With the recent popularity of serotonin re-uptake inhibitors such as Prozac, the public has acquired the idea that monoamine uptake inhibition to treat psychiatric disorders is a man-made concept. But long before the tricylics and SSRI’s were synthesized, Mother Nature had its very own potent re-uptake inhibitor: cocaine, the active alkaloid in the Erythroxylon coca plant. Because cocaine potently inhibits the re-uptake of dopamine, norepinephrine and serotonin, its mechanism resembles that of today’s synthetic antidepressants. It is even speculated that natural antidepressant alkaloids such as cocaine once served the fitness of our ancestors’ genes by aiding survival during food scarcity. These “happy plants” kept our spirits up and encouraged us to keep searching for food and reproduce even when times were bleak.

A more direct explanation of the evolutionary significance of cocaine lies in its effects in insects. Cocaine also inhibits the re-uptake of the neurotransmitter octopamine. Octopamine in insects functions similarly to the catecholamines, but unlike in mammals, cocaine doesn’t make insects high. Instead it kills them. Thus cocaine is an insecticide, effectively protecting the leaves of Erythroxylon coca.

Because of cocaine’s divergent effects in mammals as opposed to insects, it’s arguable whether Mother Nature intended it for human consumption. But pleasure-hungry humans rarely let nature’s intentions interfere too much with their actions. Cocaine has been routinely used throughout history for its pleasant effects on the central nervous system. It even makes for an excellent anesthetic. Inca Royalty, Sigmund Freud, and present day sorority girls all come to mind as cocaine enthusiasts.

So what’s the science behind this alkaloid that has developed such a following, produced many an addict and secured a place as a Schedule II drug of abuse? Lucky for us, cocaine is probably the best-characterized psychostimulant in the literature, so well characterized that this is only part I. So put down that c-note, wipe your nose and pay attention, because I’m about to deliver line after line of pure…peer reviewed information.

Cocaine Chemistry

In previous installments of Chemically Correct, I’ve used the phenylethylamines as structural prototypes to compare drugs with stimulant activity. This is because the pharmacological mechanisms of many phenylethylamines (monoamine release and re-uptake inhibition) make sense given their chemical resemblance to our endogenous neurotransmitters (dopamine, norepinephrine, etc). Cocaine, while somewhat similar, has some structural qualities that make it very different than the phenylethylamines. An ester group links cocaine’s benzene ring with a nitrogen-containing tropane ring. The ester link, while making cocaine less phenylethylamine-like, does make it resemble bupropion and cathione, both of which have double bonded oxygens on the carbon adjacent to the benzene ring. Thus one might infer that a double-bonded oxygen is important for cocaine (and stimulant) pharmacology. But with cocaine, this might not be the case. If the ester link is taken out, bringing the tropane ring closer to the benzene ring, thereby making cocaine look more like a pure phenylethylamine, affinity for the dopamine transporter increases (1).
Another aspect that makes cocaine different than its phenylethylamine cousins—such as amphetamine—is that the amine group is a part of the tropane ring instead of a substituant. Other stimulants with nitrogen containing rings include methylphenidate (Ritalin) and nomifensine. Cocaine’s nitrogen is also methylated. Taking away the methyl group on the nitrogen (producing norcocaine) increases affinity for the serotonin and norepinephrine transporters, but does not affect dopamine transporter affinity (1).

Several other structural features of cocaine are worth mentioning. Levorotatory configuration (known as l-cocaine, (-)-cocaine, or R-cocaine) is the most important factor in cocaine’s structure-activity relationship. The R compound is naturally occurring and behaviorally active while the S enantiomer is not (2). The beta configured carbomethoxy substituent at C2 on the tropane ring is also important. If replaced by a hydrogen, the resulting compound has significantly less potency for the dopamine transporter (3).

Pharmacology

The popular “dopamine hypothesis of addiction” states that dopamine is the most important neurotransmitter in modulating the rewarding effects of drugs. Since cocaine directly inhibits the re-uptake of dopamine, much of the literature has assigned dopaminergic enhancement to be the main target for cocaine pharmacology. A personal caveat of mine (and a caveat of many “new school” cocaine researchers) is that there’s much more to it than this. It’s not that dopamine isn’t important in cocaine’s effects (as you’ll see, it’s very important), but as we’ve seen with nicotine in particular, dopamine is often just one piece of the puzzle. To demonstrate why dopamine re-uptake alone isn’t the end all be all of cocaine’s actions, let me provide an example.

Methylphenidate has a higher affinity than cocaine for the dopamine transporter, yet its abuse liability is substantially less (5). While this could be attributed to non-biochemical factors such as black market appeal and availability, one can’t ignore the fact that cocaine is a less selective uptake inhibitor than methylphenidate (4). This would imply that abuse liability stems from not only dopamine, but other neurotransmitters as well. Such actions on other neurochemicals besides dopamine are essential in elucidating cocaine’s pharmacology, especially its reinforcing effects. Thus we’ll look at serotonin, norepinephrine, acetylcholine, GABA and the sigma receptors. But as usual, we’ll start with everyone’s (or at least my personal) favorite: Dopamine.

Dopamine

Activation of various dopamine receptor subtypes is necessary for the discriminative stimulus effects of cocaine (6,7). The D1 receptor is most intimately involved with cocaine’s reinforcing and locomotor effects (6,8). In the nucleus accumens, D1 receptors become supersensitive to extracellular dopamine following repeated cocaine administration, facilitating sensitization and addiction (11). But outside the nucleus accumens, D1 receptors decrease in both number and sensitivity (10). The D2 autoreceptor, which provides negative feedback on dopamine firing, is also necessary for cocaine’s locomotor effects (9). Continued cocaine use desensitizes D2 receptors, which in turn enhances dopamine firing in the ventral tegmental area, further sensitizing the response to cocaine overtime (12).

While both D1 and D2 selective agonists can function as reinforcers (13,14), neither alone nor together fully substitute for cocaine (15). This is where the D3 receptor comes in. Mixed D2/D3 receptor agonists can fully substitute for cocaine in rhesus monkeys (16), and even venlafaxine (Effexor, an NE and 5-HT re-uptake inhibitor) plus a D3 receptor agonist can almost fully substitute for cocaine in rats (17). Such observations make the D3 receptor a critical target for cocaine. Ironically, the D3 receptor inhibits locomotion, opposite the effects of the D1 and D2 receptors (19). So now you might be thinking if the D3 receptor inhibits locomotion, why is it so important? This is because the D3 receptor possesses 70 times the affinity for dopamine than either the D1 or D2 receptors (18). Such a difference in affinity causes the D3 receptors to become downregulated before the D1 and D2 receptors. Subsequent uses of cocaine effectively prime a sensitized environment in which the “braking” D3 receptors are more down regulated than the stimulating D1 and D2 receptors (18).

Norepinephrine

The noradrenergic system contributes to both the reinforcing and aversive properties of cocaine. Cocaine induced anorexia can be attenuated with the use of the alpha-1 adrenergic receptor antagonist prazosin (57). The alpha-1b adrenergic receptor plays a role in cocaine’s increases in locomotor activity and is essential for the rewarding effects of psychostimulants and even opiates (20,21). However, enhanced noradrenergic action might also be responsible for the unpleasant jitteriness experienced by cocaine users as well as cocaine’s potential to induce seizures (22,23). Further emphasizing the aversive effects of noradrenergic enhancement, genetically altered mice with deleted norepinephrine transporters display enhanced cocaine reward and self-administration (24).

Serotonin

The observation that mice lacking the dopamine transporter will still self-administer cocaine, but mice lacking the dopamine and serotonin transporter will not (55), has led to considerable interest in cocaine’s serotonergic effects. Interactions between the dopaminergic and serotonergic system often get ridiculously confusing, and cocaine’s simultaneous effect on both systems is no exception in providing plenty of contradictions. Cocaine does indeed raise extracellular levels of serotonin in the nucleus accumens (25,26), but how such increases relate to cocaine’s effects are controversial. Depletion of serotonin potentiates cocaine’s locomotor effects (27). Similarly, pretreatment with the serotonin precursor 5-HTP attenuates cocaine induced locomotor activity (28). Contrary to these observations is the finding that infusion of serotonin into the nucleus accumens and ventral tegmental area increases dopamine concentrations as well as locomotor activity (29,30). Furthermore, pretreatment with SSRIs can enhance cocaine hyperactivity as well as dopamine release (31), although conflicting results with SSRI’s and cocaine have been noted (32).

Thankfully, when we take into account the different functions of various serotonin receptor subtypes, the relationship between cocaine and serotonin becomes slightly more palatable. Indirect 5-HT1A agonism seems to be essential for cocaine’s locomotor response, as antagonism of this receptor will block such effects (34), while pretreatment with an agonist will increase them (33). In the last edition of Chemically Correct, I discussed the role of 5-HT1A as an autoreceptor that inhibits serotonin firing. Similarly, antagonism of 5-HT2A receptors can also attenuate cocaine hyperactivity (35). Stimulation of the 5-HT2A receptor is often implicated in anxiety and psychosis (36). The 5-HT3 receptor’s relationship to cocaine is unique in that cocaine has substantial affinity for directly antagonizing this receptor (37). Interestingly, stimulation of 5-HT3 receptors has an excitatory role on neurotransmitters, and pre-treatment with 5-HT3 antagonists attenuates cocaine hyperactivity (38) and increases reward thresholds (39). Here it appears that cocaine’s antagonism of 5-HT3 receptors is a sort of built in negative feedback mechanism.

The 5-HT1B receptor functions both as an autoreceptor that inhibits 5-HT firing (40), as well as a heteroreceptor on GABAergic neurons that decreases GABA release (41). Since GABA provides a check on dopamine overflow, the 5-HT1B receptor is intimately involved in cocaine’s locomotor, sensitization, and rewarding effects (41,42).

The role of 5-HT2C receptors is controversial in that antagonism of these receptors can both increase (43) and decrease (44) cocaine hyperactivity. It appears that 5-HT2C receptors have a facilitatory role on dopamine and hyperactivity inside the nucleus accumens, but an inhibitory role in other regions of the brain (43).

In summary, it appears that serotonin has a largely inhibitory role on cocaine’s effects. However, indirect stimulation of various serotonin receptors, particularly the ones that decrease serotonin release and/or increase dopamine release, is essential for cocaine’s actions.

Acetylcholine

Cholinergic neurons express D1 receptors, and when stimulated release acetylcholine (45, 46). Increases in acetylcholine following cocaine administration are involved in the development of behavioral sensitization, as muscarinic receptor blockers can prevent this phenomenon (47). Already mentioned has been the possible “internal check” via 5-HT3 antagonism on cocaine’s rewarding effects. Cocaine’s antagonism of the M2 autoreceptor (48) could function in a similar manner, preventing acetylcholine release and subsequent enhancement of sensitization.

GABA

Like everything else, interactions between cocaine and the GABA system are somewhat mysterious. As stated earlier, stimulation of 5-HT1B receptors on GABAergic neurons decreases GABA release, enhancing dopaminergic neurotransmission. Cocaine also upregulates GABA-B receptor mRNA, a phenomenon which is linked to cocaine’s seizure potential (49). How do GABA (B) receptors contribute to seizures if GABA is an anti-epileptic neurotransmitter, you might ask? In Chemically Correct: Nicotine, I mentioned the finding that the GABA-B1 receptor provides negative feedback on GABA release, an observation which sheds some light on cocaine’s GABA-B upregulation (50). But complicating the matter is the observation that GABA-B receptor agonists such as baclofen can reduce cocaine administration, presumably by inhibiting dopaminergic neurons (52).

Adding further to the irony, when mice lack the alpha 1 subunit of the GABA-A receptor (which is responsible for anxiolysis, sedation and is the target of the hypnotic drug Ambien), they do not demonstrate a locomotor response to cocaine (51). But once again returning to Chemically Correct: Nicotine, GABA-A receptors are located on noradrenergic nerve terminals and facilitate release of norepinephrine (53).

The differential effects of various GABA subtypes on inhibition and excitation of neurotransmitters seems to be responsible for such interesting and seemingly contradictory observations.

Sigma Receptors

Sigma receptors bind to several chemically unrelated drugs including steroids, PCP, amphetamine and cocaine (54). They are relevant to cocaine hyperactivity and sensitization in that they amplify dopaminergic and glutaminergic transmission (55).

We’ll talk more about sigma receptors as well as hormones, peptides, toxicity, addiction and cocaine analogues in part II of this article.

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