Ecology and neurobiology of toxin avoidance and the paradox of drug reward

Abstract

Current neurobiological theory of drug use is based on the observation that all addictive drugs induce changes in activity of dopaminergic circuitry, interfering with reward processing, and thus enhancing drug seeking and consumption behaviors. Current theory of drug origins, in contrast, views almost all major drugs of abuse, including nicotine, cocaine and opiates, as plant neurotoxins that evolved to punish and deter herbivores. According to this latter view, plants should not have evolved compounds that reward or reinforce plant consumption. Mammals, in turn, should not have evolved reinforcement mechanisms easily triggered by toxic substances. Situated in an ecological context, therefore, drug reward is a paradox. In an attempt to resolve the paradox, we review the neurobiology of aversive learning and toxin avoidance and their relationships to appetitive learning. We seek to answer the question: why does aversive learning not prevent the repeated use of plant drugs? We conclude by proposing alternative models of drug seeking and use. Specifically, we suggest that humans, like other animals, might have evolved to counter-exploit plant neurotoxins.

Introduction

Almost all major recreational drugs, including caffeine, nicotine, delta-9-tetrahydrocannabinol (THC, the active ingredient in cannabis), cocaine, amphetamines, and heroin (but excepting alcohol) are plant neurotoxins or, in the case of several synthetic drugs, their close chemical analogs. (Neurotoxins are defined by their ability to cause structural damage or functional disturbance of nervous tissues upon application of relatively small amounts.) These drugs acquire their psychoactive effects by interfering with neuronal signaling in the CNS, for example by binding to neurotransmitter receptors, or interfering with neurotransmitter transport mechanisms (Wink, 2000). Many of the components of neuron signaling targeted by these toxins are ancient, and are found in most animals. For instance, the nicotinic acetylcholine receptor (nAChR), targeted by the neurotoxin nicotine, has an evolutionary history extending back about 1 billion years (Novere and Changeux, 1995). The nAChR mediates the CNS effects of nicotine by changing the levels of dopamine (DA), which is involved in reward processing. Crucial aspects of DA function, such as the dopaminergic neuromodulation of glutamatergic synapses, appear to be conserved across the eumetazoan clades (insects, vertebrates, mollusks, and nematodes) (Hills, 2006). The DA system is directly targeted by cocaine and, as we discuss later, is also heavily involved in the CNS effects of nicotine and other addictive drugs.

Here we show that the two scientific traditions specializing in the physiological effects of plant neurotoxins are largely incompatible. The first tradition comprises phytobiologists, ecologists, and pharmacologists studying plants, plant–herbivore interactions, and plant secondary compounds. According to this tradition, many secondary compounds evolved to deter herbivores.

The second tradition focuses on the neurobiology of drug use and addiction in humans. This tradition emphasizes the important role of DA in reward-related behavior and explains addiction as the result of drug interference with natural reward systems. According to neurobiologists, drugs such as nicotine, cocaine, opium, and THC activate neural circuits involved in reward processing, thus encouraging consumption. In seeming contradiction, plant biologists argue that such drugs evolved precisely because they successfully punished and deterred consumption. This apparent contradiction has been termed the paradox of drug reward (Sullivan and Hagen 2002, Sullivan et al 2008).

After describing the two perspectives in depth, we then take steps to address the paradox by reviewing the neurobiology of aversive learning and toxin avoidance and their relationships to appetitive learning. We seek an answer to the question: Why does aversive learning not prevent the repeated use of those plant neurotoxins commonly used as drugs? We examine the possibility that drug exposure is an evolutionary novelty, and we propose alternative “ultimate” models of drug seeking and use, according to which humans might have evolved to counter-exploit plant toxins in various ways.