Some more details on the addiction process First: A Brief Review

Conscious and subconscious integration of all sensory is very important

Some Very Important Parts of the Brain Cognitive area

Substantia nigra Caudate Ventral tegmental area Locus coeruleus Some More Very Important Parts of the Brain

And Even More Very Important Parts of the Brain

Primary (SI) and secondary (SII) sensory cortex involved with the localization of pain Anterior portion of insular is most likely concerned with pain perception

All sensory information is relayed throughout different parts of the brain and our conscious interpretation of the stimuli generates a physical and emotional response which we “feel”: body/joint position, body and/or limb movement, well- being, nausea, pain … happy, sad, frustration, disappointment, joy, ecstasy, anger … Our CNS response to stimuli also includes (selective) changes in the (autonomic) sympathetic and parasympathetic nerve pathways; selective changes based on our interpretation of the stimuli.

Sympathetic N.S. Thoracic, Lumbar motor nerves –synapse close to spinal cord Fight or flight –preservation of life –heart & skeletal muscle stimulated  blood pressure  metabolism  brain activity –vegetative functions inhibited

Parasympathetic N.S. craniosacral motor nerves –synapse in wall of organ vegetative functions –internal housekeeping, recovery, rest  G.I. activity digestive organs –inhibit brain & muscle

Learning is Vital to the Addiction Process Parts of the brain that are important for learning.

Learning Hippocampus coordinates environmental stimuli and activates existing memory.

Learning New memory is constructed based on novel stimulus in comparison to existing memory. “Strength” of the memory is dependent on the frequency and strength of the neural activity.

Learning & Memory The new memory is activated either through the “novel” stimulus or through the associated memory. We remember facts as pieces of “information” in relation to other pieces of “information” which in turn are related to other …

Memory & Skill Sensory memories of physical movements are stored as patterns of neural activity in the cerebellum and are developed in much the same way as factual memories.

The most basic connection between behavior and memory is that we desire to perform behaviors which produce responses that we want….if we can’t remember that a particular behavior resulted in a desirable outcome, there is little chance we will seek out to repeat the same behavior. In addition, if a particular behavior results in an unpleasant experience, there is a strong likelihood that we will avoid that behavior. On the other hand, if a behavior is not particularly pleasant, but does result in a highly desirable outcome, there is a high likelihood that the unpleasant behavior will be continued in order to get the pleasant payoff. Memory, Learning & Behavior

Memory / Learning / Behavior With greater pleasure, reinforcement can be developed more easily and quickly. With greater activation of the memory & learning pathways during the behavior, the easier and faster the learning. With more important desired behaviors, there is greater craving in their absence.

Drug Abuse/Drug Addiction/Behavioral Addiction (the bad stuff) 1. Repeated exposures lead to CNS adaptations 2. With additional repeated exposures the CNS adaptations may lead to a diminished ability to focus on normal/essential activities of daily living 3. With still more repeated exposures the CNS adaptations may lead to an enhanced focus (both conscious and subconscious) on the drug-taking behavior itself 4. With additional exposures continual CNS adaptations may lead to a total obsession with the drug- taking behavior to the exclusion of normal/essential activities of daily living

A Quick Review of Some Important Brain Functional Areas Frontal lobe of cerebral cortex - conscious thought - voluntary initiation of movement Basal ganglia: caudate nucleus, substantia nigra, putamen, globus pallidus - subconscious initiation of movement - subconscious control of movement - learning of habits - part of limbic system Limbic system: amygdala, hippocampus, hypothalmus, nucleus accumbens, piriform cortex, olfactory tubercle, striatum, septum - generation of emotional responses based on: - integration of unconscious sensory input and conscious interpretation of sensory input and conscious interpretation of the appropriateness of the feelings

Different Drugs Effect Nerve Function in Different Ways - Drugs alter neurotransmitter function at the synapse by affecting receptor function or receptor synthesis; or by reducing or enhancing neurotransmitter release, neurotransmitter uptake, or neurotransmitter destruction - Changes in neurotransmitter levels in the synapses of specific areas of the brain (review previous slide) reveal possible effects of different drugs on various brain functions - Many (most?) drugs of abuse with high “addiction” potential affect the serotonergic (5-OH tryptophan), norepinephrinergic, and dopaminergic pathways (review next slides)

Some Serotonin - Releasing Pathways Hypothalmus Amygdala Nucleus Centralis Superior Raphe Nucleus Reticular Formation Corpus Striatum Substantia Nigra Cerebellum Cerebrum Neuron Cell Body Location Neuron Terminal Button(s) Location

Some Norepinephrine - Releasing Pathways Locus Coeruleus Hippocampus Amygdala Cerebral Cortex Cerebellum Hypothalmus Arousal

Some Dopamine - Releasing Pathways Ventral Tegmental Area Caudate Nucleus Putamen Globus Pallidus Substantia Nigra Piriform Cortex Nucleus Accumbens Amygdala Septum Hypothalmus Pituitary Some Frontal Cortex Striatum

Putting together some of the information from the previous slides, we can imagine associations between changes in neurotransmitter release and altered functions: Positive feelings of pleasure are associated with dopamine release in the nucleus accumbens and amygdala and pre-frontal cortex and orbitofrontal cortex (usually causing K + eflux = IPSP; G-protein activation). Feelings such as motivation and craving in (cocaine addicts) are strongly associated with activation of glutamate neurons in the frontal cortex, the orbitofrontal cortex, and amygdala which enhances release of glutamate (usually causing Na + and Ca ++ influx = EPSP, G-protein activation) in the nucleus accumbens.

Dopamine release into the nucleus accumbens by neurons originating in the ventral tegmental area lead to mild pleasure or reduced anxiety and frustration. Enhanced norepinephrine release by nerves originating in the locus coeruleus leads to stimulation (by activating G-proteins that then activate Ca+ release into the cytosol = EPSP as well as activation of a variety of signal transduction pathways) of a variety of brain areas associated with arousal (heightened ability to focus), pleasure, and maybe even enhanced learning. GABA (gamma-aminobuteric acid) is the major inhibitory neurotransmitter in the brain and GABA receptors are highly sensitized by ethanol leading to strong inhibition (Cl - influx = IPSP) of many brain areas including frontal cortex (depressing higher thought processes, basal ganglia (caudate and substantia nigra – leading to impaired motor coordination), and limbic system output (accounting for the anti-anxiety and depressant effects of ethanol).

The Addiction Process The duration which chemicals affect neurotransmitter release in the brain is far longer lasting than that expected from normal environmental stimuli – leading to greatly enhanced neural effects, whether from ion transport or through initiating gene responses. Following repeated exposures, both conscious (the I can remember part) and subconscious memories (the physical movement – bad habit part) of associations between behavior and rewards are developed. With repeated exposures permanently reinforced memories of behavior = reward are developed.

Most “drugs” negatively affect intellectual capacity therefore conscious memories of the associations are greatly exaggerated. They also affect VTA and basal ganglia function leading to enhanced “physical memories” (habits) of the physical sensations of the “drug-taking-behavior” movements being associated with the positive feelings of the drug-effects. Drug-induced alterations in motivation/craving pathways induce exaggerated behavioral responses (habitual?) to initiating stimuli. Following repeated exposures to addicting drugs any stimulus which activates the drug-induced, exaggerated, and drug- reinforced memories will result in the drug-induced, exaggerated feelings of craving. When ANY environmental cue leads to activation of memories and craving you are well on the road to obsession.

Obsession Simply means that the overriding driving force of your life is the focus on the object of your obsession. We can be obsessed with many things. When obsessions interfere with activities of daily living (ADL) then we as a society view the obsession as a serious personal and social problem and we create laws against the (object of) obsession. In the case of illegal drugs, society has made the decision to make the object illegal even though from a historical perspective there have been many highly productive & successful drug addicts whose addiction did not interfere in any way with their ADL and, in fact, their addiction was not publicly known.