Addiction, Dependence, and Tolerance

• Physical dependence involves dependence.
• Psychological dependence involves addiction.
• All addictive drugs induce feelings of euphoria and reward.
• Tolerance develops that requires higher doses to achieve the same effect.
• The absence of the drug induces withdrawal.
• Dependence is defined by the signs of withdrawal.
• Addiction is compulsive, relapsing drug use despite negative consequences.
• All addictive drugs increase dopamine (DA) levels in the CNS.
• Increased DA in the mesolimbic system leads to reward and reinforcement.

Dependence, Tolerance, and Withdrawal

• Pharmacokinetic tolerance means less drug arrives at the receptor and there is a shorter duration of action at the receptor because of faster removal.
• Pharmacodynamic tolerance means changes occur in the mu receptor with receptor desensitization and internalization.
• Withdrawal is poorly understood, but signs of withdrawal indicate dependence.

Addiction a Disease of Maladaptive Learning

• Addictive individuals have relapses.
• Relapse may be triggered by re-exposure to the drug, stress, or exposure to a context that recalls prior drug use.
• Patients being treated for Parkinson's with DA agonists may become pathologic gamblers.
• DA agonists can result in 1 of 7 patients developing addiction-like behavior.
• Only a small number of dependent users progress to addiction.
• See Table 32-1 for a list of addiction potential for different drugs from a low of 1 to a high of 5.
• Note the three level classification (G protein receptor coupled, ionotropic receptor

Nonaddictive Drugs of Abuse

• Some drugs of abuse do not lead to addiction because they do not induce sensations of reward and euphoria like the hallucinogens and dissociative anesthetics.
• Examples of Nonaddictive Drugs of Abuse: LSD and PCP (angel dust).

Pharmacology of Drugs of Abuse

• All addictive drugs increase DA levels in the mesolimbic projections.
• Addictive drugs can be put into three groups:
  • Act through G-protein coupled receptors; examples include: opioids, GHB, and hallucinogens (LSD, PCP).
  • Act through inotropic receptors or ion channels; examples include: nicotine, alcohol, benzodiazepines, dissociative anesthetics, and some inhalants.
  • Bind to monoamine transporters: examples include: cocaine, amphetamines, and ecstasy.

Drugs that Activate G10 Coupled Receptors

• Opioids inhibit adenylyl cyclase through G-protein coupled receptors.
• Naloxone reverses opioid overdose.
• Methadone or buprenorphine are used as substitutes for morphine in drug treatment programs.

Cannabinoids

• Endogenous cannabinoids (pot made by the brain) include include 2-arachidonyl glycerol and anandamide.
• These are called endocannabinoids (endogenous cannabinoids).
• Cannabinoids inhibit the release of GABA and glutamate.
• Marijuana contains the active ingredient tetrahydrocannabinal (THC).
• THC disinhibits DA neurons through inhibition of GABA neurons.
• The relative risk for addiction is low at a 2.
• Dronabinol and nabilone are two FDA-approved forms of THC used to treat a wide range of disorders including pain and nausea following chemotherapy.

Gamma-Hydroxybutyric Acid (GHB)

• GHB binds to GABAB receptors.
• GHB causes euphoria, enhanced sensory perceptions, and amnesia.
• GHB easily dissolves in alcoholic drinks and is called the "date rape" drug.

LSD, Mescaline & Psilocybin

• These induce neither dependence nor addiction.
• These often produce flashbacks up to years later.
• These increase glutamate release in the cortex.
• Another main target is the 5HT2A receptor.

Drugs That Mediate Their Effects Via Ionotropic Receptors

• Nicotine activates nicotinic Ach receptors.
• Nicotine excites projection neurons and causes release of DA, which explains potential for addiction.
• Its addictive potential is 4 on a scale of 1 to 5 (highest).
• Cytosine and varenicline are used to treat addiction because they block Ach receptors linked to DA release.

Benzodiazepines

• These a moderate risk for abuse.
• Dependence is very common.
• Addiction is rare.
• Withdrawal occurs within days after stopping the drug.
• Rewarding effects may occur because GABA receptors modulate (disinhibit) the mesolimbic DA system, resulting in reward effects.

Alcohol

• The withdrawal syndrome begins 6-12 hours after the last drink and includes tremor, nausea, vomiting, excessive sweating, agitation, and anxiety (for the alcoholic).
• 12-24 hours after the last drink visual and auditory hallucinations may occur.
• 24-48 hours after the last drink generalized seizures may occur.
• 48-72 hours after the last drink delirium tremens (alcohol withdrawal) may occur.
• Delirium tremens has a 5-15% mortality rate.
• Treatment includes supportive measures including benzodiazepines.

Ketamine & Phencyclidine (PCP)

• These were developed originally as general anesthetics.
• Only ketamine is still used as an anesthetic.
• Both ketamine and PCP are antagonists of NMDA receptors.
• Post-op patients reported vivid dreams and hallucinations.
• Both have a low potential for addiction, but long-term use can lead to psychosis closely resembling schizophrenia.

Inhalants

• These are chemical vapors with recreational use, like nitrates, ketones, and aromatic and aliphatic hydrocarbons (toluene etc).
• Sniffing is inhalation from an open container.
• Huffing is inhalation from a soaked cloth.
• Bagging is breathing in and out from a bag filled with solvent.
• The mechanism of action is not well understood.

Cocaine

• Cocaine i highly addictive (relative risk = 5).
• Heating cocaine in an alkaline solution yields free base, also known as crack cocaine.
• Crack is the form of cocaine that can be smoked.
• Cocaine blocks the reuptake of DA, 5HT, and NE within the CNS.
• Rewarding effects may come from the increase of DA in the nucleus accumbens.
• The increase in NE levels leads to increased blood pressure.
• There is no approved pharmacological treatment available for cocaine addiction.

Amphetamines

• Amphetamines cause the release of NE and DA from synaptic vesicles.
• Drugs are taken up by reuptake transporters into neurons where the drug depletes storage vesicles.
• Amphetamines are highly addictive.

Ecstasy (MDMA)

• Ecstasy is a derivative of the amphetamine-related compound methylene-dioxymethamphetamine (MDMA).
• Ecstasy is a designer drug sold at rave parties.
• Blocks 5HT reuptake.

Drugs to Learn (mechanisms of action)

• G10 Coupled Receptor: Includes opioids (morphine, naloxone, heroin, codeine, oxycodone, meperidine, methadone, or buprenorphine) and cannabinoids (marijuana, THC, hashish, dronabinol).
• Gamma hydroxybutyric acid (GHB).
• Hallucinogens: lysergic acid diethylamide (LSD), phencyclidine (PCP), ketamine, mescaline or psilocybin.
• Actions Through Ionic Channels or Ionotropic Receptors: nicotine, alcohol, benzodiazepines, dissociative anesthetics, inhalants (nitrates, ketones, or aromatic hydrocarbons), or barbiturates.
• Actions Through Monoamine Transporters (Reuptake Pumps): cocaine, amphetamines or ecstasy.

Other chemicals discussed

• rimonabant
• oxazepam
• lorazepam acamprosate (N-methyl-D-aspartate (NMDA) receptor antagonist
• naltrexone
• ethamol
• bupropion
• heroin
• codeine
• oxycodone
• meperidine

Overview of physical dependence, psychological dependence and tolerance. Addictive drugs induce euphoria and increased dopamine levels. Tolerance requires higher doses and absence of the drug induces withdrawal. Addiction causes compulsive, relapsing drug use despite negative consequences.