Both undernutrition and overnutrition in preweaning rats result in long-lasting functional changes in the brain. The effects of protein undernutrition on behavior, brain development, and intellectual function are well known. Unfortunately, there are far fewer studies on the effect of long-term excess consumption of any macronutrient, particularly protein, on the brain. Some reported studies on the effect of protein overnutrition on behavior are not rigorous in design and data analysis. For example, it has been reported that adult rats consuming a high-protein diet become more easily frightened and "snappish". A few years ago, some scientists undertook a series of studies to evaluate the effect of long-term (20-36 weeks) consumption of isocaloric high (50% of total calories; HP)-, moderate (20% of total calories; MP)-, and low-protein (5% of total calories; LP) diets on a variety of behavioral measures. These included the adhesive patch test and negative geotaxis commonly used to evaluate sensorimotor function, locomotor activity and stereotypy as measures of ambulatory and searching behavior, the tail-flick test for nociception, and the elevated plus-maze test as a measure of anxiety and aversive behavior. The HP group was more responsive compared with the MP or LP groups in sensorimotor function, negative geotaxis, and spontaneous locomotor activity. In addition, the HP group exhibited reduced aversion as measured by the elevated plus-maze test of anxiety and hyperalgesia as shown by tail-flick reaction time. These data suggested that long-term consumption of an HP diet may lead to hyperactivity and hyper responsiveness to the environment, a change that may not always be desirable. In a separate study, there were scientists who examined whether the HP diet had any effect on learning, memory, and sensory discrimination. The results of these studies showed the following: in the swim cylinder of Porsolt, which tests adaptation to stress, HP rats were significantly less able than was the control group (MP rats) to develop an effective coping strategy; during the recording of auditory-evoked responses to deviant tones, short-term auditory memory traces degraded more quickly in the HP rats, and finally, in the Morris water maze, diet had no significant effect on acquisition and recall of spatial information. These data suggest that a long-term HP diet may precipitate a deficit in short-term but not long-term memory and a diminution in the ability to cope with acute stress.

A review of the literature indicates that a number of food constituents (e.g., dietary macronutrients and neurotransmitter amino acid precursors) as well as food deprivation may modulate development of tolerance and physical dependence and influence self-administration of several drugs of abuse in animals. In an effort to examine further the nature of neuronal changes responsible for perturbation of spontaneous unprovoked motor behavior in animals consuming the HP diet, was examined that the sensitivity of HP, MP, and LP mice to a variety of neurotropic agents such as amphetamine, apomorphine, haloperidol, etc. The following is a summary of some of the studies that have been done amphetamine. Adult ICR mice were put on HP, MP, or LP diets for 35 weeks. At the end of this period, all mice were tested for spontaneous locomotor activity (SLA) and stereotypic behavior (SB) after administration of vehicle or amphetamine (0.1 or 1.0 mg/kg). Both SLA and SB, in the absence of amphetamine, increased with increasing levels of protein in the diet (49). Mice on the LP but not the MP or HP diets increased SLA and SB on low-dose (0.1 mg/kg) amphetamine. Mice on HP but not LP or MP diets, however, failed to respond to high-dose amphetamine (1 mg/kg). These data suggest that long-term consumption of an HP diet not only may lead to hyperactivity and hyper responsiveness to the environment but may attenuate neuronal sensitivity to amphetamine and possibly other drugs of abuse. It is generally accepted that amphetamine-induced locomotion is mediated by mesolimbic DAergic neurons, whereas stereotypy is associated with nigrostriatal neurons. Furthermore, there is abundant evidence that DA alone is largely responsible for the effect of amphetamine on SLA and SB. Therefore, it seems that a long-term HP diet may modulate multiple DAergic pathways in the brain; it is not clear how the HP diet may affect other neuronal systems. To gain further insight into the effect of dietary protein on the neurochemical make-up of the brain, there were examinations done on the distribution of DA, DA-metabolites (dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)), norepinephrine (NE), serotonin (5-HT), and 5-hydroxyindolacetic acid (5-HIAA) in the brains of rats consuming LP, MP, and HP diets for 36 weeks. Here I discuss only the data on DA and its metabolites.

In the substantia nigra, the striatum, and the dentate gyrus, DA levels decreased and increased, respectively, with a decrease and increase in dietary protein (P<0.05 compared with the MP diet) (50). The nigrostriatal system is important to a number of behaviors related to sensorimotor integration and response initiation, including extrapyramidal movement, aphagia and adipsia, emesis, and stereotypy (51-55). Our behavioral studies have shown that the HP diet produces hyperactivity. These neurochemical data suggest that an increase in DA in the nigrostriatal system may contribute to behavioral hyperactivity in HP rats. In the mesolimbic system, dietary manipulation had the most marked effect on DA metabolism. There was a diminution in amygdala DOPAC/DA and HVA/DA ratios in the rats on the HP diet, suggesting a decrease in the firing of DAergic neurons in this region. DA transmission in this region is implicated in emotion, sexual behavior, and the reward properties of many drugs of abuse. Therefore, it is conceivable that reduced sensitivity to SLA and SB after amphetamine administration to HP rats may be related to changes in DA metabolism.

In addition to its neurochemical and behavioral effects, the level of protein in the diet has also been shown to have a profound effect on food intake, body weight, and body composition. For example, White et al. have recently shown that rats given a low-protein (5%) diet for only 11 days, compared with those on a 20%-protein diet, increased NPY gene expression in the hypothalamus, resulting in augmented caloric intake. In rats on 5% protein, while their average daily food intake was increased by 20%, their body weight gain was severely attenuated, and body composition analysis revealed increased water retention, decreased body protein, and increased body fat. While these studies underscore the effect of a low-protein diet-mediated increase in NPY gene expression on appetite, other behavioral consequences associated with increased NPY remain to be elucidated.

By TTS Cofounder Botanical Chef Omid Jaffari