The paper describes some interesting new findings that are likely to inform …

• (Abstract)
• The Dopaminergic Pathway
• Alcohol Withdrawal: the role of glutamate
• Opioid Dependence: what other neurotransmitter systems are involved?
• Ecstacy: the 5-HT system and neurotoxicity
• The Gabaergic System: target for sedatives
• Conclusion
• References

Biology Articles » Neurobiology » Neurobiology of Diseases & Aging » Neurobiology of addiction and implications for treatment » The Dopaminergic Pathway

The Dopaminergic Pathway

- Neurobiology of addiction and implications for treatment

Reward
Over the past 20 years there has been immense interest in the mesolimbic dopaminergic system; most drugs of misuse (except benzodiazepines) increase dopamine here. It is widely accepted that increased levels of dopamine in the nucleus accumbens are key in mediating the rewarding effects or positive reinforcement of drugs of misuse (Koob & Le Moal, 2001). Evidence is still accruing to support this. For instance, alcohol and morphine are no longer rewarding in mice lacking the D₂ receptor (D₂ knockout mice; Maldonado et al, 1997; Risinger et al, 2000). In humans, Volkow et al (1999) showed in a series of neuroimaging studies using cocaine or methylphenidate that increased dopamine levels in the brain were associated with euphoria and pleasure. Interestingly, low levels of dopamine D₂ receptors were associated with pleasure after methylphenidate in drug-naïve individuals, whereas high receptor levels were associated with unpleasant feelings. This study gives us an insight into the role of neurobiology in explaining why drug use for some people is pleasurable and likely to be repeated and for others is unpleasant and not repeated.

Anticipation
The role of dopamine in addiction is now recognised as critical in anticipation and withdrawal as well. In an elegant series of experiments, Schultz (2001) found that in primates trained to associate a cue with a pleasurable experience (food), increased dopaminergic activity was seen in response to the cue and not to the food. If the food was not then presented, dopaminergic function dropped. Reduced dopaminergic function is thought to be associated with negative affect (e.g. dysphoria). Thus, an individual with an addiction may see a ‘cue’ (e.g. a public house, mirror or needle) and if their drug of choice is not available may feel dysphoric, which is likely to increase the drive to obtain the drug.

Withdrawal
Reduced dopaminergic function has been seen in withdrawal and early abstinence from many drugs of misuse. Neuroimaging studies in cocaine, opiate and alcohol addictions have revealed reduced levels of dopamine D₂ receptors, which may recover to some extent during abstinence, but have been shown to persist for months (Volkow et al, 1999). Early stages of abstinence are associated with elevated levels of craving, drug-seeking and risk of relapse, and it is likely that hypodopaminergic function plays a mediating role. Presumably the release of dopamine produced by the drug of choice provides relief from withdrawal, although this has not yet been studied.

Pharmacotherapy (Table 1)
Because of the pre-eminence of the dopaminergic reward system in addiction, this has been a target for pharmacotherapy, but with mixed results. One strategy, for instance, has been to block the binding of cocaine to the dopamine transporter site (Nutt, 1993). In cocaine addiction, the development of dopaminergic partial agonists at the D₃ receptor, such as BP-897, currently holds some promise. In rats, BP-897 inhibits cocaine-seeking behaviour in response to cues (Pilla et al, 1999). As a partial agonist, this drug stimulates the D₃ receptor enough to keep withdrawal at bay, but not enough to cause a ‘high’ or to be rewarding. It is currently in phase 1 trials.

Table 1 Molecular targets of drugs of misuse and pharmacological approaches (current and theoretical) directed at these

One drug that affects the dopaminergic system and has proven efficacy in the treatment of nicotine addiction is bupropion (Jorenby et al, 1999). The exact mechanism underlying this effect still has to be fully characterised; however, it has been shown that bupropion increases dopamine and noradrenaline levels by acting as an uptake inhibitor (Ascher et al, 1995).

Related systems involved in reward
Our understanding of other neurotransmitter systems that are involved in reward and that may modulate dopaminergic activity provides further targets for pharmacotherapy.

Opioids
The opioid system has three receptor subtypes: mu, kappa and delta. The mu subtype appears to be key in opiate addiction: for mice lacking this receptor, morphine is no longer rewarding or reinforcing (Kieffer, 1999). In addition, a morphine withdrawal syndrome is not seen in these animals. Neuroimaging studies suggest that alterations in mu opiate receptor levels may be fundamental to addiction. Using [¹¹C]-carfentanil positron emission tomography (PET) to label mu opiate receptors in the brain, Zubieta et al (2000) found increased receptor levels in the anterior cingulate in recently abstinent humans addicted to cocaine or opiates. This may reflect elevated mu opiate receptor levels or decreased endogenous opioid levels. In either case, craving may result.

Roles for kappa and delta opiate receptors in addiction are also evident. Unlike mu receptors, kappa receptor stimulation reduces dopamine function in the nucleus accumbens. This may possibly result in dysphoria. In animal models, delta antagonists can reduce self-administration of alcohol, suggesting that this receptor also plays a key role in reinforcement.

Naltrexone is a long-acting opiate antagonist. Its use in opiate addiction is based on its ability to antagonise any effects of opiates. However, in alcoholism the efficacy of naltrexone is thought to be a consequence of its ability to block the actions of endorphins that are released by alcohol and that mediate pleasure (Herz, 1997).

Glutamate
Glutamate is the brain's principal excitatory neurotransmitter for which there are three receptors — the ion channels N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate — and also another receptor family which is coupled to G-proteins and the second (metabotropic) messenger system. Glutamatergic neurons from the prefrontal cortex and amygdala project onto the mesolimbic reward pathway, from which reciprocal dopaminergic projections arise (Louk et al, 2000). There is evidence that the glutamatergic projection from the prefrontal cortex to the nucleus accumbens plays a role in the reinstatement of stimulant-seeking behaviour.

The NMDA receptor has been implicated in nicotine, ethanol, benzodiazepine and cannabinoid addiction (Wolf, 1998). For example, NMDA antagonists inhibit sensitisation (i.e. enhanced responses) to stimulants such as cocaine and amphetamine and the development of opioid dependence. Not all NMDA antagonists are clinically useful, owing to their psychomimetic properties (cf. ketamine, phencyclidine). Nevertheless, memantine is a non-competitive NMDA receptor antagonist, used to treat neurological disorders, which has recently been shown to attenuate naloxone-precipitated withdrawal in humans addicted to opiates (Bisaga et al, 2001).

There is recent evidence to suggest an important role for other glutamate receptors, such as the metabotropic receptor, that may be independent of the dopaminergic system. In mice lacking the mGlu5 subtype of the metabotropic glutamatergic receptor, cocaine still increases dopamine in the nucleus accumbens; but the mice do not self-administer cocaine or show increased locomotor activity (Chiamulera et al, 2001).

Cannabinoids
Opioids and cannabinoids share some pharmacological properties producing effects such as sedation, hypothermia and anti-nociception. In addition, there is increasing recognition that opiate—cannabinoid interactions are important in drug addiction, although their precise nature remains to be characterised. The most potent cannabinoid in cannabis is ⁹-tetrahydrocannabinol (⁹-THC) (Ashton, 2001). Cannabinoids have been shown to increase opioid synthesis and/or release (Manzanares et al, 1999). This may explain why opiate antagonists block some effects of cannabis and induce withdrawal in ⁹-THC-dependent rats or, conversely, why marijuana may reduce opiate withdrawal.

There are two cannabinoid receptors: CB₁ in the brain, for which the endogenous compound is anandamide, and CB₂ on immune cells. CB₁ receptors are widely distributed throughout the brain, but particularly in the cerebral cortex, hippocampus, cerebellum, thalamus and basal ganglia (Ameri, 1999). In mice lacking the CB₁ receptor, rewarding and withdrawal responses to morphine and cannabinoids but not to cocaine are reduced (Ledent et al, 1999; Martin et al, 2000). This suggests that the CB₁ receptor is involved in dependence on not only cannabinoids but also opiates. As a result, CB₁ agonists may have clinical utility in treating opiate addiction.

The development of a CB₁ receptor antagonist, SR141716A (Rinaldi-Carmona et al, 1995), not only accelerated research into cannabinoids but also provided a possible treatment. This antagonist blocks both the physiological and psychological effects of smoked marijuana and therefore could be to cannabis what naltrexone is to heroin.