Drugs of Abuse and the Neural Mechanisms of Reward

The positive reinforcement model proposes that addiction occurs due to the rewarding/euphoric effects of drugs. Is there a neural mechanism of reward that most or all drugs of abuse might be acting on to produce these effects? There does appear to be a neural “reward circuit,”as indicated by the eagerness with which laboratory animals and even humans will electrically stimulate specific parts of their brain if given the opportunity.This phenomenon of intracranial self-stimulation (ICSS) was first demonstrated many years ago by James Olds and has been extensively studied since then. One important kind of evidence for an interaction between drugs of abuse and the reward circuit concerns drug-induced changes in the threshold for ICSS.

Researchers can experimentally determine how much current must be delivered for the electrical stimulation to be reinforcing (that is, to promote an operant response such as lever pressing).The lower the threshold, the more sensitive is the reward circuit. As shown in the table, a variety of different abused drugs all reduce the threshold for ICSS when given acutely. Such results indicate that the underlying neural circuitry for drug reward overlaps with the circuitry for brain stimulation reward.On the other hand, withdrawal of animals from chronic treatment with these substances causes an increased ICSS threshold. A similar phenomenon occurring in a drug-dependent addict might contribute to the negative mood state and difficulty in experiencing pleasure that are often reported during withdrawal.

Another important link between abused drugs and reward mechanisms is provided by the neurotransmitter dopamine (DA).The mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens is an important component of the reward circuit. Moreover, the same drugs that acutely reduce the threshold for ICSS also increase synaptic DA levels in the accumbens, either by enhancing the firing of VTA neurons (opiates, nicotine, ethanol, and THC) or by stimulating DA release and/or inhibiting DA reuptake from the nerve terminals (psychostimulants). Finally, just as withdrawal from these drugs leads to decreased brain reward (as indicated by elevated thresholds for ICSS), it can also produce subnormal DA levels in the nucleus accumbens.

These findings suggest that the mesolimbic DA pathway plays a sig-nificant role in the reinforcing effects of many (perhaps most) drugs of abuse. Further discussion on this topic can be found in later  posts covering specific drugs or drug classes. Here, however, we would like to dispel two widely held ideas about DA that are not correct: first, that enhanced DA transmission in the nucleus accumbens is always required for drug reinforcement, and second, that DA in the accumbens directly produces feelings of pleasure (or, in animals, whatever is analogous to human pleasure).Concerning the first point, there are several ways of experimentally testing whether the mesolimbic DA pathway from the VTA to the nucleus accumbens is essential for drug reinforcement. One of the most direct tests is to lesion the dopaminergic nerve terminals in the accumbens with the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) and see whether this blocks drug selfadministration. For the psychostimulants cocaine and amphetamine, selfadministration is abolished by such lesions, lending strong support to the notion that accumbens DA is essential for the reinforcing effects of these compounds. In contrast, many other drugs including alcohol and heroin continue to be self-administered even after severe damage to the VTA-accumbens DA pathway.This does not rule out the possibility that DA release contributes to the reinforcing properties of these substances, but it does strongly argue that accumbens DA is not required for reinforcement by drugs other than cocaine and amphetamine.

The second idea of DA as the “pleasure neurotransmitter” has been even more pervasive, but it, too, is contradicted by various experimental findings. In one important set of studies carried out by Wolfram Schultz and his colleagues, the investigators recorded the firing of midbrain DA neurons (substantia nigra and VTA) in awake monkeys under different behavioral conditions (Schultz, 1998). These cells showed a burst of activity in response to a novel sensory stimulus or an unsignaled (unexpected) reward such as a food treat. Interestingly, if the reward was paired in a classical conditioning paradigm with a conditioned stimulus (CS) so that the CS reliably predicted the reward, DA cell firing came to be elicited by the CS rather than the reward itself.

Finally, if the conditioned monkeys were presented with the CS and then no reward followed, there was actually a depression in DA cell firing. According to Schultz, therefore, one function of DA neuronal firing is to signal the difference between prediction and actual occurrence of rewards. An unpredicted reward leads to increased firing, a predicted reward causes no change, and the failure of a reward to occur after being predicted leads to a brief depression in cellular activity. Redgrave and coworkers (1999) offered an alternative hypothesis, namely that DA cell firing under these conditions is critically involved in switching the animal’s attention and behavior toward unexpected, behaviorally significant events that can include reward. In neither case is DA proposed to mediate “pleasure” per se.

Drug class Acute

administration

Withdrawal from chronic treatment
Psychostimulants (cocaine, amphetamine)

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Opiates (morphine, heroin)

Nicotine

Sedative-hypnotic drugs (ethanol)

THC

An even more startling finding was obtained by a group of researchers headed by Mark Wight- man (Garris et al., 1999). In this case, in vivo voltammetry was used to monitor DA release in the nucleus accumbens of rats during electrical stimulation of the VTA or substantia nigra. For most of the subjects, experimenter-controlled application of the electrical stimulus led to significant DA release in the accumbens.These animals learned to press a lever to obtain ICSS through the same electrode. Surprisingly, however, ICSS only evoked DA release during the beginning of a test session and not afterwards.Thus, as the sessions progressed, rats were repeatedly pressing the lever to obtain the rewarding brain stimulation without a measurable increase in DA transmission in the nucleus accumbens. These results are inconsistent with the idea that DA release in the accumbens mediates feelings of reward or pleasure.

We have seen that drugs of abuse interact with the neural circuit that mediates reward. Although the mesolimbic DA pathway from the VTA to the nucleus accumbens is part of this circuit and many drugs of abuse stimulate DA release in the accumbens, such release is required for drug reinforcement only in the case of cocaine, amphetamine, and closely related psychostimulants. DA seems to play some kind of role in the learning or anticipation of reward, or orienting toward salient stimuli, but it is clearly not a “pleasure transmitter” as is sometimes claimed.

Dopamine cell firing under various behavioral conditions Under baseline conditions, midbrain DA cells in monkeys fire intermittently at a low rate, as depicted by the straight horizontal lines. Brief (about 100 ms long) bursts of firing occur in response to novel stimuli (A), presentation of an unexpected reward (B),and presenta-tion of a CS associated with reward (C). If an expected reward is withheld, then DA cell firing is transiently suppressed (D).

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