General Principles of Drug Use Use is not abuse Most users do not abuse or form dependence (Who? When? Where? Why?) Every drug has multiple effects Although a user might seek only one effect, drugs work at multiple sites in the brain and other organs Amount matters Larger doses, more frequent doses, or faster onset of effects can produce different effects compared to small doses User’s history and expectations affect drug-related effects Experience and Expectation matters Drugs are not good or bad Drugs are chemicals on a shelf that are inactive until they enter the body Blaming the substance ignores all the factors that may lead to abuse

Drug Related Terms Drug Any substance, natural or artificial, other than food, that by its chemical nature alters structure or function in a living organism Illicit drug A drug that is unlawful to possess or use Deviant drug use Drug use that is not common within a social group and disapproved Drug misuse Drug use in greater amounts than, or for purposes other than, those prescribed Drug abuse Substance use in a manner, an amount, or in situations such that it causes social, occupational, psychological, or physical problems Drug dependence A state in which an individual uses a drug so frequently or consistently that it would be difficult for the person to stop

History of Drug Use Advances in chemistry Syringe development Drug laws or lack thereof Addiction Models “War on Drugs”

History of Drug Use

Drug Schedule Criteria

Correlates of Drug Use Gender Race and ethnicity Level of education Men use more drugs than women Race and ethnicity Caucasians are more likely to drink alcohol than African Americans Level of education College graduates are less likely to smoke tobacco than high school graduates Personality variables “Impulsive” individuals may use drugs at a higher rate Genetics Genetics may play a role in who will develop a substance use disorder Antecedents A factor that occurs before an event such as the initiation of drug use Aggressiveness Conduct problems Poor academic performance Attachment to a drug-using peer group Parental and community norms that support drug use Sensation seeking behavior Motives Identification with a deviant subculture Rebelliousness Fads and cultural trends Reinforcing properties of drugs Desire to experience an altered state

Drug Related Social Problems Problems related to taking the drug Toxicity (poisonous, dangerous, deadly) Acute/Chronic Overdose High BP/Heart Disease/Cancer/Cirrhosis Physiological/Behavioral Lifestyle changes Relationship issues Driving factors Secondary Effects HIV/Hepatitis other infections Dependence/Addiction Problems related to drug use as deviant behavior arrests, fines, jailing expenses associated with drug prevention and treatment work related problems relationship related problems family related problems

Monitoring the Future Source: Monitoring the Future Study, The University of Michigan.

NSDUH Source: National Survey on Drug Use and Health.

NSDUH Source: National Survey on Drug Use and Health.

Trends in ER Drug Mentions Cocaine Heroin/Morphine Marijuana Meth/Speed

The Most Lethal Drugs (after Mathias, 1994)

Models of Addiction Moral Model Disease Model Physical Dependence Model Reward Model

Current DSM V classification Substance Use Disorder: A maladaptive pattern of substance use for at least 12 months that has led to significant impairment or distress. At least 2 of 11 additional criteria must be met: Craving for the substance Increasing use of the substance beyond the original intent Unsuccessful attempts to control or stop using the substance Development of Tolerance Development of Withdrawal symptoms Failure to fulfill major societal obligations Continued use despite knowledge of social, interpersonal, or health problems caused by the substance Repeated use of the substance in hazardous situations (e.g., driving a car) Spending excessive time obtaining the substance Spending excessive time using the substance Reduced time spent in other activities because of substance use 14

Intra-Cranial Self-Stimulation ICSS: Electrodes are placed in the Medial Forebrain Bundle (MFB)

Microdialysis Data Dopamine levels in Nucleus Accumbens following self-administration of cocaine in rats

Reward Pathway Ventral Tegmental Area (VTA) to Nucleus Accumbens via the Medial Forebrain Bundle and then to the Prefrontal Cortex

Drug Rush PET scans of Human Cocaine Addicts: Brain area activation during the Drug Rush: Nucleus Accumbens Amygdala Sublenticular Extended Amygdala VTA

Drug Craving PET scans of Human Cocaine Addicts: Nucleus Accumbens and the Amygdala Brain area activation during Drug Craving: Craving becomes stronger as the drug wears off

Drug Addiction Initially the CREB protein dominates leading to Tolerance and the feeling of discomfort with the absence of the drug But the CREB protein falls after a few days if drug use discontinues But Delta fosB stays elevated for weeks after the discontinued use of the drug leading to Drug Sensitivity

Dependence Tolerance Physical dependence Psychological dependence Three basic processes that may occur with repeated drug use Tolerance Tolerance typically precedes physical dependence Physical dependence the occurrence of a withdrawal syndrome If drug use is stopped suddenly, withdrawal symptoms occur, ranging from mild to severe Physical dependence means the body has adapted to the presence of the drug Psychological dependence High frequency of drug use Craving for the drug Tendency to relapse after stopping use Drug-taking is reinforced by consequences (the drug effects)

Tolerance and Withdrawal Symptoms Drug disposition (pharmacokinetic) tolerance Increased metabolism or excretion reduces the effect of the subsequent dose May relate to enzyme activity or alteration of urine pH Behavioral tolerance Drug may have the same biochemical effect Reduced behavioral effect as drug user learns to compensate Pharmacodynamic tolerance Sensitivity of neurons may change after repeated drug use May cause withdrawal symptoms

Drug Tolerance During drug use VTA cells are stimulated and release Dopamine triggering the reward circuit Dopamine binds the receptors of the Nucleus Accumbens and increases cAMP and Ca2+ ion concentrations cAMP and Ca2+ activate the CREB protein CREB activates the Dynorphin gene to make the Dynorphin protein The Dynorphin protein is released back on the VTA where it inhibits Dopamine release depressing the reward circuit and causing the user to need more drug for the same high

Neurobiology of Drug Addiction Drug Sensitivity Neurobiology of Drug Addiction During drug use VTA cells are stimulated and release Dopamine triggering the reward circuit Dopamine stimulates the formation of Delta fosB Delta fosB inactivates the Dynorphin gene and activates the CDK5 gene The CDK5 protein stimulates dendritic spine growth in the Nucleus Accumbens Nucleus Accumbens neuron Increasing Drug Sensitivity/Addiction

Drug Sensitivity/Addiction Nucleus Accumbens neurons in non-human animals: Non-Addictive Drugs Cocaine Greater density of Dendritic Spines Contributes to Drug Sensitivity (increased risk of drug relapse) Delta fosB may be the contributing factor of increased spine growth