Psychostimulants

George F. Koob,Michael A. Arends,Mandy L McCracken,Michel Le Moal

• Publisher: Academic Press
• Year: 2020
• ISBN:
  9780128169919
• Topic: Psychologie
• Subtopic: Neuropsychologie

A current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction are detailed in our Neurobiology of Addiction series, each volume addressing a specific area of addiction. Psychostimulants, Volume 2 in the series, explores the molecular and cellular systems in the brain responsible for psychostimulant addiction, including both direct/indirect sympathomimetics and nonsympathomimetics. This volume introduces the readers to the history of psychostimulant use. The authors clearly differentiate the neurobiological effects into three distinct stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

• Highlights recent advances in psychostimulant addiction
• Includes neurocircuitry, cellular and molecular neurobiological mechanisms of psychostimulant addiction
• Defines the abuse and addiction potentials of both direct and indirect sympathomimetics and nonsympathomimetics

Volume TWO

Psychostimulants

Abstract

Psychostimulant drugs, such as cocaine and amphetamines, of the indirect sympathomimetic class have a long history as tonics and other preparations to allay fatigue and sustain performance. These drugs also have a long history of abuse and dependence. Abuse potential varies with the availability of the drug both environmentally and physiologically, with intravenous and smoked forms of both cocaine and amphetamines producing much more severe substance use disorder. Cocaine and amphetamines have a characteristic abuse cycle that involves binge administration, withdrawal dysphoria, paranoia, and psychosis-like symptoms as the cycle continues or intensifies. Significant advances have been made in our understanding of the mechanisms of action of psychomotor stimulant drugs at the behavioral, neuropharmacological, cellular, and molecular levels that can be heuristically framed in the three-stage cycle of addiction:  binge/intoxication, withdrawal/negative affect, and  preoccupation/anticipation. Eventually, three corresponding domains and neurocircuits coalesced around these three stages: binge/intoxication (incentive salience/pathological habits domain, basal ganglia neurocircuits), withdrawal/negative affect (negative affect domain, extended amygdala), and preoccupation/anticipation (executive function, prefrontal cortex). Thus, the new revised book, Neurobiology of Addiction, is now organized along the three stage/three domain construct while retaining synthesis at the circuit, cellular, and molecular levels of analysis.

Keywords

Addiction; Amphetamine; Cocaine; Dark side; Dependence; Methamphetamine; Neurobiology; Neurocircuitry; Psychostimulant; Withdrawal

1. Acknowledgements
2. 1. Definitions
3. 2. History of psychostimulant use
4. 3. Physiological effects
5. 4. Behavioral effects
6. 5. Pharmacokinetics
7. 6. Behavioral mechanism of action
8. 7. Medical use, abuse, and addiction
   1. 7.1 Medical uses
   2. 7.2 Psychostimulant abuse cycle
   3. 7.3 Withdrawal
9. 8. Neurobiological effects
   1. 8.1 Binge/intoxication stage: acute reinforcing and stimulant effects
      1. 8.1.1 Neurobiological mechanism: neurocircuitry
      2. 8.1.2 Neurobiological mechanism: cellular
      3. 8.1.3 Neurobiological mechanism: molecular
      4. 8.1.4 Sex differences
      5. 8.1.5 Summary of binge/intoxication stage
   2. 8.2 Withdrawal/negative affect stage: withdrawal and dependence
      1. 8.2.1 Neurobiological mechanism: tolerance
      2. 8.2.2 Neurobiological mechanism: neurocircuitry
      3. 8.2.3 Neurobiological mechanism: cellular
      4. 8.2.4 Neurobiological mechanism: molecular
      5. 8.2.5 Summary of withdrawal/negative affect stage
   3. 8.3 Preoccupation/anticipation stage: reinstatement
      1. 8.3.1 Neurobiological mechanism: neurocircuitry
      2. 8.3.2 Neurobiological mechanism: cellular
      3. 8.3.3 Neurobiological mechanism: molecular
      4. 8.3.4 Summary of preoccupation/anticipation stage
10. 9. Overall summary
11. References

1. Definitions

Psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, have medical uses but also considerable abuse potential. There are two major classes of psychomotor stimulants (Table 1, Fig. 1): (1) direct or indirect sympathomimetics, such as cocaine and amphetamine, and (2) nonsympathomimetics. This volume focuses on indirect sympathomimetics. Indirect sympathomimetic compounds, such as cocaine and amphetamines, share a common molecular structure—a benzene ring with an ethylamine side chain. Amphetamine differs from the parent compound, β-phenethylamine, by the addition of a methyl group, whereas methamphetamine has two additional methyl groups. Psychomotor stimulants are drugs that produce behavioral activation that is usually accompanied by increases in arousal, alertness, and motor activity. The term sympathomimetic derived originally from the description of the mechanism of action of these drugs. Sympathomimetics mimic the action of the sympathetic nervous system when it is activated. The term sympathin was originally used to describe the hormone noradrenaline (norepinephrine) in the central nervous system [1–3]. Thus, sympathomimetic drugs mimic the peripheral actions of norepinephrine in the autonomic system and neuropharmacologically either directly or indirectly activate monoamine receptors. Indirect sympathomimetics mimic this action by acting on neuronal mechanisms that do not involve the direct activation of postsynaptic receptors. The present volume focuses only on the neurobiological mechanisms that are involved in the addiction liability of indirect sympathomimetics. Nonsympathomimetics act via different neuropharmacological mechanisms altogether.

Table 1

Psychomotor stimulant drugs.

Direct sympathomimetics	Indirect sympathomimetics	Nonsympathomimetics
Isoproterenol Epinephrine Norepinephrine Phenylephrine Phenylpropanolamine Apomorphine	Amphetamine Methamphetamine Cocaine Methylphenidate Phenmetrazine Pipradrol Tyramine Pemoline	Caffeine Nicotine Scopolamine Strychnine Pentylenetetrazol Modafinil

Fig. 1 Chemical structures of various psychostimulants.

Historically, there have been numerous eras of stimulant addiction that are often linked to ease of access and distorted or misinformed perceptions of the abuse potential of these drugs [4] (Fig. 2).

2. History of psychostimulant use

Cocaine is derived from the coca plant (Erythroxylum coca) and has a long history as a stimulant. Cocaine has been used for centuries in tonics and other preparations to allay fatigue, sustain performance, and treat a large variety of ailments [5,6]. Cocaine was once a component of Coca Cola®, and its extract from the coca plant (without cocaine) is still used as an ingredient today. In 1886, the druggist John Styth Pemberton devised a patented medicine that contained two natural stimulants, cocaine and caffeine, to formulate the syrup base for Coca-Cola®. He blended a whole-leaf extract of coca with an extract from the African kola nut that contains caffeine. Coca-Cola® was initially manufactured and marketed as an “intellectual beverage” and “brain tonic,” and until 1903 Coca-Cola® contained approximately 60 mg cocaine per 8 ounce serving. It was also touted as a temperance drink because it had no alcohol though cocaine was still a key ingredient. The manufacturer believed that their product should not only be strongly associated with cocaine by the product name but also that the product pa...