Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 7 • November 2012


Hypothesis

Activation of Cholinergic Nervous System May Promote Satiety by Signaling the End of a Meal

A new paper1 proposes that activation of cholinergic interneurons in the nucleus accumbens (NAc) and cholinergic projections to the ventral tegmental area affect feeding behavior. “In vivo microdialysis studies in rats have revealed that the cessation of a meal is associated with a rise in acetylcholine (ACh) levels in the NAc.” Moreover, the researchers note. ACh activation will suppress feeding, and this is also associated with an increase in synaptic accumulation of ACh.”1

The paper also discusses the relationship between cholinergic activity and drug addiction and withdrawal. “Studies reveal that accumbens ACh is increased during withdrawal from several different drugs of abuse (including cocaine, nicotine and morphine). This rise in extracellular ACh, coupled with a decrease in extracellular levels of DA [dopamine] is believed to contribute to an aversive state, which can manifest as behaviors associated with drug withdrawal.” The authors suggest that these changes, observed both in the cessation of feeding and in drug withdrawal, may point to a form of “food addiction” and “withdrawal” from overeating.1

Acetylcholine participates in the regulatory pathways of many behaviors, including (for example) learning and memory and muscular contraction. Particularly interesting is, as the authors explain, that “two major ACh projections innervate key components of the reward system.” The authors then propose that these projections may play a key role in the reward of drug addiction as well as in the promotion of either satiety or appetite, depending upon their specific co-transmitters.

As explained above, the rise in extracellular ACh, coupled with a decrease in extracellular levels of dopamine (DA) are part of the regulatory pathway that is observed both in the cessation of feeding and in drug withdrawal. The rewarding signal at the start of a meal that stimulates eating includes increased DA: “The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity.”2 The researchers found in their study2 that there was a blunted dopaminergic response to food which, they surmise. implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.” Unfortunately, the latter study did not include examining the effects of acetylcholine.

In another paper,3 researchers reported that “[o]ur recent data suggest that one such interaction is the regulation of ACh of DA synapse signalling of reward-related activity.” This comment was in relation to interactions between ACh and DA in the striatum in motor response selection, particularly in reward-related learning of stimulus-response associations or habits, acquired through positive reinforcement. “… striatal ACh neuron activity and ACh release are inhibited by DA.”3 This cross-talk between striatal ACh and DA in reward-related motor activity would be consistent with another appetitive activity (meal cessation) associated with ACh increase and DA decrease in the striatum.

As noted earlier, microdialysis studies have shown that there is an increase in extracellular ACh in the NAc at the end of a meal. 1 “Further support for the theory that increased extracellular levels of accumbens ACh are associated with the cessation of feeding comes from data showing that when rats binge eat sugar while at a reduced body weight, or when they are sham fed* sucrose using a gastric cannula, accumbens ACh is blunted.” Thus, the authors hypothesize. in situations in which it would be physiologically advantageous for the animal to continue to eat, such as when they are underweight or not retaining the food that is consumed, ACh levels in the NAc are not increased.”1


* The sham feeding of sucrose through a gastric cannula means the animals are fitted with a gastric cannula, but do not receive sucrose. That way, there is no confounding effect in the interpretation of the effects of sucrose feeding as compared to placebo by possible effects induced by receiving — or not receiving — a gastric cannula. The goal in experiments is to change only the variable you are studying and to keep everything else the same.


“Other studies suggest that food intake can be promoted by depleting ACh via local injection of the selective cholinergic neurotoxin ethylcholine azirdinium mustard (AF64A) into the NAc. In an acute (1 wk.) feeding test, rats that were given this lesion showed a 2-fold increase in food intake.”1 (There was, however, a significant and lasting lag in body weight gain in these animals, which the authors of paper #1 suggest may point to a compensatory mechanism when cholinergic function is ablated.) Nicotine-induced decreases in eating by mice may be, as suggested by recent studies, due to the activation of nicotinic cholinergic receptors in the hypothalamus, which activates pro-opiomelanocortin neurons leading to the activation of melanocortin 4 receptors critical for nicotine-induced decreases in food intake in mice.1

In the mouse neurotoxin study mentioned in the paragraph above, 1B the researchers noted that their study’s data showed an increase in food and water intake after cholinotoxic lesions (which decreased the number of ACh interneurons and, hence, reduced their inhibitory influence on eating. “Recently, it has been suggested that NAcc [also referred to as NAc] ACh has a unique role in stopping behavior.”1B The latter refers to such stopping effects as when experimental animals discontinue eating when ACh increases in response to exposure to a noxious flavor.

In comparing the biochemical pathways that involve the cholinergic nervous system in both drug or food withdrawal, the authors of paper #1 suggest: “Thus, rats in withdrawal from palatable food appear to show the profile of ACh in the NAc that has been seen in withdrawal from drugs of abuse.”

The researchers conclude that “increased levels of ACh in the NAc act to promote satiety.”1

In a 2011 paper,4 researchers examined cholinergic function in the regulation of reward, noting that “[m]ore than three decades of research into the neurobiological substrates of reward have focused attention on the nucleus accumbens (NAc) …” “The preponderance of this research effort has centered on dopamine (DA) as the primary neurotransmitter in this regard.” “Studies by Hoebel and colleagues have demonstrated increases in the release of DA in the NAc as a function of a variety of behaviors including feeding, rehydration, models of binge eating, and hypothalamic stimulation.” The authors4 then point to the work of Hoebel and other scientists for contributing work that has brought about an increasing appreciation of the importance of the role of acetylcholine in the brain reward circuit.

As the authors of paper #4 indicate, the fact that dopamine (DA) plays a major role in the modulation of ingestive behavior is now well documented. They describe studies in hungry rats showing that “hungry rats stop feeding if the DA/ACh balance in the NAc is tilted in favor of excess cholinergic tone.” In one rat study, rats were implanted with bilateral microdialysis probes in the NAc and allowed to eat ad lib during their active period (night). When the probes implanted in the animals were perfused with neostigmine, an acetylcholinesterase inhibitor (which increases cholinergic activation), there was an almost complete discontinuation of eating, which did not happen in the control animals that received perfusion of standard Ringer’s solution. The animals treated with neostigmine continued to drink water, though, showing that the discontinuation of eating was not caused by malaise or immobility.

A 1998 paper5 was an early paper describing increased dopamine release combined with reduced acetylcholine release as a possible mechanism for hypothalamic initiation of feeding behavior. Using adult male Sprague-Dawley rats as subjects, animals received microinjections of the orexigenic (eating inducing) peptide galanin, neuropeptide Y, or saline into the hypothalamic paraventricular nucleus (PVN). The results showed that the injection of galanin in the PVN induced eating, causing the release of dopamine in the NAc and decreasing the release of ACh in the NAc. (The injection of neuropeptide Y also induced eating, but had no effect on either dopamine or acetylcholine.)

In a 2007 paper,6 researchers reviewed studies on the effects of the ACh/DA ratio on approach and avoidance. They examine several animal models of human behavior on meal satiation, taste aversion, escape from aversive brain stimulation, depression, drug withdrawal, and sugar withdrawal (following binge eating of sugar). They explain that in their own work, they tested the opposite effects of DA and ACh in the accumbens loop controlling motivation and some aspects of learning by injecting neurotransmitter agonists and antagonists into the NAc to reveal their effects on ACh/DA balance and observing animal behaviors. They also observed avoidance behaviors to see whether ACh is released in the NAc. “The evidence suggests that ACh inhibits the approach system via muscarinic M1 [cholinergic] receptors, and thereby counteracts the effects of DA at the D1 [dopaminergic] receptors.”6

One study they reviewed, for example, was the effect of a mildly distasteful (bitter) solution that, when drunk, triggered injection of a nutritious ingredient into the stomachs of the subject rats. Ordinarily, rats avoid bitter tasting substances, but in this case, as compared to their other choice, a bitter tasting solution that triggered only a water injection into the stomach, the animals soon developed a preference for the bitter tasting solution that delivered nutrition. The researchers found that squirting the (mildly) bitter flavor into an animal’s mouth (after it had developed a preference for its taste) resulted in the release of DA in the NAc, to which the authors attribute the approach behavior (the desire to eat). On the other hand, rats generally like sweet tastes, including that of sugar or saccharin. In a study where rats have developed an aversion to saccharin (because of pairing the saccharin with nausea) the taste significantly increases ACh release in the NAc, with the induction of avoidance (not wanting to eat).

The implications of these observations, that feeding behavior may be initiated by increased dopamine accompanied by decreased acetylcholine in the NAc and that feeding behavior may be terminated by decreased dopamine release accompanied by increased acetylcholine release, should they be affirmed in further studies (especially ones with human subjects), is that one may be able to induce the cessation of feeding by taking a cholinergic agonist (a substance like choline itself that increases acetylcholine synthesis and release) at an appropriate time at the start of a meal or slightly before starting the meal. Another possible way to get the increased cholinergic activity in the NAc is to take a cholinesterase inhibitor such as galantamine, that increases cholinergic activity by causing acetylcholine to remain in the neuronal synapse for a longer period of time. For example, a choline or galantamine (cholinesterase inhibitor) supplement an hour or two before meals might reduce food intake.

Assuming the hypothesis is correct, there are a couple of things to keep in mind when attempting to make practical use of the ACh/DA balance in regulating the intake of food:

  1. The TIMING of the increase in cholinergic neuronal activity in relation to the cessation of eating is likely to be important. That information may not be available from published data, particularly in light of individual variation in sensitivity to cholinergic agonists; hence, some self-experimentation using safe ways to increase cholinergic activity (such as supplemental choline or a cholinesterase inhibitor such as galantamine) will be required.
  2. A cholinergic agonist such as choline is going to be used throughout the body and brain, not just in the NAc, for the synthesis of acetylcholine so possible side effects of increased cholinergic activity, such as headache caused by excessive muscle tone, could occur that have nothing to do with the desired effect on eating and, indeed, probably nothing to do with the NAc, another reason that some experimentation would be required.
  3. We note that much of the experimental work resulting in published papers on the interaction of ACh and DA in reward and eating appears to have been done by the same group of researchers. We hope to see additional followup by other groups on the ACh/DA work.

    References

    1. Avena and Rada. Cholinergic modulation of food and drug satiety and withdrawal. Physiol Behav 106:332-6 (2012).
    1B. Hajnal et al. Accumbens cholinergic interneurons play a role in the regulation of body weight and metabolism. Physiol Behav 70:95-103 (2000).
    2. Stice et al. Relation between obesity and blunted striatal response to food is moderated by TaqlA A1 allele. Science 322:449-52 (2008).
    3. Cragg et al. Striatal acetylcholine control of reward-related dopamine signaling. ADV. IN BEHAV. BIOL. 56 (Basal ganglia VIII):99-107 (2005).
    4. Mark et al. Cholinergic modulation of mesolimbic dopame function and reward. Physiol Behav 104:76-81 (2011).
    5. Rada et al. Galanin in the hypothalamus raises dopamine and lowers acetylcholine release in the nucleus accumbens: a possible mechanism for hypothalamic initiation of feeding behavior. Brain Res 798:1-6 (1998).
    6. Hoebel et al. Accumbens dopamine-acetylcholine balance in approach and avoidance. Curr Opin Pharmacol 7:617-27 (2007).

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