Neurobiological Effects

Endogenous Brain Dopamine Systems

At the neuropharmacological level, indirect sympathomimetics, such as amphetamine and cocaine, enhance the amount of monoamines available within the synaptic cleft in the central nervous system, but for the psychotropic actions related to psychostimulant addiction the effects are largely mediated by the monoamine dopamine. Numerous ways exist to enhance neurotransmission and increase levels of neurotransmitters: enhance synthesis, enhance release from presynaptic vesicles, block reuptake of the neurotransmitter back into the presynaptic terminal, and block enzymes that metabolize the neurotransmitters (see Introduction to the Neuropsychopharmacology; Figure 4.12). Amphetamine and cocaine, for example, block the reuptake of the neurotransmitters norepinephrine, dopamine, and serotonin, but each drug affects each neurotransmitter in different ways and to differing degrees. The rank order of potency for cocaine’s ability to block monoamine reuptake is serotonin > dopamine > norepinephrine, and for methamphetamine and D-amphetamine the rank order for their ability to block reuptake and facilitate release is norepinephrine ≥ dopamine > serotonin. Amphetamine inhibits monoamine oxidase to some extent. All of these actions contribute to the psychomotor stimulant and reinforcing effects of indirect sympathomimetics, but a key neurotransmitter for the psychostimulant effects of all of these drugs is dopamine.

FIGURE 4.12 Cocaine increases the quantity of dopamine present in the synapse by blocking neurotransmitter reuptake. Amphetamine increases the quantity of dopamine present in the synapse by increasing neurotransmitter release. (A) Normal release and reuptake of dopamine from the presynaptic terminal. (B) Blockade of reuptake by cocaine increases dopamine in the synaptic cleft. (C) Increased dopamine release is produced by amphetamine, in which amphetamine reverses the action of the dopamine transporter.

BOX 4.10


A 24-year-old white female worked as a secretary and had no history of significant prior depression. She periodically used cocaine by the intranasal route, and, at one point, was given an unusually large quantity of cocaine. (The material was professionally analyzed by a street drug analysis laboratory in the San Francisco Bay Area, which found it to contain 93 percent cocaine.) After “snorting” five to eight lines of the cocaine per night for several days, she began waking up feeling depressed. To overcome this depression, and go to work, she snorted one to two lines of cocaine in the morning. By the end of the second week, she was progressively developing severe anxiety, depression and increasing irritability which was interfering with her interpersonal relationships. Her concern over this drug-induced depression and anxiety faded in approximately two days and she re-established her usual level of positive affect and mood. Since this occurrence, she periodically uses cocaine in social-recreational settings; however, she is careful to keep her dosage at a low enough level to avoid recurrence of this drug-induced depression. Wesson DR, Smith DE, Cocaine: its use for central nervous system stimulation including recreational and medical uses. In: Petersen RC, Stillman RC (Eds.), Cocaine: 1977, (series title: NIDA Research Monograph, vol. 13), National Institute on Drug Abuse, Rockville MD, 1977, pp. 137–152.

BOX 4.11


Phase 1 (the “crash”) – Day 1 to 4

dysphoria, decreased energy, agitation, depressive symptoms, craving, anxiety, paranoia, hyperphagia (dramatically increased appetite), insomnia

Phase 2 – Week 1 to 10

prolonged dysphoria, anhedonia, lack of motivation, craving

Phase 3 – Indefinite episodic craving

BOX 4.12


A 31-year-old white male law student in his fourth year of law school had a long history of experimental drug use including alcohol (his first drug), marijuana and LSD; but at no time had he abused a psychoactive drug. Approximately two years ago he was introduced to cocaine in a social setting by a group of friends and fellow law students. He became a regular recreational user of cocaine and in a social setting during an evening would chop up and snort between 10 and 20 lines of cocaine in the usual fashion. (Often, as with this case, cocaine is used in a recreational setting along with alcohol and marihuana.) With this law student, the pattern of recreational cocaine use continued for some time, but moved to a more daily pattern when he found that the inhalation of cocaine stimulated his performance and ability to study at night, something he found desirable because he had begun to prepare for the bar examinations. One evening, a female friend with whom he was periodically having sexual relations produced a needle and syringe and indicated that the injection of cocaine produced a pleasurable, orgasmic-like “rush.” The law student injected the cocaine simultaneously with his female sexual acquaintance and found the orgasmic “rush” quite desirable. Over a several month period he escalated his intravenous cocaine use on a daily basis, injecting from approximately 10 p.m. until 7 a.m., on a 15 minute to 1 hour repeated schedule, using approximately 2 g of cocaine per night. Despite the fact that the law student was independently wealthy as a result of a family inheritance, he found that he was rapidly consuming his inheritance as his cocaine habit was costing him $50–150 per day. As a consequence he began dealing cocaine to his friends in order to help support his own habit. While the injection of cocaine involved both male and female figures, he would almost invariably inject with a woman in a sexual context, although he reported that as he became more deeply involved with cocaine, his libido dropped dramatically; for both he and his female sexual partners, the orgasmic effects of the cocaine injection became a substitute for actual sexual intercourse. One evening he injected a female friend in his usual fashion (he would first inject the woman and then himself). She suddenly had a series of seizures, became comatose, required mouth-to-mouth resuscitation and was subsequently transported to an emergency room. During this particular cocaine run, he also experienced the first evidence of a cocaine psychosis, with auditory and visual hallucinations and extreme paranoia. The negative effects both on himself and on his girlfriend were quite shocking, because he had believed cocaine to be as free of adverse consequences as marihuana. Because of these two episodes, he decided to quit cocaine use and seek treatment. During the “withdrawal period” he experienced difficulty sleeping and a severe drug-induced depression associated with anxiety that lasted for approximately one week. Most depressive symptoms gradually abated; however, the anxiety continued along with an urge to use cocaine late in the evening at the time for his previous cocaine runs. To help with the anxiety, depression and sleep disorder, 10 mg of Valium(R) p.o. was administered each night. As there was no evidence of a prolonged underlying depression which preceded the cocaine abuse or that lasted following the “fade out” period of the drug-induced depression, no tricyclic antidepressants were administered. He made a decision to self-medicate the lethargy and reactive depression with the intranasal use of cocaine which he resumed on a daily basis. He expressed great surprise at the toxic effects of cocaine, but was also quite ambivalent about whether he would completely discontinue cocaine.

Wesson DR, Smith DE, Cocaine: its use for central nervous system stimulation including recreational and medical uses. In: Petersen RC, Stillman RC (Eds.), Cocaine: 1977, (series title: NIDA Research Monograph, vol. 13), National Institute on Drug Abuse, Rockville MD, 1977, pp. 137–152.

Dopamine neurons are organized into major pathways in the brain which originate in the midbrain and project to numerous forebrain and cortical regions (see Introduction to the Neuropsychopharmacology). Each projection is responsible for particular psychomotor stimulant actions. The mesocorticolimbic dopamine system originates in the ventral tegmental area and projects to the ventral forebrain, including the nucleus accumbens, olfactory tubercle, septum, and frontal cortex. It mediates exploratory activity, incentive salience, and locomotor activity induced by indirect sympathomimetics. The nigrostriatal dopamine system originates in the substantia nigra and projects to the corpus striatum and is associated with motor function and response initiation and mediates stereotyped behavior produced by psychostimulants. Degeneration or destruction of the nigrostriatal and mesocorticolimbic dopamine systems (by disease, trauma, or experimental lesions) results in the severe motor disturbances observed in Parkinson’s disease patients, including tremor, dystonic involuntary movements, and akinesia. Large bilateral lesions of the midbrain dopamine system using the selective dopamine neurotoxin 6-hydroxydopamine reproduce many of these Parkinsonian-like deficits. Rats become akinetic to the point of aphagia (won’t eat) and adipsia (won’t drink) and will die unless intubated by the experimenter. These rats also exhibit severe learning deficits in a conditioned avoidance task, in which an animal learns to avoid an aversive stimulus (such as a footshock) by responding to a cue that precedes the aversive stimulus. The motor and learning impairments can be successfully treated with L-DOPA (3,4-dihydroxy-L-phenylalanine, also called levodopa), a dopamine precursor for dopamine synthesis that makes more dopamine available in the synapse (Box 4.13).

Destruction of the mesocorticolimbic dopamine system with 6-hydroxydopamine blocks amphetamine- and cocaine-stimulated locomotor activity, and similar effects have been observed following injections of selective dopamine receptor antagonists into the nucleus accumbens. Functional disruption of the nigrostriatal dopamine system blocks the stereotyped behavior associated with high-dose D-amphetamine. Specific 6-hydroxydopamine lesions of the dorsal striatum block the intense, restricted, repetitive behavior produced by high-dose amphetamine, resulting in more robust locomotor activity. Notably, however, the functions of the mesocorticolimbic or nigrostriatal dopamine system largely depend on their specific connections and not any intrinsic functional attributes.

BOX 4.13


Historically in neuroscience, the technique of destroying neurons to observe functional deficits has been used extensively to delineate function. Conceptually, such techniques have proved significant when positive results have been obtained, with the proper controls and interpretations. However, negative results with lesion studies have always been suspect because of the issue of redundancy. Three types of lesion techniques have been used. With electrolytic lesions, sufficient current is passed through the tip of an electrode to destroy the tissue in the immediate area around the tip of the electrode. The amount of tissue destroyed is directly related to the current intensity and size of the electrode. With cell body-specific lesions, a drug such as ibotenic acid is used that overexcites the cell to the extent that the cell dies. Such lesions are specific to cell bodies and in theory do not destroy fibers of passage. Lesions of the terminal projections of specific neurochemical systems can be effected using neurotoxins that are taken up by the nerve terminals and selectively destroy them. 6-Hydroxydopamine is selectively taken up by dopamine and norepinephrine nerve terminals and has been shown to selectively deplete either pathways or terminal areas of dopamine and norepinephrine, respectively. To selectively destroy dopamine neurons, a noradrenergic reuptake inhibitor can be concomitantly administered to spare uptake of 6-hydroxydopamine into the norepinephrine projections.
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