Psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, have medical uses but also considerable abuse potential
(Figure 4.1). Direct and indirect sympathomimetics, such as cocaine and amphetamine, and nonsympathomimetics are two major classes of psychostimulants
(Table 4.1, Box 4.1). This section focuses solely on indirect sympathomimetics. All indirect sympathomimetic compounds are chemically similar and share a common structure – a benzene ring with an ethylamine side chain. Amphetamine differs from its parent compound, β-phenethylamine, by the addition of a methyl group, whereas methamphetamine has two additional methyl groups (Box 4.2).
Psychomotor stimulants are drugs that produce behavioral activation, usually accompanied by increased arousal, alertness, and motor activity. Historically, eras of increased stimulant addiction in the general population have been linked to the increased availability and distorted or misinformed perceptions of the abuse potential of these drugs. This section describes psychostimulant use, abuse, and addiction, and delves into the physiological, behavioral, and neuroscientific mechanisms by which the psychostimulant effects occur.
Figure 4-1 From nonhumans to humans, cocaine and related psychostimulants have numerous effects on the brain and behavior. [From: Sanchez-Ramos JR, Neurological complications of cocaine abuse include seizure and strokes, The Psychiatric Times, 1990, February, pp. 20, 22. © 2013. UBM Medica. 103986:8135P.]
Psychomotor Stimulant Drugs
WHAT IS AN INDIRECT SYMPATHOMIMETIC?
A drug that indirectly mimics “sympathin,” which was the original term for norepinephrine (also known as noradrenaline). Norepinephrine is well known to be a primary mediator of the sympathetic nervous system (“fight or flight” response), which is a part of the autonomic nervous system. An indirect sympathomimetic is a drug that increases the availability of norepinephrine in the synapse by promoting neurotransmitter release, blocking neurotransmitter reuptake, or blocking transmitter metabolism. Note that the hormones norepinephrine (a.k.a., noradrenaline) and epinephrine (a.k.a., adrenaline) do not cross the blood-brain barrier. Therefore, any release in the brain is caused by the indirect sympathomimetics, which themselves cross the blood-brain barrier.
SYNOPSIS OF THE NEUROPHARMACOLOGICAL TARGETS FOR PSYCHOSTIMULANTS
Cocaine, amphetamines, and methamphetamine are indirect sympathomimetics that increase the availability of monoamine neurotransmitters at the synapse, such as dopamine, norepinephrine, and serotonin. All three drugs bind to the dopamine, norepinephrine, and serotonin reuptake transporters to block the reuptake of monoamines. Amphetamines and methamphetamine also bind to the vesicular transporter and enhance the release of monoamines into the synapse. The enhanced availability of monoamines at the synapse are transduced by five different dopamine receptors, two different families of norepinephrine receptors, and seven different families of serotonin receptors throughout different regions of the brain. The psychostimulant effects of indirect sympathomimetic psychostimulants are largely mediated by the release of dopamine which acts on dopamine receptors in the terminal areas of the mesocorticolimbic dopamine system and nigrostriatal dopamine system in the frontal cortex–nucleus accumbens-amygdala and corpus striatum, respectively. The addiction potential of psychostimulants largely derives from powerful within-system neuroadaptations (signal transduction mechanisms) and between-system neuroadaptations (neurocircuitry changes) in the brain motivational and stress systems.