Human Physiology, 14th edition (2016)

The Central Nervous System 229

Figure 8.21 Dopaminergic pathways in the brain. Axons that use dopamine as a neurotransmitter (that are dopaminergic)
leave the substantia nigra of the midbrain and synapse in the corpus striatum. This is the nigrostriatal system, used for motor control.
Dopaminergic axons from the ventral tegmental area of the midbrain to the nucleus accumbens and prefrontal cortex constitute the
mesolimbic system, which functions in emotional reward.

Nigrostriatal

dopamine system

Prefrontal

cortex

Mesolimbic

dopamine system

Corpus striatum

Caudate

nucleus

(head)

Nucleus

accumbens

Medial

forebrain

bundle

Pons

Cerebellum

Fourth

ventricle

Locus ceruleus

Substantia nigra

Ventral

tegmental area

Corpus callosum

Caudate

nucleus (tail)

Putamen

CLINICAL APPLICATION

The positive reinforcement elicited by abused drugs involves

the release of dopamine by axons of the mesolimbic dopa-

mine system. These axons arise in the midbrain and termi-

nate in the nucleus accumbens of the forebrain. Nicotine

from tobacco stimulates dopaminergic neurons in the mid-

brain by means of nicotinic ACh receptors. Chronic exposure

to nicotine desensitizes the nicotinic ACh receptors in the

midbrain, contributing to nicotine tolerance and increased

dependence. The opioids ( heroin and morphine ) stimulate

opioid receptors, and the cannabinoids (from marijuana )

stimulate endocannabinoid receptors in the midbrain. This

leads to reduced activity of GABA-releasing inhibitory neu-

rons that synapse on the dopaminergic neurons in the ven-

tral tegmental area. Benzodiazepines ( Valium and zolpidem )

may similarly reduce the inhibition of these dopaminergic

neurons, increasing dopamine release by the mesolimbic

system. Cocaine and amphetamines promote dopamine

stimulation in the nucleus accumbens by inhibiting the reup-

take of dopamine into presynaptic axons. Ironically, drug

abuse can desensitize neurons to dopamine and so lessen

the rewarding effects of dopamine release. Ethanol ( alcohol )

stimulates the mesolimbic dopamine pathways, particularly

in the nucleus accumbens, but it also affects receptors for

other neurotransmitters and thereby affects the function of a

variety of brain regions.

The immediately rewarding effects of addictive drugs

appear to be mediated by dopamine released in the nucleus

accumbens, and this reward reinforces drug-seeking behav-

ior. The nucleus accumbens receives information regarding

emotions from other limbic system structures (amygdala,

hippocampus, and frontal cortex) and has output to the cor-

pus striatum (caudate nucleus and globus pallidus). This

affords it an ability to relate emotions to motivated actions.

Stopping the use of an addictive drug (such as nicotine)

can produce withdrawal symptoms, which cause anxiety and

stress. To avoid this, the person may relapse —that is, resume

the use of the drug despite the desire to quit and the knowledge

of its negative consequences. For example, despite knowing

that smoking causes 1 in 5 deaths per year in the United States

(over 5 million deaths worldwide per year), each year only 3%

of smokers who attempt to quit unaided are successful. Evi-

dence suggests that relapse may result from some failure of