The second INTEGRAL AGN catalogue

5

that they are rewarding, often to a greater extent than natural stimuli, thereby making the consumer want them.⁴⁸⁴ The establishment of the relationship between the drug and the reward is learned by a process of operant conditioning. Therefore, the strength, frequency, and speed of onset of the effects of the compound in question (i.e., how strongly and quickly the reward follows the behavior) are all key factors in establishing the association between taking the drug and its rewarding properties and therefore how much it is wanted or, alternatively, its addictiveness. Typically, drugs that have a faster onset or are taken by a route associated with faster bioavailability in the brain are more addictive.^487,488 For the more potent drugs the subsequent descent into addiction can then be seen as a chain of events. This starts with the activation of the mesolimbic dopamine reward pathways the first time the drug is taken and then progresses with continued use via a wide-ranging and complex series of neuro-adaptations, including habituation and sensitization to the effects of the drug within the relevant neurotrans-mitter systems. These culminate in the negative physical and affective symptoms as-sociated with withdrawal. Eventually, disruption of the functioning of the prefrontal cortex and activation of the brain’s stress system can also lead to a powerful drive to seek the drug, which is coupled with a lack of overriding, prefrontal control over the inadvisable behavior.⁴⁸⁴

Each of the rewarding drugs exerts its own individual palette of neuropharmaco-logical effects, and the mode by which they activate the ventral tegmental area and the nucleus accumbens is therefore different in each case.⁴⁸⁴ These mechanisms of action will be described in the individual sections for each alkaloid secondary metabolite below. Nicotine has been included alongside the other deliriants from the Solanaceae family in Chapter 6, and tetrahydrocannabinol, which belongs to the terpene group of phytochemicals, will be reviewed separately in Chapter 12.

■ M O R P H I N E

The home range of the opium poppy (Papaver somniferum) is on the Anatolian coast of the Black Sea.⁴⁸⁹ The exudate that oozes from the cut skin of the poppy’s immature seed pod has been collected, air-dried, and used as a euphoric, analgesic, and me-dicinal panacea since at least the epoch of the Sumerian culture that flourished from

~4000 to 3000 bc in Mesopotamia.²⁹ The subsequent use of opium followed the tides of migration and the ebb and flow of trade, civilizations, and empires as it radiated across the Eurasian continent (see Chapter 1).

The milky latex of the opium poppy contains approximately 40 alkaloids, but the bulk of the alkaloid content is attributable to just five: morphine, the principal con-stituent, which makes up 8% to 17% of the dried latex, codeine (0.7% to 5%), narcotine (1% to 10%), papaverine (0.5% to 1.5%), and thebaine (0.1% to 2.5%).²⁹

The opium alkaloids themselves belong to a wider group of over 2,500 benzylisoquin-oline alkaloids that are derived from the amino acid tyrosine via dopamine. The struc-ture of morphine and its precursors are shown in Figure 4.2 in Chapter 4. This group of alkaloids comprise a wide range of typically species-specific compounds, synthesized by a diverse minority of species within a number of orders of angiosperm. The abil-ity to synthesize benzylisoquinoline alkaloids arose monophyletically prior to the dif-ferentiation of the eudicot and monocot clades, and the “latent molecular fingerprint”

that would have allowed their synthesis can still be detected in many non- synthesizing eudicot plants.³⁵³ Naturally, the factors that lead to the switching on of synthesis in the

minority of eudicot species that express benzylisoquinoline alkaloids must be rooted in the selective pressure of environmental factors or the emergence of other facilitating physiological mechanisms. In the case of Papaver somniferum the selective pressure for the synthesis of the opiate alkaloids can be assumed to be defense against insect herbi-vores. However, it may well have been the case that the emergence of specialized cells, known as laticifers, which are external to the vasculature of the plant and which pro-duce toxic alkaloids and store them safely in a sticky latex (see below), ultimately tilted the cost/benefit balance in favor of the synthetic pathway being activated.^353,490

The opiates and their many semisynthetic derivatives have provided us with a trea-sure trove of contemporary medicinal drugs. However, the opium poppy is probably most notorious for providing us with drugs of abuse. While the air-dried latex, known as opium, has no doubt been used in a social or recreational context throughout its his-tory, three separate events propelled its principal alkaloid, morphine, to the front rank of the addictive drugs. The first was the isolation of morphine as a single compound by Friedrich Sertürner in 1806. This was followed by the invention of the hypodermic needle and syringe in 1853 by the Scottish physician Alexander Wood, who modeled his creation on the bee sting and originally intended it solely for the administration of morphine. The much faster mode of intravenous administration increased morphine’s rewarding properties and led to it becoming widely preferred over previous oral opium preparations.⁴⁹¹ The final event was the synthesis of diacetylmorphine by the English chemist C. R. Alder, who failed to appreciate the importance of his discovery. It was subsequent rediscovered two decades later by the Bayer AG pharmaceutical company.

Diacetylmorphine was originally marketed in Germany as a cough remedy and later as a supposedly nonaddictive treatment for morphine dependence. Its original brand name, Heroin, remains in common usage when describing the drug when used illicitly.

The key property of heroin that makes it so potent is the addition of the two acetyl groups. These increase the molecule’s lipophilicity and allow it to cross the blood–brain barrier far more quickly than morphine. Once in the brain it is rapidly metabolized back to morphine and mono-acetylmorphine.⁴⁶⁶ The introduction of heroin at the turn of the 20th century created a huge illicit demand for the drug, which persists today.⁶⁹ Indeed, the global market value of the illicit opium and heroin trade is estimated by the United Nations at $68 billion, of which heroin represents approximately 90%. More than 16 million people around the world use illegal opiate products each year.⁴⁹²

In terms of human pharmacology, morphine is primarily a selective agonist at the G-protein-coupled μ-opioid receptors that are the natural binding sites for the body’s endogenous painkillers, the endorphins and enkephalins. This binding affinity is due to the structural residue of tyrosine that can be detected in the structure of both morphine and the endogenous opioids (see Fig. 4.2).¹⁹⁵ The site of morphine’s activity was actually discovered before the natural ligands for the receptor were first identified, so μ, the Greek letter “mu,” refers to morphine. When the first endogenous ligands for these receptors were identified in 1974 they were then named endorphins, a contrac-tion of “endogenous morphine.”

The μ-opioid receptors themselves are distributed throughout the key areas of the nervous system involved in the perception and management of pain, including the dorsal horn of the spinal cord, the amygdala, and brainstem regions such as the peri-aqueductal gray area. They are also expressed in several layers of the cerebral cortex, the mesolimbic reward pathways, the nucleus accumbens, and peripherally in the in-testinal tract. This widespread distribution means that, as well as analgesic properties,

μ-opioid receptor activation also leads to euphoria, sedation, reduced gastrointesti-nal activity, and, courtesy of the brainstem, the respiratory depression that kills in the event of a morphine overdose.⁶⁹ Within the mesolimbic dopamine reward pathways the μ-opioid receptors themselves function by inhibiting the release of the inhibitory neurotransmitter GABA, leading to a net increase in the release of other neurotrans-mitters, including dopamine, and therefore neuronal excitability. The rewarding prop-erties of morphine are then dependent on its direct binding to μ-opioid receptors within the ventral tegmental area and nucleus accumbens, leading to increased ac-tivation via dopamine release.^466,484 As noted above the comparative rewarding prop-erties, and therefore addictiveness, of differing modes of morphine delivery depend on the amount of morphine delivered and the tightness of the relationship between administration of the drug and activation of the reward pathways. So, pure morphine is more potent than opium; smoking, which bypasses the digestive system, provides a quicker reward than oral consumption; injection directly into the bloodstream pro-vides the reward faster again than smoking; and diacetylmorphine (heroin) crosses the blood–brain barrier more rapidly than morphine but is then rapidly metabolized back to morphine in the brain. The multifarious permutations of drug and delivery dictate the potential for abuse of morphine, with injected heroin the most potent combination in terms of potential for dependence and abuse.^487,488

The extended use of morphine (and the “psychostimulants,” see below) leads to long-term regulatory changes in neurotransmitter systems that far outlive cessation of drug taking and that lead to a multitude of unpleasant withdrawal symptoms.

These changes include a particularly long-term upregulation of the κ-opioid receptor system at which the endogenous painkiller dynorphin acts. Although both systems produce analgesia, the κ-opioid/dynorphin system naturally antagonizes the effects of the μ-opioid/endorphin system, and therefore it naturally downregulates the effects of morphine, both in terms of its euphoric effects and the dopaminergic activation of the nucleus accumbens. Unfortunately, continued use of morphine leads to a compensa-tory upregulation of the κ-opioid system that persists long after any μ-opioid–related effects have dissipated. The net effect is the long-term dysphoria, depression, and anxi-ety that outlives physical withdrawal symptoms and provides ongoing negative rein-forcement for the reinstatement of morphine consumption.⁴⁶⁶

Naturally we tend to think of morphine and related opiates as chemicals synthe-sized by a plant that just happen to usurp the functioning of opioid receptors. However, endogenous synthesis of morphine and several related alkaloids, by similar enzymatic pathways to those seen in plants, has recently been confirmed in both invertebrate and vertebrate animal tissue, including the brain.^264,266 Alongside this, specialized

“µ₃”-opioid receptors have been identified that are insensitive to the classic endog-enous opioids (endorphins/enkephalins) but that strongly bind morphine (and the synthetic μ-opioid receptor antagonist naloxone).^264,329 It transpires that endogenously synthesized morphine, acting via µ₃-opioid receptors, plays a variety of signaling roles across phyla, including modulation of vascular and immune function and the modulation of stress responses. All of these effects can be attributed to interaction with constitutive nitric oxide synthesis.²⁶⁴ In this endogenous role morphine has been shown to extend the lifespan of rodents and insects and to have a wide range of pro-tective metabolic, cellular, and physiological properties, including enhanced synaptic plasticity and neuroprotection in mammals and a modulatory effect on the activity of the structurally related catecholamine neurotransmitters (see Fig. 4.2).^266,493

Ecological Roles of Opiates and Brain Function

The first steps of opiate synthesis take place within the vascular bundles throughout the opium poppy, with the final enzymatic stages and alkaloid accumulation taking place in the laticifer network itself, where the alkaloids are stored in vesicles.⁴⁹⁴ Latici-fers in the aerial parts of plant, and their associated latex, are specifically mechanisms for the defense against insect herbivory. They deliver the double defense of physically compromising the insect with their sticky exudate, which can immobilize/drown the insect or gum up its mouth parts, and at the same time they deliver a variety of toxic secondary metabolites. In the case of the opium poppy, morphine represents up to 17%

of the dry weight of latex.²⁹ It can therefore be assumed that morphine and the other opiates primarily function as chemical defense agents targeting insects, although as latex also provides a physical barrier that hardens over any wound they may also func-tion as antimicrobial agents.^136,490

Research using invertebrate models confirms that morphine affects behavior in insects and other invertebrates in a similar manner to mammals. For instance, ad-ministration of morphine increases pain thresholds and decreases protective behaviors and “fearful” responses to noxious stimuli.465,495,496 As an example, it suppresses the escape behavior of crickets from a heated box to the extent that they suffer irreparable damage.⁴⁹⁶ It also modulates insect feeding behavior and motor activity, with dem-onstrations of both increased activity and long periods of immobility, although these effects depend on the species and administration regime.^328,465 The similarities with humans extend to the development of both tolerance and behavioral sensitization to the drug’s effects with extended administration.⁴⁹⁶ Morphine also plays some distinct ecological roles specifically relevant to insects, in particular disrupting their life course by producing a dose-dependent delay in pupation and in the eclosion of adults, and significantly reducing survival to adulthood.³²⁷ Similar effects are also seen in the off-spring of adult flies administered morphine prior to egg laying.⁴⁹⁷

In terms of mechanisms, both µ- and κ-opioid receptors and the endogenous opioid receptor ligand enkephalin are widely expressed in the insect brain and ner-vous system,^325–328 and this system has been confirmed as the site of morphine’s activity by studies involving the co-administration of the opioid receptor antagonist naloxone, which blocks its analgesic and behavioral effects.326,328,496,498 As noted above, endog-enously synthesized morphine and its recently identified µ₃-receptors have also been identified across invertebrate phyla,²⁶⁴ including insects.³²⁹

The potential deleterious effects of compromising the insect opioid system is nicely illustrated by the parasitoid wasp Ampulex compressa, which injects an opioid receptor agonist directly into the brain of its cockroach victim, reducing its volitional control of its own movement, and allowing the wasp to lead it by an antenna to its fate as an edible, living egg depository within its burrow.³²⁵

■ T H E P S Y C H O S T I M U L A N T S ( C O C A I N E , E P H E D R I N E , C A T H I N O N E , A M P H E T A M I N E , M E T H A M P H E T A M I N E ) The psychostimulant plant alkaloids—cocaine, ephedrine, and cathinone, and their semisynthetic derivatives, amphetamine and methamphetamine—exert a common pattern of psychological effects in humans. To a greater or lesser extent they all pro-duce elation, euphoria, mood elevation, increased alertness and concentration, and

reductions in fatigue.⁴⁹⁹ They also exert common “sympathomimetic” physiological ef-fects related to their noradrenergic activity, for instance engendering similar increases in blood pressure and heart rate.³⁷⁷ Finally they are all also “rewarding,” with a poten-tial to become addictive and engender negative symptoms of withdrawal. They owe these effects to either one or both of two mechanisms. The first is the binding to and blocking of one or more of the reuptake transporters that actively transport molecules of the monoamine neurotransmitters dopamine, noradrenaline, or serotonin back into the cytoplasm of the presynaptic terminal from which it was originally released. The second mechanism is by increasing neuronal release of the same neurotransmitters by disrupting vesicular storage, thereby increasing cytoplasmic levels of the neuro-transmitter and promoting efflux into the synapse by reversing transporter-mediated exchange. In both cases the net effect is increased levels of the neurotransmitter in the synapse.^441,444

The profile of these uptake and storage effects varies between the compounds. Co-caine is solely a reuptake inhibitor, blocking dopamine, noradrenaline, and serotonin transporters. Ephedrine, on the other hand, primarily increases noradrenaline release and inhibits its reuptake and has modest similar effects with regard to dopamine and no effect on serotonin levels. Amphetamine and methamphetamine release and inhibit the uptake of both noradrenaline and dopamine, with markedly more modest effects on serotonin.⁴⁴¹ Cathinone similarly has noradrenergic and dopaminergic properties.

While these compounds do not typically bind directly to the classic monoamine recep-tors, emerging evidence does suggest that the amphetamine-like psychostimulants do bind directly to the recently identified “trace amine associated receptors” (TAAR1 to TAAR9; see also Chapter 3). These receptors co-localize with monoamine transport-ers and play a modulatory role by binding endogenous monoamine neurotransmitttransport-ers and other trace amines such as tyramine and octopamine. Direct agonist properties at these receptors may well modulate the psychostimulants’ effects on neurotransmitter uptake and release.⁵⁰⁰

The above stimulants also have one other related common property: potent acti-vation of the dopaminergic mesolimbic reward pathways, in particular the nucleus accumbens, via their direct actions on extracellular dopamine levels at nerve terminals within these areas.484,499,501 The reward pathways are also particularly rich in TAAR1 receptors, which appear to have a natural function as mediators of the modulatory ef-fects of trace amines on dopamine neuron firing activity. This may go some way toward explaining the relative specificity of these compounds with regard to these brain re-gions and may provide a possible mechanism underlying the behavioral sensitization produced by extended use of psychostimulants.⁵⁰² Overall, the euphoriant and rein-forcing or addictive potential of each psychostimulant is predicated on its comparative dopaminergic potency. So, for instance, ephedrine, which has only modest effects on the release and reuptake of dopamine, is a comparatively mild euphoriant and has low potential for addiction in humans.⁵⁰³ The differences in mechanisms of action and the resultant behavioral/psychological effects of each alkaloid will be reviewed below.

Of course, the ability of the psychostimulants to bind to and modulate the activity of vesicular and membrane monoamine transporters and TAARs is directly related to their structural similarity to the monoamine or trace amine neurotransmitter in question. In turn, this similarity is predicated on their common precursors. In ani-mals the trace amines/neurotransmitters tyramine, octopamine, dopamine, adrenal-ine, and noradrenaline are synthesized from the amino acid L-phenylalanine via the

decarboxylation of L-tyrosine. In plants L-phenylalanine serves as the precursor for the synthesis of the phenethylamine alkaloids cathinone and ephedrine and a suite of related alkaloids found in the plants from the Ephedra genus and Celastraceae family.^195,377 The archetypal members of these groups of plants in terms of human con-sumption are Ephedra sinica and Catha edulis (khat). The alkaloids from these plants, in turn, serve as precursors in the illicit manufacture of semisynthetic drugs of abuse such as amphetamine and methamphetamine. While cocaine belongs to the tropane alkaloids, a separate group partially derived from the amino acid ornithine, its struc-ture incorporates a benzoyl moiety that is derived from L-phenylalanine, lending it structural similarity to the phenethylamines and the catecholamine neurotransmit-ters.¹⁹⁵ The amino acid precursors, neurotransmitters, and psychostimulant alkaloids are shown in Figure 4.2.

Cocaine

Erythroxylum, the genus of South American tropical flowering shrubs, includes more than 200 species of coca plant. However, the leaves associated with chewing coca and cocaine production are obtained from either of two geographically separated species, E. coca and E. novogranatense, that grow naturally on the Eastern slopes and Western slopes and highlands of the Andes respectively.¹⁹⁵ Coca leaves contain a cocktail of al-kaloids that represent between 0.7% and 2.5% of their dry weight. Cocaine is the most abundant alkaloid, but other alkaloids include cynnamoylcocaine, α- and β-truxilline, tropococaine, hygrine, hygroline, and cuscohygrine. In keeping with a protective role the alkaloids are preferentially synthesized in young leaves at the ends of branches and

Erythroxylum, the genus of South American tropical flowering shrubs, includes more than 200 species of coca plant. However, the leaves associated with chewing coca and cocaine production are obtained from either of two geographically separated species, E. coca and E. novogranatense, that grow naturally on the Eastern slopes and Western slopes and highlands of the Andes respectively.¹⁹⁵ Coca leaves contain a cocktail of al-kaloids that represent between 0.7% and 2.5% of their dry weight. Cocaine is the most abundant alkaloid, but other alkaloids include cynnamoylcocaine, α- and β-truxilline, tropococaine, hygrine, hygroline, and cuscohygrine. In keeping with a protective role the alkaloids are preferentially synthesized in young leaves at the ends of branches and