Ellen Oxenham

Compare and Contrast the mechanisms employed by cocaine, ecstasy, heroin,

and cannabis to stimulate dopamine release in the brain, and how this relates to

their abuse potential.

Dopamine is a neurotransmitter in the brain that is a precursor of norepinephrine and

epinephrine (Udenfriend & Wyngaarden, 1956). It coordinates movement, via the nigrostriatal

dopaminergic system (Miklyaeva, Castañeda, & Whishaw, 1994); and emotional responses via

the mesolimbic dopaminergic system (Salimpoor, Benovoy, Larcher, Dagher, & Zatorre,

2011). It has been found that psychostimulant drugs such as cocaine effect the levels of

dopamine in brain (Pierce & Kumaresan, 2006), and as dopamine has a positively reinforcing

effect (Old & Milner, 1954), drugs that directly affect dopamine levels have a higher abuse

potential (Volkow et al., 1997). This essay will look at how commonly used drugs act on the

brain and how this effects their abuse potential; comparing opioid analgesics, behavioural

stimulants, and psychedelic/hallucinogenic stimulants.

Cannabis is an anandamide psychedelic drug obtained from the hemp plant, cannabis

sativa. It causes a disruption of psychomotor behaviour and a euphoric state of mind. This is a

result of the active compound tetrahydrocannabinol (THC) binding with CB1 cannabinoid

receptors, which causes an inhibitory effect on amino acids and monoamine neurotransmitters

(Iversen 2003). The inhibition of amino acids, such as gamma-aminobutyric acid (GABA),

subsequently increases dopamine release (Schlicker & Kathmann, 2001), and this increase of

dopamine causes cannabis to have reinforcing effects, leading to an increased abuse potential.

Chait and Zacny (1992) conducted a study that directly looked at the reinforcing effects

of cannabis in humans. They found that both smoking cannabis and ingestion of THC acted as

positive reinforcement, leading to the choice of re-administration. This may be because

cannabinoid receptors are found within the brain substrates that are associated with reward

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functions (Gardner & Vorel, 1998), or that cannabinoids cause an increased firing rate of

dopamine neurons in brain areas that are associated with reinforcing effects; such as the

mesolimbic and striatal tissues (French, Dillon, & Wu, 1997). From this research we can see

that there is a well-established link between cannabis and dopamine, suggesting that cannabis

has a high abuse potential as a result of the reinforcing effects of dopamine. But how does this

compare to other drugs than cause dopamine levels to increase?

The abuse rates of different drugs were assessed in a study by Compton, Thomas,

Stinson, and Grant (2007). The study found that, of a large sample of United States citizens

aged 18 and above, 8.5% fitted the DSM-IV criteria for Substance abuse or dependence

specifically for cannabis. This was much higher than that of cocaine, which had an overall

prevalence of 2.8%. This could be because cannabis has a direct effect of the levels of dopamine

in the brain, however, cocaine also has a similar neurochemical effect. Therefore, it may be

because more people use cannabis as opposed to cocaine as a result of permissive beliefs about

cannabis use; for example, that it is not dangerous in comparison to other illicit drugs such as

cocaine (Chabrol, Massot, & Mullet, 2004). These beliefs, would suggest an increased rate of

cannabis use and decreased rate of cocaine use, which would subsequently effect the rate of

substance abuse for each drug.

Cocaine differs from cannabis in that it is a psychotropic drug, specifically a

behavioural stimulant, extracted from the Peruvian coca shrub. It is a dopamine antagonist and

works by blocking dopamine transporters, and inhibiting the reuptake of dopamine in the brain;

causes increased levels of the neurotransmitter in the synaptic cleft (Volkow et al, 1997). As a

result of increased dopamine levels, cocaine causes increased alertness, elevated mood, and

euphoria; which can make it appealing to use again. This can be seen in studies that show re-

administration of dopamine antagonist drugs to be directly proportional to the number of

dopaminergic nerve terminals (Lyness, Friedle, & Moore, 1979); suggesting a strong link

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between dopamine and substance abuse potential. In addition to this, it has been found that

repeated administration of cocaine increases the turnover of dopamine and therefore decreases

natural levels of the neurotransmitter in the absence of cocaine (Dackis, & Gold, 1985); this

increases the feeling of dependency and need to re-administer the drug.

Heroin, unlike cocaine, is similar to cannabis in that it doesn’t inhibit the reuptake of

dopamine, but instead acts on other receptors which increase dopamine levels. Heroin is

converted into morphine in the brain and binds with opiate receptors, activating the mesolimbic

dopamine system and providing similar effects to cannabis such as a feeling of well-being and

relaxation (Tanda, Pontieri, Di Chiara, 1997). It is a synthetic opioid analgesic drug that is

synthesized from morphine, but is more potent and has a higher uptake rate than morphine

(Oldendorf, Hyman, Braunm & Oldendorf, 1972); which may explain its high abuse potential.

The abuse potential of heroin can be seen in a study by De Vries, Schoffelmeer,

Binnekade, Raaso, and Vanderschuren (2002). They found that, after training rats to poke their

nose to receive either cocaine or heroin and withdrawing the drug for a week, administration

of Quinpirole (a D2 receptor agonist) causes the animal to repeatedly poke it’s nose in an

attempt to self-administer more drugs. These findings were true for both heroin and cocaine

trained rats, suggesting that increased dopamine levels, directly effects the abuse potential of

both cocaine and heroin. However, after three weeks of withdrawal the findings were only

consistent for cocaine trained rats and heroin trained rats no longer responded to the activation

of D2 receptors. This may suggest that the abuse potential for heroin and cocaine is similar for

the first week of withdrawal, but after three weeks of withdrawal the abuse potential of heroin

is reduced. This supports the findings of Compton, Thomas, Stinson, and Grant (2007) that

found the rate of heroin abuse to be lower than that of cocaine abuse.

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Research also suggests that the abuse potential of cocaine and heroin may be different

as a result of different neural substrates mediating the reinforcing effects of the drugs

(Ettenberg, Pettit, Bloom, & Koob, 1982). Which would explain why the abuse rate of heroin

is lower than that of cocaine, however it may also be the effect of whether drug is antagonist

or agonist that causes this difference in abuse rates. However, Thomas, Stinson, and Grant

(2007) also found cocaine abuse rates to be higher than that of ecstasy, and the abuse rate of

ecstasy is lower than that of heroin. Therefore, because ecstasy is also an antagonist like

cocaine we cannot conclude that the difference in abuse rates is a result of whether a drug is

agonist or antagonist.

Much like cocaine, ecstasy is also a psychotropic drug, specifically a psychedelic

stimulant that causes an increased sense of well-being, increased energy, and distorted sensory

perception (I.e. visual distortion). Ecstasy works in the same way as cocaine, in that it inhibits

the reuptake pre-synaptic dopamine, increasing the levels of these neurotransmitters in the

synaptic cleft and increasing the activation of post-synaptic receptors (De la Torre et al. 2004)

However, ecstasy also works by inhibiting the reuptake of serotonin increasing a person’s sense

of well-being, as well as reinforcing administration of the drug as a result of increased

dopamine (De la Torre et al. 2004). There is research to suggest that the difference between the

abuse potential of ecstasy and other drugs, such as cocaine, is a result of the drug effecting

serotonin levels as well as dopamine levels, suggesting serotonin plays a role in the reinforcing

effects of ecstasy (Doly et al, 2009). However, this role of serotonin could also mean that

ecstasy has less of a reinforcing effect than other drugs such as cocaine. Research has shown

that of monkeys that are self-administering drugs, the number of doses of ecstasy administered

was lower than that of cocaine, suggesting cocaine has a higher abuse potential (Lile, Ross, &

Nader, 2005); which supports the findings of Compton, Thomas, Stinson, and Grant (2007).

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Overall it can be seen that cannabis, cocaine, heroin, and ecstasy all act on the brain in

a way that results in increased dopamine levels. As a result of dopamine having reinforcing

effects, most drugs have a high abuse potential, with Cannabis having the highest abuse rate

(Compton, Thomas, Stinson, & Grant, 2007). Research suggests that the abuse rate of cannabis

is a result of the combined effect of permissive beliefs about the drug (Chabrol, Massot, &

Mullet, 2004) and increased dopamine levels in the brain (Schlicker & Kathmann, 2001).

Dopamine levels are also increased by Cocaine, heroin, and ecstasy, although ecstasy also

increases serotonin levels; which may explain why it has a lower abuse rate than cocaine and

cannabis. In conclusion, the reinforcing effects of dopamine definitely increase the abuse

potential of cannabis, cocaine, heroin, and ecstasy. However, other factors such as the role of

serotonin (De la Torre et al. 2004), the effect of withdrawal time (De Vris, Schoffelmeer,

Binnekade, Raaso, & Vanderschuren, 2002), the number of dopaminergic nerve terminals

available (Lyness, Friedle, & Moore, 1979), and beliefs about different drugs (Chabrol, Massot,

& Mullet, 2004) all contribute to the difference in the abuse potential of each drug.

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