Psychoactive Substances - Substance Abuse

Substance abuse and behavioral treatments

What type of reinforcement initiates drug use?

Positive reinforcement

What type of reinforcement maintains drug use?

Negative reinforcement

Define positive reinforcement

an appetitive stimulus activates the reinforcement mechanism that increases the likelihood that the most recent behavior will be expressed

What is an example for positive reinforcement with inhaling nicotine?

Smoking makes you feel more alert; you will smoke more in the future

What would IMPEDE addiction potential?

a delay in drug effects

What would ENHANCE addiction potential?

immediate and robust positive reinforcement

What is positive reinforcement’s role in drug abuse?

reinforcement effects are greatest if it occurs immediately after a response

• heroin is more addictive than morphine because it has more rapid effects (heroin is more lipid-soluble)

• up regulation of cocaine with AMPA receptors occurs after ONE time with the brain learning that cocaine is good

What are the neural mechanisms of positive reinforcement?

• addictive drugs trigger the release of dopamine in the nucleus accumbens

  • necessary but not sufficient for positive reinforcement

• drug “hijack” normal mechanism

• increased activation of other brain regions

• synaptic changes that are responsible for compulsive behaviors occur within the dorsal striatum after continued use

What are the long-term changes produced by positive reinforcement

• drugs increase the strength of excitatory synapses on dopaminergic neurons in the VTA

  • leads to increased activation in regions that receive dopaminergic input from the VTA

What brain regions have increased activation during positive reinforcement?

• first changes appear in the ventral tegmental area (VTA)

• insertions of AMPA receptors into the postsynaptic membrane of dopamine neurons

• changes last a few days after a single injection of an addictive drug

Define negative reinforcement

a behavior that reduces/turns off an aversive stimulus will be reinforced

What is an example for negative reinforcement with inhaling nicotine?

smoking makes your craving for a cigarette go away; you will smoke more in the future

True or false; negative reinforcement is the same as punishment

false; a responsive action makes the unpleasant stimulus appear

Describe tolerance in relation to negative reinforcement

• decrease sensitivity to a drug

• body’s attempt to compensate for having the drug present

Describe withdrawal symptoms in relation to negative reinforcement

• primarily the opposite effect of the drug itself

• taking drugs prevents the unwanted withdrawal and could provide negative reinforcement

• could explain addiction to drugs that reduce anxiety

What are the components of addiction?

• self-administered maintenance

  • increased consumption over time to combat tolerance

• abstinence

  • during this period, individuals are most vulnerable for relapse due to craving and withdrawal symptoms

• relapse

Describe therapeutic interventions

• must be supported by research as effective treatment

• successful treatment is challenging

  • 40 to 60% are abstinent one year after a substance abuse intervention

Describe the role of the prefrontal cortex in relation to craving and relapse

• activity of this area was lower than controls during abstinence

• people with a long history of abuse have deficits on tasks involving this area and have structural abnormalities here

• can’t tell if abnormalities in the PFC predispose people to addiction or are caused by addiction

  • nature AND nurture

• high comorbidity of schizophrenia and substance abuse

Describe the comorbidity of schizophrenia and substance abuse

• up to half os schizophrenics have a substance abuse disorder

• 70 to 90% of schizophrenics are nicotine dependent

• all have reduced prefrontal gray matter volume, suggesting a common factor

  • they also have hypofrontality (low impulse control)

Does the medial prefrontal cortex decrease or increase in activity in individuals abusing substances?

Decrease

What brain region is most involved in craving and relapse?

medial prefrontal cortex

Describe the lower activation of the medial prefrontal cortex during craving/relapse?

• deficits on tasks and structural abnormalities

  • less gray matter (less myelinated cell axons)

• hypofrontality (low activation of the MPFC)

• involved in the extinction of conditioned emotional responses

What is the relationship between cocaine intake and the medial prefrontal cortex?

negative correlation (inverse relationship)

• less cocaine consumption = more medial prefrontal cortex activation

Describe the reinstatement model in relation to craving and relapse

• animal trained to respond to stimulus with drug

• behavior is extinguished

• “free” drug is given

• responding behavior returns

How do you get from abstinence to relapse?

• being within the drug environment/context/queues

• being in a non-enriching environment

• environmental stressors

How can stress trigger a relapse?

• stress-induced release of CRH (cortical-releasing hormones)

  • CRH caused an enhanced activation of dopaminergic neurons in the VTA, heightens dopamine release, enhancing positive reinforcement

Opiates increases what neurotransmitter in what brain area?

Dopamine in the VTA

What receptors do opiates stimulate?

mu receptors

Where do rats NOT self-administer opiates into?

Medial prefrontal cortex

What is NOT an example of a stimulant?

Nicotine

What is the mechanism of action for cocaine?

deactivates dopamine transporters

What is the mechanism of action for amphetamine?

inhibits reuptake and stimulates the release of dopamine

How do stimulants increase dopamine release in the nucleus accumbens?

• dopamine antagonists into the NAC block cocaine’s reinforcing effects

• destruction of dopaminergic terminals in the NAC interferes with the reinforcing effects of cocaine and amphetamine

Describe methamphetamine

more potent version of amphetamines

• inhibits reuptake and stimulates the release of dopmaine

What commonly abused substance is methadone used for?

opiates

Describe methadone maintenance for opiates

• full agonist that binds to the mu receptor that has a lower affinity

• oral administration prevents high

  • increases the opiate level in the brain slowly

  • injecting heroin has little effect if treatment drug present

• not effective, they just switch addiction from heroin

Describe the lower affinity aspect of methadone

methadone provides some of the opiate action but doesn’t provide the full opiate experience; decreases withdrawal symptoms

Is methadone a full or partial agonist of the mu receptor?

full agonist

define full agonist

opens the ion channel completely (a lot of ions will flow into the cell)

define partial agonist

the ion channel is only slightly opened

What commonly abused substance is buprenorphine used for?

opiates

Describe buprenorphine for opiates

• partial agonist for the mu-receptor

  • blocks the effects of opiates and produces a weak opiate effect

• leads to a longer length of abstinence (compared to methadone), but they still relapse long-term

• can be used in an office-based treatment setting

• no abuse potential (unlike methadone)

Is bupreneorphrine a full or partial agonist?

partial agonist

describe suboxone for opiates

• combination of buprenorphine (partial agonist) and naloxone (full antagonist)

• shows more promise than buprenorphrine but still doesn’t prevent long-term relapse

What commonly abused substance is suboxone used for?

opiates

What commonly abused substance is ibogaine used for?

opiates

Describe ibogaine for opiates

• psychoactive alkaloid extracted from the iboga plant (ibogaine is the main psychoactive compound)

• being heavily researched but not FDA approved yet

• has almost immediate effects after 1 treatment but the detox lasts days

Describe the neurological effects of ibogaine

similar to other psychedelics, they have similar chemical structures to serotonin and work on the 2A receptor site (agonist and antagonist in different brain regions)

• default mode network (DMN) is involved in self-referential, identity, ego

  • gets excited when you think about oneself

    • identity foreclosure

  • made of the tract between the anterior and posterior cingulate cortex

    • pschadelics DISRUPTS the connection between the ACC and PCC

How does ibogaine and other psychodelics affects the default mode network?

DISRUPTS (changes the firing pattern) the connection between the anterior cingulate cortex (PCC) and posterior cingulate cortex (ACC)

• no matter how rigid you are in your identity, this network is willing to change/adapt

• temporary rewiring

What is facilitating the new connections between the PCC and ACC within the default mode network while on psychadelics?

• BDNF and GDNF are proteins that are essential for neurogenesis and synaptic-genesis

  • psychedelics increase BDNF and GDNF

    • BDNF = brain derived neurotrophic factor

    • GDNF = glial cell line-derived neurotrophic factor

Describe immunization for cocaine

• vaccines that prevent cocaine molecules from crossing the blood-brain barrier

  • drug molecules are tagged with a hapten molecule making it too large to pass through the BBB

    • patient will receive no reward from the drug so they are less likely to take it again

    • BUT, individuals still experience withdrawal symptoms

• while vaccinated, your body will see it as a virus and make antibodies to attack the drug molecules

What are the issues with using traditional pharmaceutic treatments for cocaine?

• because cocaine and amphetamines work directly on the reward pathway, there are no PDA prescriptions

  • why would you give a dopamine agonist to somone who is addicted to a dopamine agonist"?

  • why can’t you give a dopamine antagonist to someone?

    • absolutely no pleasure for the patient

Describe the reinforcing effects of nicotine

activation of nicotinic receptors in the VTA

Describe the maintenance program for nicotine

• ineffective when used alone

  • most effective if combined with counseling program

  • fails to provide non-nicotine components of smoking

• ex: nicotine gum, transdermal patches, etc.

What commonly abused substance is rimanobant used for?

nicotine

Describe rimonabant for nicotine

• CB1 receptor antagonist

  • if you target the CB1 receptor, you can indirectly modulate dopamine release in the presence of a stimulator

  • if you block the CB1 receptor, the dopaminergic receptor is being repressed because this receptor is a heteroreceptor

• effective at smoking cessation but not FDA approved due to its side effects (anxiety and depression)

What commonly abused substance is bupropion used for?

nicotine

Describe bupropion for nicotine

• antidepressant

• serves as a catecholamine reuptake inhibitor

  • mimics nicotine’s effects

• less activation of medial prefrontal cortex and reduced craving in response to cigarette cues

• doesn’t support longer term abstinence

What commonly abused substance is varenicline used for?

nicotine

Describe varenicline for nicotine

partial agonist for nicotinic ACh receptor but doesn’t support longer term abstinence

What commonly abused substance is deep brain treatment (DBT) and transcranial magnetic stimulation (TMS) used for?

nicotine

Describe deep brain treatment (DBT) for nicotine

• invasive because it involves neurosurgery

  • putting electrodes in places associated in nicotine addiction

• long been used to treat movement disorders like Parkinson’s disease

• EXCLUSIVE for nicotine

  • electrodes are place in the insula because it has a high concentration of nicontinic acetylcholine receptors

  • this is unlike treatment for other drug addictions

Where are electrodes placed during DBT?

in the insula because it has a high concentration of nicontinic acetylcholine receptors

What areas are targeted/changed from deep brain treatment?

• ventral tegmental area

  • substantria nigra in limbic system

• medial prefrontal cortex to enhance activation so they have the neural hardware to ignore craving

Describe transcranial magnetic stimulation (TMS) for nicotine

• repetitive treatments but non-invasive

• uses magnetic waves at different frequencies to affect neural firing events

• can target brain regions associated with addiction causing synaptic genesis (plasticity)

What brain regions are targeted during transcranial magnetic stimulation (TMS)?

• right inferior frontal gyrus AKA medial prefrontal cortex

  • associated with impulse control, craving, and emotional regulation

• dorsal lateral prefrontal cortex

  • associated with decision making

• reward pathway can be restored without drug involvement

Which treatment is more invasive?

deep brain treatment (DBT)

Describe the neural mechanisms of alcohol

• indirect antagonist at NMDA receptors

• indirect agonist at GABAA receptors

• indirect agonist for mu receptors

  • opiate endogenous receptor site (site for reinforcing alcohol/when someone is trying to abstain indirect agonist for endorphins)

How does alcohol produce both negative and positive reinforcing effects?

• release of dopamine in the nucleus accumbens

• ability to trigger the release of endogenous opioids

• effects of alcohol withdrawal are serious and can be fatal

What commonly abused substance is naltrexone used for?

alcohol

Describe naltrexone for alcohol

• opiate antagonist

  • blocks opiate mu receptor to a lesser degree

    • individuals with blocked opiate receptors report high levels of craving events

• decreases the reinforcing value of alcohol

What commonly abused substance is rimanobant used for?

potentially all abused drugs

What commonly abused substance is amcamprosate used for?

alcohol

Describe acamprosate for alcohol

• NMDA receptor antagonist

  • glutamate antagonist

• reduces the likelihood of drinking

What is addiction?

Learning a maladaptive response to feel safe

What are some problems with treatment?

• pharmacotherapies result in little to no long-term success

  • need to focus on both neurological and enviornmental contingencies

What is the best way to help sustain long-term abstinence?

combining treatment medications with behavioral therapy

How does behavioral treatment work?

• provide incentives to remain abstinent

• teach important life skills that will help support abstinence in the presence of stressors or other environmental cues that may trigger intense craving for drugs

• LEARNING abstinence

Describe Contingency Management

re-arrange the drug user’s environment to that drug abstinence is positively reinforced and drug use results in an immediate loss of reinforcement

• uses both positive and negative consequences

• need to met a set/pre-determined criteria to receive reward

• individual learns that they CAN be abstinent based on their environment

What are the strengths of contingency management?

• increase in the duration of abstinence

  • increased number of clients who fulfilled specified periods of abstinence

• acceptance of therapy

• uses both reinforcement and punishment strategies

What are the limitations of contingency management?

• abstinence is only promoted when the contingency is in place

• needs to be generalized in natural settings

• cost of vouchers add up

  • increase cost of voucher with increased length of abstinence

Describe how contingency management gives individuals robust, non-pharmacological rewards

• no negatives associated with positive enrichment (can outweigh drug reinforcing effects)

• creates behavioral contrast where when you have the choice between a drug and reward, you choose the reward

What does contingency management build to?

environmental enrichment

What is the definition of Environmental Enrichment

Non-contingent procedures that presents a choice between drug and other types of alternative natural rewards (e.g. food, social interaction, exercise, etc.) so that the organism can learn that another choice is concurrently avaliable besides relapse

Describe aspects of environmental enrichment

• potential rewards include career enrichment in their dream field so they can maintain the extravagent lifestyle of their “perfect/unlimited reward”

• addiction has almost all negative reinforcements

• environmental enrichment has almost all positive reinforcements

• even if the individual consumes the drug, it is NOT taken away because the reinforcement of EE is more robust

Describe the research behind environmental enrichment

• if animals have the choice between a drug and other types of rewards, they will typically prefer the alternative rewards over the drug

  • as they learn enrichment, they slowly reduce drug intake

  • maximize reinforcement opportunities to reach behavioral bliss

• in humans, whether or not environmental enrichment can sustain long-term abstinence is relatively unknown

What if you maximize behavioral bliss through environmental enrichment?

• you’re reward pathway cannot maintain the amount of dopamine release

• you need a hedonic reset

  • a period where you decrease the amount of pleasurable stimuli to recalibrate the brain's reward system

  • AKA when you are overstimulated because you have maximized hedonism

What is the final goal of self enrichment?

understanding that you are enough within yourself without any external factors

Describe hypnosis

• cognitive approach (rather than behavioral)

• “meditation with a goal”

• real altered state of consciousness so they are heightened for repeatability

  • suggest sobriety while in this state

    • related to different adaptive patterns so they are not “identifying” as an addict

Why must one be in an altered state for hypnosis?

• if an individual is in a non-altered state, they are non-receptive to anything that is counterintuitive to their maladaptive behaviors

  • hypnosis exposes the internal maladaptive behaviors and suggest adaptive treatments

What are post hypnotic suggestions?

strategies used to remain in abstinence

What is hypnosis similar to?

psychedelic treatment (ex: ibogaine)