Drugs and behaviors may initially lead to dopamine increase in the ventral striatum and reward (Figures 14-1,

14-
2, 14-4, 14-6, 14-7), but with repeated administration, as habits develop, dopamine increases shift from the
drug/behavior to the conditioned response/ environmental trigger, as the dopamine increases shift from the ventral
striatum/nucleus accumbens (Figure 14-2) to the dorsal striatum (Figure 14-3).
Dopamine is associated with motivation, and the motivation to procure drugs is the hallmark of addiction. Drug
seeking and drug taking become the main motivational drive when one is addicted, and thus the addicted subject
is aroused and motivated when seeking to procure the drug, but is withdrawn and apathetic when exposed to non-
drug-related activities (Figures 14-5 and 14-8).What starts out as increased DA release leading to increased ventral
striatum and anterior cingluate cortex (ACC) activity with reward may end up as a compulsive drive with
escalating dosing in an attempt to get increased reward stimulation to restore a resultant DA deficiency. The
discrepancy between expectation for drug effects and the blunted DA effects maintains drug taking in an attempt
to achieve the expected reward. High doses of stimulants can cause tremor, emotional lability, restlessness,
irritability, panic, and repetitive stereotyped behavior. At even higher repetitive doses, stimulants can induce
paranoia and hallucinations, with hypertension, tachycardia, ventricular irritability, hyperthermia, and respiratory
depression. In overdose, stimulants can cause acute heart failure, stroke, and seizures.
Not only methylphenidate and amphetamines, but also cocaine are all inhibitors of the dopamine transporter
(DAT) and the norepinephrine transporter (NET) (see discussion in Chapter 12, and Figures 12-25 and 12-28).
Cocaine also inhibits the serotonin transporter (SERT) and is also a local anesthetic, which Freud himself exploited
to help dull the pain of his cancer of the jaw and mouth. He may have also exploited the second property of the
drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of
dopamine reuptake at the dopamine transporter, at least for a while, until drug-induced reward is replaced by drug-
induced compulsivity.
Although there are no approved treatments for stimulant addicts, in the future there may be a cocaine vaccine that
removes the drug before it reaches the brain so there are no more reinforcing effects that accompany drug
ingestion. Theoretically, it may also be possible to administer intravenously a long-acting form of the enzyme
cocaine esterase that destroys cocaine before it can exert its reinforcing effects, as has been shown in animal
models. Naltrexone, a μ-opioid antagonist approved for the treatment of both opioid and alcohol addiction, is also
being investigated for patients with stimulant addiction, particularly for those patients with polydrug dependence
on both the opioid heroin and the stimulant amphetamine. Buprenorphine, a synthetic opioid used for treatment
of pain and for opioid addiction, stimulates as a partial agonist both μ- and κ-opioid receptors, and can decrease
cocaine use in opioid addicts. It is also being studied in combination with naltrexone for cocaine addicts who do
not have opioid addiction. The combination results in stimulation only of κ-opioid receptors and not of μ-opioid
receptors and may decrease compulsive cocaine self-administration in animals without producing opioid addiction
– suggesting that, at least in this case, three drugs might be better than one!

Nicotine
How common is smoking in clinical psychopharmacology practices? Some estimates are that more than half of
all cigarettes are consumed by patients with a concurrent psychiatric disorder, and that smoking is the most
common comorbidity among seriously mentally ill patients. It is estimated that about 20% of the general
population (in theUS) smoke, about 30%of people who regularly see general physicians smoke, but that 40–50%
of patients in a psychopharmacology practice smoke, including 60–85% of patients with ADHD, schizophrenia,
and bipolar disorder. Unfortunately, histories of current smoking are often not carefully taken nor recorded as one
of the diagnoses for smokers in mental health practices, and only about 10% of smokers report being offered
treatment proactively by psychopharmacologists and other clinicians.
Nicotine acts directly upon nicotinic cholinergic receptors in reward circuits (Figure 14-7). Cholinergic neurons
and the neurotransmitter acetylcholine are discussed in Chapter 13 and illustrated in Figures 13-17 through 13-
24. Nicotinic receptors are illustrated in Figures 13-20 through 13-22. There are two major subtypes of nicotinic
receptors that are known to be present in the brain, the α4β2 subtype and the α7 subtype (discussed in Chapter 13
and illustrated in Figure 13-20). Nicotine’s actions in the ventral tegmental area are those that are theoretically
linked to addiction, namely at α4β2-nicotinic postsynaptic receptors on dopamine neurons, leading to dopamine
release in the nucleus accumbens, and at α7-nicotinic presynaptic receptors on glutamate neurons, which causes
glutamate release, and in turn dopamine release in the nucleus accumbens (Figure 14-9). The release-promoting
actions of presynaptic α7-nicotinic receptors on glutamate neurons are discussed in Chapter 13 and illustrated in
Figure 13-20. Nicotine also appears to desensitize α4β2 postsynaptic receptors on inhibitory GABAergic
interneurons in the VTA (Figure 14-9); this also leads to DA release in nucleus accumbens by disinhibiting
dopaminergic mesolimbic neurons. Actions of nicotine on postsynaptic α7-nicotinic receptors in the prefrontal
cortex may be linked to the pro-cognitive and mentally alerting actions of nicotine, but not to addictive actions.
The α4β2-nicotinic receptors adapt to the chronic intermittent pulsatile delivery of nicotine in a way that leads to
addiction (Figure 14-10). That is, initially these receptors in the resting state are opened by delivery of nicotine,
Figure 14-9. Actions of nicotine. Nicotine directly causes dopamine release in the nucleus accumbens by binding to α4β2 nicotinic
postsynaptic receptors on dopamine neurons in the ventral tegmental area (VTA). In addition, nicotine binds to α7 nicotinic
presynaptic receptors on glutamate neurons in the VTA, which in turn leads to dopamine release in the nucleus accumbens.
Nicotine also seems to desensitize α4β2 postsynaptic receptors on GABA interneurons in the VTA; the reduction of GABA
neurotransmission disinhibits mesolimbic dopamine neurons and thus is a third mechanism for enhancing dopamine release in
the nucleus accumbens. PFC, prefrontal cortex; PPT/LDT, pedunculopontine tegmental and laterodorsal tegmental nuclei.

which in turns leads to dopamine release and reinforcement, pleasure, and reward (Figure 14-10A). By the time
the cigarette is finished, these receptors become desensitized, so that they cannot function temporarily and thus
cannot react either to acetylcholine or to nicotine (Figure 14-10A). In terms of obtaining any further reward, you
might as well stop smoking at this point. An interesting question to ask is: how long does it take for the nicotinic
receptors to desensitize? The answer seems to be: about as long as it takes to inhale all the puffs of a standard
cigarette and burn it down to a butt. Thus, it is probably not an accident that cigarettes are the length that they are.
Shorter does not maximize the pleasure. Longer is a waste since by then the receptors are all desensitized anyway
(Figure 14-10A).
The problem for the smoker is that when the receptors resensitize to their resting state, this initiates craving and
withdrawal due to the lack of release of further dopamine (Figure 14-10A). Another interesting question is: how
long does it take to resensitize nicotinic receptors? The answer seems to be: about the length of time that smokers
take between cigarettes. For the average one pack per day smoker awake for 16 hours, that would be about 45
minutes, possibly explaining why there are 20 cigarettes in a pack (i.e., enough for an average smoker to keep his
or her nicotinic receptors completely desensitized all day long).
Putting nicotinic receptors out of business by desensitizing them causes neurons to attempt to overcome this lack
of functioning receptors by upregulating the number of receptors (Figure 14-10B). That, however, is futile, since
nicotine just desensitizes all of them the next time a cigarette is smoked (Figure 14-10C). Furthermore, this
upregulation is self-defeating because it serves to amplify the craving that occurs when the extra receptors are
resensitizing to their resting state (Figure 14-10C).
From a receptor point of view, the goal of smoking is to desensitize all nicotinic α4β2 receptors, get the maximum
dopamine release at first, but eventually mostly to prevent craving. Positron emission tomography (PET) scans of
α4β2-nicotinic receptors in human smokers confirm that nicotinic receptors are exposed to just about enough
nicotine for just about long enough from each cigarette to accomplish this. Craving seems to be initiated at the
first sign of nicotinic receptor resensitization. Thus, the bad thing about receptor resensitization is craving. The
good thing from a smoker’s point of view is that as the receptors resensitize, they are available to release more
dopamine and cause pleasure or suppress craving and withdrawal again.

Treating nicotine dependence is not easy. There is evidence that nicotine addiction begins with the first cigarette,
with the first dose showing signs of lasting a month in experimental animals (e.g., activation of the anterior
cingulate cortex for this long after a single dose). Craving begins within a month of repeated administration.
Perhaps even more troublesome is the finding that the “diabolical learning” that occurs from substance abuse of
all sorts including nicotine may be very, very long-lasting once exposure to nicotine is stopped. Some evidence
suggests that these changes even last a lifetime, with a form of “molecular memory” to nicotine, even in long-term
abstinent former smokers. One of the first successful agents proven to be effective is nicotine itself, but in a route
of administration other than smoking: gums, lozenges, nasal sprays, inhalers, and transdermal patches. Delivering
nicotine by these other routes does not attain the high levels or the pulsatile blasts that are delivered to the brain
by smoking, so they are not very reinforcing. However, these alternative forms of nicotine delivery can help to
reduce craving due to a steady amount of nicotine that is delivered, presumably desensitizing an important number
of resensitizing and craving nicotinic receptors.
Another treatment for nicotine dependence is varenicline, a selective α4β2-nicotinic acetylcholine receptor partial
agonist (Figures 14-11 and 14-12). Figure 14-11 contrasts the effects of nicotinic partial agonists (NPAs) with
nicotinic full agonists and nicotinic antagonists on the cation channel associated with nicotinic cholinergic
receptors. Nicotinic full agonists include acetylcholine, a short-acting full agonist, and nicotine, a long-acting full
agonist. They open the channel fully and frequently (Figure 14-11, left). By contrast, nicotinic antagonists stabilize
the channel in the closed state, but do not desensitize these receptors (Figure 14-11, right). NPAs stabilize nicotinic
receptors in an intermediate state which is not desensitized and where the channel is open less frequently than
with a full agonist, but more frequently than with an antagonist (Figure 14-11, middle).
How addicting is tobacco, and how well do NPAs work to achieve cessation of smoking? About two-thirds of
smokers want to quit, one-third try, but only 2–3% succeed long-term. Of all the substances of abuse, some
surveys show that tobacco has the highest probability of making you become dependent when you have tried a
substance at least once (Table 14-3). It could be argued, therefore, that nicotine might be the most addicting
substance known. The good news is that the NPA varenicline triples or quadruples the 1-month, 6-month, and 1-
year quit rates compared to placebo; the bad news is that this means only about 10% of smokers who have taken
varenicline are still abstinent a year later. Many of these patients are prescribed varenicline for only 12 weeks,
which might be far too short a period of time for maximal effectiveness.
Another approach to the treatment of smoking cessation is to try to reduce the craving that occurs during
abstinence by boosting dopamine with the norepinephrine–dopamine reuptake inhibitor (NDRI) bupropion (see
Chapter 7, and Figures 7-35 through 7-37). The idea is to give back some of the dopamine downstream to the
craving postsynaptic D2 receptors in the nucleus accumbens while they are readjusting to the lack of getting their
dopamine “fix” from the recent withdrawal of nicotine (Figure 14-13). Thus, while smoking, dopamine is happily
released in the nucleus accumbens because of the actions of nicotine on α4β2 receptors on the VTA dopamine
neuron (Figure 14-13A). During smoking cessation, resensitized nicotinic receptors no longer receiving nicotine
are craving due to an absence of dopamine release in the nucleus accumbens (“where’s my dopamine?” – Figur
14-13B). When the NDRI bupropion is administered, theoretically a bit of dopamine is now released in the nucleus
accumbens, making the craving less but usually not eliminating it (Figure 14-13C). How effective is bupropion
in smoking cessation? Quit rates for bupropion are about half that of the NPA varenicline. Quit rates for nicotine
in alternative routes of administration such as transdermal patches are similar to those of bupropion. Novel
approaches to treating nicotine addiction include the investigation of nicotine vaccines and other direct-acting
nicotinic cholinergic agents.
Alcohol
The famous artist Vincent van Gogh reportedly drank ruinously, some speculating that he self-medicated his
bipolar disorder this way, a notion reinforced by his explanation, “If the storm within gets too loud, I take a glass
too much to stun myself.” Alcohol may stun but it does not treat psychiatric disorders adaptively long term.
Unfortunately, many alcoholics who have comorbid psychiatric disorders continue to selfmedicate with alcohol
rather than seeking treatment to receive a more appropriate psychopharmacologic agent. In addition to frequent
comorbidity with psychiatric disorders, it is estimated that 85% of alcoholics also smoke.
An oversimplified view of alcohol’s mechanism of action is that it enhances inhibition at GABA synapses and
reduces excitation at glutamate synapses. Alcohol actions at GABA synapses enhance GABA release via blocking
presynaptic GABAB receptors, and also directly stimulate postsynaptic GABAA receptors, especially those of the
δ subtype that are responsive to neurosteroid modulation but not to benzodiazepine modulation, either via direct
actions or by releasing neurosteroids (Figure 14-14). Delta subtypes of GABAA receptors are discussed in Chapter
9 and illustrated in Figure 9-21. Alcohol also acts at presynaptic metabotropic glutamate receptors (mGluRs) and
presynaptic voltagesensitive calcium channels (VSCCs) to inhibit glutamate release (Figure 14-15). mGluRs are
introduced in Chapter 4 and illustrated in Figures 4-22 and 4-23. VSCCs and their role in glutamate release are
introduced in Chapter 3 and illustrated in Figures 3-22 through 3-24. Alcohol may also have some direct or indirect
effects on reducing the actions of glutamate at postsynaptic NMDA receptors and at postsynaptic mGluR receptors
(Figure 14-15). Alcohol’s reinforcing effects are theoretically mediated not only by its effects at GABA and
glutamate synapses but also by actions at opioid synapses within mesolimbic reward circuitry (Figure 14-15).
Opioid neurons arise in the arcuate nucleus and project to the VTA, synapsing on both glutamate and GABA
neurons. The net result of alcohol actions on opioid synapses is thought to be the release of dopamine in the
nucleus acccumbens (Figure 14-15). Alcohol may do this either by directly acting upon μ-opioid receptors or by
releasing endogenous opioids such as enkephalin. These actions of alcohol create the rationale for blocking μ-
opioid receptors with antagonists such as naltrexone (Figure 14-16). Figure 14-7 also shows the presence of
presynaptic cannabinoid receptors at both glutamate and GABA synapses, where alcohol may have actions.
Cannabinoid antagonists such as rimonabant, which blocks CB1 receptors, can reduce alcohol consumption and
reduce craving in animals dependent upon alcohol.
Several therapeutic agents exploit the known pharmacology of alcohol and are approved for treating alcohol
dependence. One of these, naltrexone, blocks μ-opioid receptors (Figure 14-16). As for opioid abuse, μ-opioid
receptors theoretically also contribute to the euphoria and “high” of heavy drinking. It is therefore not surprising
that a μ-opioid antagonist would block the enjoyment of heavy drinking and increase abstinence by its actions
upon reward circuitry (Figure 14-16). This theory is supported by clinical trials, which show that naltrexone not
only increases the chances of attaining complete abstinence from alcohol, but also reduces “heavy drinking”
(defined as five or more drinks per day for a man and four or more for a woman).
Outcomes for patients with alcohol dependence who take naltrexone may be more favorable when the form of
naltrexone that is administrated is given once monthly by intramuscular injection, called XRnaltrexone. This may
be due to the fact that this method of drug administration forces compliance for at least a month. Monthly rather
than daily drug administration may be just what the reward circuitry needs for someone with a substance-abuse
problem. As discussed earlier in this chapter, patients addicted to various substances lose their ability to make
rational decisions, and instead respond immediately and impulsively to the desire to seek drugs, and have vast
capacity for denial of the maladaptive nature of their compulsive decisions. It is hard enough to get a patient with
a substance-abuse disorder to enter treatment or take medications at all, let alone make that person decide every
day not only to stay abstinent but also to take a medication. Addiction and human nature being what they are, it
is not surprising that patients frequently drop out of treatment and resume substance abuse. If you drink when you
take naltrexone, the opioids released do not lead to pleasure, so why bother drinking? Some patients may also of
course say, why bother taking naltrexone? – and relapse back into drinking alcohol. However, if you have been
given an injection that lasts for a month, and have an irresistible impulse to drink, and you “slip” and start to drink,
you are not able to discontinue your naltrexone. Thus, if you “drink over” your naltrexone, you may discover that
you do not get the buzz or enjoyment out of intoxication, and therefore might stop after a few drinks. You might
even become abstinent for several days again.
Acamprosate is a derivative of the amino acid taurine and interacts with both the glutamate system, to inhibit it,
and with the GABA system, to enhance it, a bit like a form of “artificial alcohol” (compare Figure 14-15 with
Figure 14-17). Thus, when alcohol is taken chronically and then withdrawn, the adaptive changes that it causes in
both the glutamate system and the GABA system create a state of glutamate overexcitement and even
excitotoxicity as well as GABA deficiency. Too much glutamate can cause neuronal damage, as discussed in
Chapter 13 and illustrated in Figures 13-28 and 13-29. To the extent that acamprosate can substitute for alcohol
in patients during withdrawal, the actions of acamprosate mitigate the glutamate hyperactivity and the GABA
deficiency (Figure 14-17). This occurs because acamprosate appears to have direct blocking actions on certain
glutamate receptors, particularly mGlu receptors (specifically mGluR5 and perhaps mGluR2). One way or
another, acamprosate apparently reduces the glutamate release associated with alcohol withdrawal (Figure 14-17).
Actions, if any, at NMDA receptors may be indirect, as are actions at GABA systems, both of which may be
secondary downstream effects from acamprosate’s actions on mGlu receptors (Figure 14-17).
Disulfiram is the classic drug for treating alcoholism. It is an irreversible inhibitor of aldehyde dehydrogenase
and, when alcohol is ingested, results in the build-up of toxic levels of acetaldehyde. This creates an aversive
experience with flushing, nausea, vomiting, and hypotension, hopefully conditioning the patient to a negative
rather than positive response to drinking. Obviously, compliance is a problem with this agent, and its aversive
reactions are occasionally dangerous.
Experimental agents that show some promise in treating alcohol dependence include the anticonvulsant topiramate
(discussed in more detail below in the section on obesity), the 5HT3 antagonists (mechanism discussed in Chapter
7 and illustrated in Figure 7-46), and cannabinoid CB1 receptor antagonists. New opioid antagonists such as
nalmefene (Selinco) are also in late-stage clinical testing. The subject of how to treat alcohol abuse and
dependence is obviously complex, and the psychopharmacological treatments are most effective when integrated
with structured therapies such as 12-step programs, a topic which is beyond the scope of this text. Hopefully,
clinicians will learn how to better leverage the various treatments for alcoholism that are available today, and
determine whether they can be used to treat this devastating illness to attain far better outcomes than are available
when no treatment is provided, accepted, or sustained.

Sedative hypnotics
Sedative hypnotics include barbiturates and related agents such as ethclorvynol and ethinamate, chloral hydrate
and derivatives, and piperidinedione derivatives such as glutethimide and methyprylon. Experts often include
alcohol, benzodiazepines (discussed in Chapter 9), and Z-drug hypnotics (discussed in Chapter 11) in this class
as well. The mechanism of action of sedative hypnotics is basically the same as those described in Chapter 9 and
illustrated in Figure 9-23 for the action of benzodiazepines: namely, they are positive allosteric modulators
(PAMs) for GABAA receptors. Actions of sedative hypnotics are at GABA A receptor sites in reward circuits
(Figure 14-7). Molecular actions of all sedative hypnotics are similar, but benzodiazepines and barbiturates seem
to work at different sites from each other, and also only on some GABAA receptor subtypes, namely those with
α1, α2, α3, or α5 subunits (Figure 14-14). Barbiturates are much less safe in overdose than benzodiazepines, cause
dependence more frequently, are abused more frequently, and produce much more dangerous withdrawal
reactions. Apparently, the receptor site at GABAA receptors mediating the pharmacologic actions of barbiturates
is even more readily desensitized with even more dangerous consequences than the benzodiazepine receptor
(Figure 14-14). The barbiturate site must also mediate a more intense euphoria and a more desirable sense of
tranquility than the benzodiazepine receptor site. Since benzodiazepinesare generally an adequate alternative to
barbiturates, psychopharmacologists can help to minimize abuse of barbiturates by prescribing them rarely if ever.
In the case of withdrawal reactions, reinstituting and then tapering the offending barbiturate under close clinical
supervision can assist the detoxification process.

Opioids
Opioids act as neurotransmitters released from neurons that arise in the arcuate nucleus and project both to the
VTA and to the nucleus accumbens, and release enkephalin (Figure 14-18). Naturally occurring endogenous
opioids act upon a variety of receptor subtypes. The three most important receptor subtypes are the μ-, δ-, and κ-
opioid receptors (Figure 14-18). The brain makes a variety of its own endogenous opioid-like substances,
sometimes referred to as the “brain’s own morphine.” These are all peptides derived from precursor proteins called
pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin (Figure 14-18). Parts of these precursor
proteins are cleaved off to form endorphins, enkephalins, or dynorphins, stored in opioid neurons, and presumably
released during neurotransmission to mediate endogenous opioid-like actions, including a role in mediating
reinforcement and pleasure in reward circuitry (Figure 14-7).
Exogenous opioids in the form of pain relievers (such as oxycodone, hydrocodone, and many others) or drugs of
abuse (such as heroin) are also thought to act as agonists at μ-, δ-, and κ-opioid receptors, particularly at μ sites.
At and above pain-relieving doses, the opioids induce euphoria, which is the main reinforcing property of the
opioids. Opioids can also induce a very intense but brief euphoria, sometimes called a “rush,” followed by a
profound sense of tranquility which may last several hours, followed in turn by drowsiness (“nodding”), mood
swings, mental clouding, apathy, and slowed motor movements. In overdose, these same agents act as depressants
of respiration, and can also induce coma. The acute actions of opioids can be reversed by synthetic opioid
antagonists, such as naloxone and naltrexone, which compete as antagonists at opioid receptors.