). In one trial of Aktivait involving 24 control dogs and 20 dogs who met the inclusion criteria for cognitive dysfunction syndrome (the dogs had to be >8 years of age and show some signs of disorientation associated with signs of either alterations in social interaction or changes in sleep/wake cycle or alterations in house soiling incidents), there was a significant difference between placebo and treatment groups. The largest effects were found for improvement in disorientation, interaction, and house soiling scores (Heath et al., 2007). Trials of individual components must be interpreted cautiously. In one study that supplemented acetyl-l-carnitine and alpha-lipoic acid, a decrease in the number of errors for learning a new task was noted, but there was no effect for variable delay versions of standard spatial memory tasks in laboratory dogs (Milgram et al., 2005). Tests of single or paired components of supplements for spatial learning have been disappointing (Christie et al., 2010), so the mechanism by which supplements may work is still unclear. What is clear is that the best effects of anti-oxidant diets and supplements is found when they are given to patients who also have increased physical and cognitive exercise (Cotman et al., 2007; Fahnestock et al., 2012; Head et al., 2009; Siwak-Tapp et al., 2008) suggesting that inflammation and components in the inflammatory cascade may also be involved in brain aging (Cotman et al., 2007). Similar to humans and rodents, old dogs show increased expression of genes associated with inflammation and stress response and decreased expression of genes associated with neuropeptide signaling and synaptic transmission (Swanson et al., 2009). We should expect dietary interventions and supplements to address and test relevant interventions that could affect inflammation and expression of genes involved in inflammatory/stress responses in a preventive manner. Melatonin is often offered as a “safe,” over-the-counter alternative to behavioral medications. Melatonin (N-acetyl-5-methoxytryptamine) is synthesized from serotonin in the pineal gland, which is largely responsible for diurnal hormonal and physiological responses associated with sleep-wake cycles. Melatonin has been shown to inhibit TDO competitively (Turner et al., 2006) and, independent of its effects on TDO, may stimulate pro-inflammatory cytokines. Both of these effects of melatonin ultimately lead to a decrease in the biosynthesis of 5-HTP and serotonin. Melatonin is also an anti-oxidant that easily crosses the BBB, and it may act as a ROS scavenger. It also appears to prohibit the organization of β-amyloid into neurofibrillary tangles, but clinical data are lacking. 5-HTP is an over-the-counter supplement that readily crosses the BBB and is converted to serotonin. It has a relatively short half-life (approximately 4 hours) and an even shorter time to maximum concentration (1 to 2 hours) in humans, times that are likely to be similar or less in dogs. Because 5-HTP is so readily available to be converted to serotonin, serotonin syndrome is a risk, and serotonin syndrome has been reported in rodents at dosages of 5-HTP of 100 to 200 mg/kg (Turner et al., 2006). The signs seen in rodents were potentiated by concomitant administration of SSRIs. 5-HTP has not been shown to lead to serotonin syndrome in humans, even when combined with TCAs and SSRIs in reasonable dosages, and it has been hypothesized to be efficacious alone or in combination with other medications in the treatment of human depression (Turner et al., 2006). • Calmex (VetPlus), which contains a combination of l-theanine, l-tryptophan, an array of B vitamins, and Piper methysticum. Alpha-casozepine, an alpha casein derivative, has been used to treat non-specific anxiety in cats and dogs (Beata et al., 2007a, 2007b). Alpha-casozepine is similar in structure to gamma-aminobutyric acid (GABA) and has an affinity for GABA-A receptors (Beata et al., 2007a). In a blinded, controlled study, dogs with a variety of anxiety-related conditions improved when treated with alpha-casozepine to the same extent as dogs treated with selegiline using a standardized, scored assessment (the Emotional Disorders Evaluation in Dogs [EDED] scale) (Beata et al., 2007b). However, the conditions varied considerably, and outcomes were based on client scores, so it is likely that this study could be replicated or that a placebo effect of simply participating in a study could be ruled out. Palestrini et al. (2010) conducted a placebo-controlled, double-blind study on the effects of a diet containing caseinate hydrolysate using both behavioral and physiological assays in anxious and non-anxious laboratory beagles. Anxiety scores were not affected by diet, and behavioral scores were only mildly affected. A large and statistically significant effect was found for decreased cortisol for anxious dogs fed the diet with caseinate hydrolysate, suggesting that such diets may play some role in alleviating some aspects of distress. Alpha-casozepine is also one of the main ingredients in the CALM Diet (Royal Canin). This diet, which also contains an anti-oxidant complex of vitamin E, vitamin C, taurine, and lutein, is intended to be fed to a dog 10 days before an expected stressful procedure and then for an additional 2 to 3 months. Kato et al. (2012) examined the effect of the CALM Diet compared with a control diet (both with approximately 25% protein) on behavior and urinary cortisol creatinine ratios (UCCR) in anxious pet dogs. They found a small but statistically significant effect on UCCR for the dogs eating the CALM Diet. UCCR increased less in response to a stressor in the dogs fed the CALM Diet than in dogs fed a control diet, but this effect could have been confounded by the casozepine or slightly higher fat and protein (in g/kg) in the CALM Diet. Also, the study design used did not control for effects of habituation, a common design concern in many behavioral studies. An additional confounding factor in determining effects of such therapeutic diets is that of determining the effect of dosage. Animals vary in size and intake and if fed other foods may experience effects such as those of large neutral AAs on tryptophan. Harmonease (Veterinary Products Laboratories) is a “natural proprietary blend of a patented extract of Magnolia officinalis and a proprietary extract of Phellodendron amurense” (www.vpl.com/literature/pdfs/Harmonease_NewProductVet_DM_300503660_08-2057.pdf; last accessed October 8, 2011). These compounds have been reported to decrease mild, transient stress (Kalman et al., 2008), and the derivatives honokiol and magnolol from Magnolia have been shown to have in vitro GABAA modulation capability (Kuribara et al., 1998, 1999). In one cross-over study of laboratory beagles who were mildly reactive to recordings of storms but who did not show clinical signs of noise phobia, there was a mild but significant effect of Harmonease on activity level (De Porter et al., 2012). l-Theanine (Anxitane; Virbac Animal Health) is the levorotatory isomer of theanine. It is naturally occurring in the tea plant and thought to lessen some stress conditions and mild anxiety-related problems in pets (Araujo et al., 2010; Kimura et al., 2007). l-Theanine is an analogue of glutamic acid. As such, it may inhibit reuptake of glutamate by the glutamate transporter (Sadzuka et al., 2001) and so increase GABA concentrations. Because high glutamate levels have been associated with neurocytotoxicity, l-theanine may also have a neuroprotectant effect and may modulate any neurotransmitters that interact with glutamate receptor subtypes (e.g., serotonin, dopamine). As with most nutraceuticals, side effects are inapparent even at dosages in excess of the recommended dose (www.virbacvet.com/images/resources/other/anxitane; last accessed October 8, 2011). The supplements discussed and some prescription diets (e.g., Hill’s B/D) contain bioactive compounds that may act as precursors or enhancers for some neurochemicals. Although side effects are rare, attention should be paid when also treating these patients with medication. No dosage adjustments will be necessary in most cases but we should be mindful of what we do not know. The recommended amounts of supplements/nutraceuticals for cats and dogs are presented in Table 10-3. TABLE 10-3 Recommended Amounts of Supplements/Nutraceuticals to Administer Based on Manufacturer Information
Pharmacological Approaches to Changing Behavior and Neurochemistry
Roles for Diet, Supplements, Nutraceuticals, and Medication
Overview of Diet and Behavior
Substance
Presumptive Effect
Acetate
Brain energy source
Alpha-lipoic acid
Free radical scavenger and co-factor for mitochondrial respiratory chain enzymes (redox reactions that would recycle other anti-oxidants and increase glutathione)
Arachidonic acid
Essential fatty acid; maintains hippocampal cell membrane fluidity and protects from oxidative stress
Carotenoids (alpha-, beta-, and cys-beta-carotene, lutein, zeaxanthine, alpha-cryptoxanthine, lycopene, cis-lycopene)
Anti-oxidant and generalized neuroprotective agents
Chondroitin sulfate
Chondroprotective agents
Cod liver oil
Anti-oxidant and neuroprotective agent
Co-enzyme Q/co-enzyme Q10
Provides cellular energy by generating it on the inner mitochondrial membrane
d-Alpha-tocopherol (vitamin E)
Anti-oxidant and neuroprotective agent (“natural” form)
Docosahexaenoic acid
Long-chain polyunsaturated fatty acid integral to brain membrane development and integrity and to neurodevelopment; may have direct effect on learning ability, especially during development; essential for the development of the brain and retina in dogs
Eicosapentaenoic acid
Long-chain polyunsaturated fatty acid integral to brain membrane development and integrity and to neurodevelopment
Essential fatty acids
Examples: docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid
Ginkgo biloba
Anti-oxidant with postulated cerebrovascular metabolism effects
Glutamate
Brain energy source and excitatory amino acid that is responsible for much neuron-neuron communication
Insulin-like growth factor-I
Control of brain energy expenditure and neuronal plasticity with concomitant neuroprotective effects
l-Carnitine
Precursor to acetyl-l-carnitine involved in mitochondrial function
l-Theanine (5-N-ethyl-l-glutamine)
Psychoactive agent that appears to affect GABA synthesis; may affect other neurochemicals
Long-chain polyunsaturated fatty acids
Anti-oxidant and neuroprotective agents
N-acetyl cysteine—precursor to glutathione
Free radical/reactive oxygen species scavenger
Phosphatidylserine
Constituent of neuronal membranes that affects plasma membrane functionality
Pyroxidine (vitamin B6)
Co-enzyme for neurotransmitters including serotonin
Resveratrol (polyphenolic compound from grape skins)
Free radical scavenger
Salmon oil
Omega fatty acids
Selenium
Trace element with neuroprotective properties
Tryptophan
Precursor neurochemical
Vitamin C
Free radical scavenger and required for maintaining oxidative protection in soluble cell phases
Potential Roles for the Most Common Dietary Compounds and Supplements
Precursor Neurochemicals That Possibly Affect Behaviors Associated with Specific Neurochemicals
Precursor Amino Acids
Neurotransmitter Pathway Effects
Tryptophan
tryptophan → 5-HTP → serotonin → melatonin
tryptophan →5-HTP→serotonin→5-HIAA
tryptophan → N′-formylkynurenine → kynurenine → 2-amino-3-(3-oxoprop-1-enyl)-fumaric acid → quinolinate → niacin (vitamin B3)
Tyrosine
phenylalanine → tyrosine → DOPA → dopamine → norepinephrine → epinephrine
Phenylalanine
phenylalanine → tyrosine → DOPA → dopamine → norepinephrine → epinephrine
Relative Availability of Tryptophan
Extent of Protein Binding in Serum
Structure of Neuronal Membranes and Potential Roles for Supplements and Diet
Nutritional Redress of Oxidative Stress
Emerging Role for Brain Energy in Cognitive Function in Dogs
Lactate
Medium-Chain Triglycerides
Supplements
Melatonin
5-Hydroxy-L-tryptophan
Nutraceuticals
Supplement/Nutraceutical
Dosage/Recommended Capsule Size/Frequency
Aktivait
Cats: 1 tablet daily (DHA/EPA 35 mg; no alpha-lipoic acid)
Small dog breeds (<10 kg), 1 tablet daily (DHA/EPA 35 mg)
Large dog breeds: <20 kg, 1 tablet daily; >20 kg, 2 tablets daily (DHA/EPA 35 mg)
Senilife
Regular: Cats and dogs up to 30 lb, 1 capsule; 31-50 lb, 2 capsules
Senilife XL: Dogs >50 lb, 51-99 lb, 1 capsule; ≥100 lb, 2 capsules
NOVIFIT
S—for dogs ≤22 lb and cats
M—for dogs 22.1-44 lb
L—for dogs 44.1-88 lb
Zylkene
Cats and small dogs: 75 mg once daily
Medium-sized dogs: 10-20 kg, 225 mg once daily
Large dogs: 20-40 kg, 450 mg once daily; >40 kg, twice daily
Anxitane
50-mg tablets (S) for dogs and cats ≤22 lb
100-mg tablets (M and L) for dogs >22 lb
Harmonease
500-mg tablets of extracts of M. officinalis and P. amurense: for dogs ≤50 lb, ½ tablet daily; for dogs >50 lb, 1 tablet daily
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