Introduction

Octopamine is a trace amine, a class of molecules that naturally occur in both vertebrate and invertebrate species. Octopamine was first identified 50 years ago in the octopus [1], and while the biological role it plays in many invertebrate species is well established, the physiological role octopamine plays in mammals is not well known. Octopamine is derived from tyramine, another trace amine that is derived from tyrosine or from tyramine-containing food. Octopamine can also be further metabolized into synephrine via the enzyme pheylethanolamine N-methyltransferase [2]. In invertebrates, the role of octopamine is analogous to that of norepinephrine (NE) in vertebrates, and it is responsible for the "fight or flight" effect and fat mobilizing [1].

In mammals, octopamine exists in low concentrations in the central and sympethatic nervous systems [3]. The two isomers para-octopamine (p-octopamine) and meta-octopamine (m-octopamine) tend to be found together in the same tissues [4]. Levels of octopamine and other trace amines can become elevated in certain pathological states, and are also elevated by inhibition of monoamine oxidase (MAO) [2]. Until recently, the primary role of trace amines was assumed to be as "false neurotransmitters," as they can concentrate in nerve terminals containing neurotransmitters such as dopamine (DA), NE, and serotonin, thus changing receptor function or neurotransmitter uptake. However, a class of receptors called trace amine receptors (TARs) was recently discovered, but the relevance of these receptors has not yet been established [2]. Because of this, the known actions of octopamine on the better understood receptors will be the focus of this article.

Alpha adrenoceptors

Octopamine has numerous effects on the adrenergic system, as it shares structural and functional similarities with NE [5]. Octopamine can have effects that are both similar to and that oppose those of NE [3]. In vivo animal studies indicate that octopamine can stimulate both alpha- and beta-adrenoceptors [6]. Inhibition of MAO also amplifies the effect of octopamine [3].

In vitro, octopamine has alpha(1) agonist properties. Under certain conditions, p-Octopamine is a full alpha(1A) and partial alpha(1B) agonist, while m-octopamine is a partial alpha(1A) and full alpha(1B) agonist [7]. The alpha(1) agonist properties of octopamine appear to have little if any relevance in vivo [3, 8].

Octopamine also has alpha(2) agonist properties, with a greater effect at the alpha(2C) receptor [9]. The m- isomer appears to be the active one in this case, while p-octopamine is devoid of activity at alpha(2)-adrenoceptors under physiological conditions [5, 8]. In vitro, the alpha(2) agonist properties have been established in Chinese hamster ovary cells transfected with human alpha(2)-adrenoceptors, Syrian hamster adipocytes, and human adipocytes [10]. However, the effects of octopamine at alpha(2)-adrenoceptors do not parallel those of catecholamines [9]. Whereas epinephrine inhibits lipolysis in human adipocytes via alpha(2) agonism, octopamine does not share this effect, and it causes only a weak antilipolytic response in Syrian hamster adipocytes [10]. However, the alpha(2) agonist properties of octopamine may be relevant in vivo, as administration of octopamine to chicks and other animals significantly increases food intake, an effect which can be prevented by administration of the alpha(2) antagonist yohimbine [3, 8].

Beta adrenoceptors

Although octopamine may have some beta(2) agonist properties [5], the majority of the literature reports that it is a highly selective beta(3) agonist [10-12]. This is based primarily on in vitro studies. Octopamine has the highest lipolytic potency in tissues of animals such as hibernators, which have high sensitivity to beta(3) agonists. In rat fat cells, octopamine reduced insulin-dependent glucose transport, a property common in beta(3) agonists [10]. In human fat cells, the response to beta(3) agonists is limited compared to other animals, and studies with octopamine find it to have little or no effect in human adipocytes [5, 10]. On the other hand, this may not necessarily reflect the effectiveness of beta(3) agonists in vivo, as beta(3) agonism can change the functional characteristics of fat cells with chronic treatment, resulting in a greater rate of lipolysis [13]. In humans, administration of beta(3) antagonists can result in hyperlipidaemia [14]. Also, other selective beta(3) agonists cause lipolysis in human white fat cells [13].

With octopamine specifically, other effects may confound the picture. Octopamine is readily destroyed by MAO and SSAO, which are present in fat cells [5, 10]. This is also the case with NE [10], but this is also lipolytic through multiple mechanisms other than beta(3) activation. The oxidation of octopamine by these enzymes results in the production of hydrogen peroxide, which in turn results in increased glucose uptake by fat cells. So, while octopamine can cause lipolysis in tissues where beta(3) receptors play a major role, in human adipose tissue the effects of these two competing factors basically cancel each other out [5].

Dopamine & acetylcholine

Octopamine may have effects outside of the adrenergic system in mammals, primarily related to the dopaminergic system. Octopamine is a selective antagonist at the D1 receptor [15-16]. It also inhibits reuptake in vitro, leading to higher concentrations of dopamine [17-18]. In turn, one of these effects may be responsible for the reduction of prolactin secretion seen with octopamine [18]. There is also a report of octopamine decreasing acetylcholine release by rat peripheral nerves. This effect seems to be downward of the effects at alpha(2) and/or D1 receptors [19].

Practical implications

There are few studies on the responses to octopamine supplementation in vivo. Other than those finding increased food intake mentioned above, animal studies indicate that octopamine increases blood pressure, locomotor activity, and may have an antidepressant effect (although this is commonly loosely defined) [5, 20-21]. Octopamine has reportedly been used to treat low blood pressure in humans [22].

Whether or not octopamine will lead to fat loss is still up in the air. There is evidence for a possible weak lipolytic effect on balance from beta(3) agonism. However, there are also studies indicating that it increases food intake via alpha(2) agonism, which would not be helpful on a diet. Although the in vitro studies would indicate otherwise, an antilipolytic effect from alpha(2) agonism cannot be ruled out, especially in tissues with high amounts of alpha(2) receptors. It is possible that these effects may be partly prevented by taking yohimbine and potent antioxidants. However, if one is looking for a beta(3) agonist, ephedrine is a much better choice, as it has been shown to cause fat loss (especially when coadministered with caffeine) in numerous clinical trials. Ephedrine can also directly or indirectly (via release of NE) stimulate other adrenoceptors.

In addition to the problems above, octopamine has low oral bioavailability. Not only is it readily broken down by MAOI, it is extensively metabolized by the gut wall [23]. This does not mean it is completely ineffective orally, only that large doses are required for an effect (probably much larger than those found in most supplements). In conclusion, there are reasons for and against octopamine use which could only be fully resolved by further research in humans. There are other agents that are preferable to octopamine.

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