Exam 2 Flashcards
encephalon
the brain
structures in the forebrain
telencephalon, diencephalon
structures in the telecephalon
neocortex, basal ganglia, limbic system
structures in the diencephalon
thalamus, hypothalamus
mesencephalon
midbrain
structures in the hindbrain
metencephalon, myelencephalon
structures in the metencephalon
cerebellum, pons
myelencephalon
medulla
brainstem
midbrain, pons, medulla
major striatum components
nucleus accumbens, caudate nucleus, putamen
caudate nucleus
dorsomedial striatum
putamen
dorsolateral striatum
function of nucleus accumbens (core and shell)
pleasure, motivation, reward cues
major target of dopamine axon terminals
striatum
dopamine neurons in the striatum
no DA neurons in the striatum; cell bodies are in the brainstem and send axon projections into the striatum
monoamine neurons
dopamine, serotonin, norepinephrine
monoamine neurons in the brain
primarily in the brainstem; cell bodies in the brainstem and send axon projections throughout the brain
dopamine neuron locations
in the substantia nigra and ventral tegmental area
nigrostriatal pathway
dopamine neurons in the substantia nigra send axon projections to the dorsal striatum
mesolimbic pathway
dopamine neurons in the VTA send axon projections to the nucleus accumbens and amygdala
mesocortical pathway
DA neurons in the VTA send axon projections into the prefrontal cortex
basal ganglia circuits/loops are important for:
voluntary movement, action selection, procedural learning, habits
input structures for the basal ganglia
cortex; glutamatergic/excitatory
output structures for basal ganglia
GPi, SNr; GABAergic/inhibitory
striatum projections are…
GABAergic
direct striatum projection
excites target of basal ganglia output, “go”
indirect striatum projection
inhibits targets of basal ganglia output, “no-go”
feedback for basal ganglia
provided by thalamus and midbrain dopamine
GABA neurons in striatum
half express D1 receptor, half express D2
D1 neurons
part of direct pathway “go,” excited by dopamine
D2 neurons
part of the indirect pathway, “no-go,” inhibited by dopamine
common property of addictive drugs
increase dopamine (but through different mechanism)
components of reward learning
liking, wanting, reward prediction
liking
pleasurable aspect of reward, does not involve dopamine
wanting
motivational drive to work for rewards, involves DA
reward prediction
involves DA
reward prediction: unexpected reward
increase in DA firing
reward prediction: response to CS
increase in DA firing when CS presented, not the reward itself
reward prediction: CS + no reward
decrease in DA firing
positive prediction error
reward is greater than expected
negative prediction error
reward is less than expected
positive prediction error effects
activates D1 cells (Gs coupled) and direct pathway
negative prediction error effects
activates D2 cells (Gi coupled) and indirect pathway
properties of a drug that can cause addiction
- route of administration
- increased lipid solubility
individual differences that can cause addiction
genes, environment, and the interaction between the two
genetic factors that increase addiction likelihood
- high impulsivity
- history of stress or trauma
genetic factor that decreases addiction likelihood
environmental enrichment
impulsivity in meth abusers
decreased D2 receptor availability in the striatum correlated with higher impulsivity
impulsivity in rats
high level of premature responding shows decreased D2 binding in ventral striatum
impulsivity and cocaine
high-impulsivity rats will self-administer more cocaine; indicated impulsivity may be a pre-existing condition for addiction
stress
influences all aspects of addiction process (drug taking, vulnerability to addiction, relapse)
stress: enhanced vulnerability
history of social defeat stress shows enhanced place preference for low-dose cocaine
environmental enrichment
reduced conditioned place preference for cocaine
prefrontal cortex (PFC)
behavioral inhibition, self-control, executive function
nucleus accumbens (ventral striatum)
reward, motivation, cues
dorsomedial striatum (DMS)
goal-directed learning
dorsolateral striatum (DLS)
habit learning
habit behavior is what type of association?
stimulus-response association
goal directed behavior is what type of association?
response-outcome association
chronic stress causes:
- enhanced habit learning
- loss of PFC volume
- reduced dendritic complexity
chronic stress affects striatum:
changes neuronal density in dorsal striatum → DLS more dominant that DMS
drug-induced neural adaptations
- sensitization of drug effects
- enhanced habit learning
- reduced behavioral inhibition
enhanced drug motivation experiment
intermittent cocaine use followed by abstinence → increased cocaine potency and drug motivation
habit learning
history of cocaine exposure to habitual learning
behavioral inhibition: resistance to negative consequences
some rats continue to self-administer cocaine despite getting footshock, resistant to punishment
behavioral inhibition: role for PFC
- optogenetic stimulation of PFC restores sensitivity to footshock
- optogenetic inhibition of PFC makes animals resistant to footshock
drug class of cocaine and amphetamines
stimulants/psychostimulants/psychomotor stimulants/uppers
drugs in stimulant category
cocaine, amphetamines, nicotine, caffeine
properties of cocaine
- psychoactive alkaloid
- weak base
natural form of cocaine
- raw coca leaf chewed with lime/ash to increase saliva pH (enhances absorption)
- < 2% cocaine
- absorbed in mouth
cocaine in 1800s and early 1900s
widely used; doctors and scientists highly praised its properties
coca paste
- crude extraction from leaves
- ~80% cocaine sulfate
- can only be smoked
- aka “paco” or “basuco”
cocaine HCl
- crystalline powder
- extracted and purified from coca paste
- very high concentration
- water soluble
- can be taken orally, intranasally, or intravenously; CANNOT be smoked
cocaine free base
- made from cocaine HCl + water + base
- vaporized and smoked (“freebasing”)
- residual can be dangerous and explode with flame
crack cocaine
- made from cocaine HCl
- baking soda instead of solvent, making it safer
- 75-90% cocaine
- smoked
- led to new cocaine epidemic in 80s-90s
cocaine products
widely used in many products in the 1800s
current medical uses for cocaine
local anesthetic effects (Schedule II)
effects at high doses of cocaine (in the brain)
inhibits voltage-gated Na+ channels (involved in action potentials)
cocaine absorption and distribution
extremely rapid absorption with smoking/IV
peak subjective effects for crack cocaine
within ~1-2 mins
inactive major metabolite in cocaine
benzoylecgonine
half-life of cocaine
0.5-1.5 hrs
active metabolite in cocaine
cocaethylene; formed when cocaine and ethanol are ingested simultaneously
amphetamines
chemical family of synthetic and natural psychostimulants
ephedrine
- comes from ephedra or “mormon tea” plant (natural)
- active components: ephedrine and pseudoephedrine
- decongestants
cathinone
- comes from “qat” or “khat” shrub leaves (natural)
- commonly chewed
bath salts
- synthetic variant of cathinone
- methcathinone (“cat”) and mephedrone (“meow meow”)
- designer drugs
- DEA schedule I
timeline of use of amphetamines and methamphetamines
1920s-30s: medical use developed
40s: widespread adoption b/c of WWII
early 70s: peak use of “speed”
first uses of amphetamines/methamphetamines
- benzadrine inhaler (for congestion)
- narcolepsy
forms of synthetic amphetamines
D-Amphetamine, L-Amphetamine, Adderall
route of administration for synthetic amphetamines
typically orally or injection (IV, SC)
methamphetamines (synthetic)
most potent of amphetamines
route of administration for methamphetamines
oral, snorted, injected IV, or smoked
amphetamine-related synthetics
- differ in chemical structure
- methylphenidate, modafinil
previous uses for amphetamine
- congestion
- mood and weight control
- fatigue
- increase attention and decrease fatigue in military
meth epidemic
- easily prepared in common household ingredients
- greater abuse potential
- can be smoked
current medical uses for amphetamines
- narcolepsy
- ADD/ADHD
metabolism and excretion of amphetamines
- slower metabolism and elimination compared to cocaine
- half-life is 7-30 hours
stimulants: major effects
- mild to moderate: heightened energy, hyperactive ideation, anger, verbal aggression, inflated self-esteem, etc.
- severe: total insomnia, rambling, incoherent speech, possible extreme violence, delusions of grandiosity
- autonomic effects: increased BP, hyperthermia, bronchodilation
cocaine vs amphetamines: duration of action
cocaine has a shorter duration of action
cocaine vs amphetamines: cardiovascular effects
cocaine has worse cardiovascular effects, can be lethal
cocaine vs amphetamines: seizures
higher convulsive seizure properties in cocaine
major effects of stimulants in animals
- locomotor activity can appear to decrease with high AMPH doses because rats perform with stereotypy behavior instead
- reinforcing/rewarding effects
effects of withdrawal
mostly psychological, especially in chronic, high-dose users
tolerance to some effects of psychostimulants
autonomic and anorexic effects
sensitization to other effects of psychostimulants
rewarding effects, psychotomimetic effects (psychosis), locomotor stimulant effects
negative effects of chronic amphetamine use
psychosis, anorexia, physical damage
history of MDMA
- never used clinically
- can enhance communication and openness
- club drug in 80s-90s
- Schedule I
- taken orally; long-half life (8 hrs)
MDMA effects at low doses
- increased empathy and sociability/empathy; mild euphoria
- increased heart rate and temperature
MDMA effects at high doses
- mild hallucinogenic effects
- hyperthermia and dehydration, increased heart rate and blood pressure can lead to stroke
cocaine as an indirect agonist
blocks reuptake of monoamines (DA, NE, 5-HT)
amphetamines as indirect agonists
- cause vesicles to release transmitter
- cause monoamines to be transported out of neuron via reversal of transporter
- results in very high DA in synaptic cleft
categories of monoamines
catecholamines and indolamines
catecholamines
dopamine, norepinephrine, epinephrine
indolamines
serotonin only
tyrosine
precursor for catecholamines
tyrosine hydroxylase
rate-limiting step in catecholamine synthesis
all monoamines are one type of neurotransmitter
classical
catecholamines are inactivated by
- reuptake via transporters
- enzymatic degradation
catecholamine reuptake
- primary mechanism for inactivation
- much faster than metabolism
vesicular monoamine transporter VMAT2
packages all monoamines into vesicles
each monoamine has their own…
synaptic transporters and receptors
enzymes involved in catecholamine metabolism
MAO and COMT
D1-like receptors
D1 and D5, coupled to Gs
D2-like receptors
D2, D3, D4; coupled to Gi
presynaptic autoreceptors are mostly what type of receptor
D2
area dopamine receptors are primarily concentrated
prefrontal cortex areas
monoamine systems
a few thousand neurons in each system send broad, diffuse projections to large areas of the forebrain
where the majority of dopamine neurons can be found
substantia nigra and VTA (midbrain)
nigrostriatal pathway
DA neurons in substantia nigra target dorsal striatum
mesolimbic pathway
DA neurons in VTA target ventral striatum (nucleus accumbens) and amygdala
mesocortical pathway
DA neurons in VTA target prefrontal cortex
dopamine in the striatum
no DA neurons, but has lots of DA fibers, DA release at synapses, and DA receptors/transporters
classification of dopamine receptors in striatum
half D1, half D2
cause of parkinson’s disease
progressive death of midbrain dopamine neurons and their striatal terminals
symptoms of parkinson’s
- bradykinesia (slow movement)
- akinesis (frozen) in severe cases
L-DOPA
can relieve symptoms, but can lead to dyskinesias and other problems
drug-induced parkinson’s disease
- MPPP+ is a potent DA neurotoxin that can cause parkinson’s symptoms within days
- converts MPTP to MAO-B
MPTP research
used to produce dopamine lesions in non-human primates
catecholamine neurotoxin
6-OHDA used instead of MPTP to create lesions of catecholamine neurons and/or axon fibers
drugs that affect DA system
DOPA, 6-OHDA, amphetamine, cocaine, methylphenidate
antischizophrenia drugs
D2 antagonists that cause sedation and cataplexy at higher doses
4 primary adrenergic receptors are what type of receptor?
all GPCRs
alpha-1 adrenergic receptor
coupled to Gq
alpha-2 adrenergic receptor
coupled to Gi, serves as autoreceptor
beta-1 and beta-2 adrenergic receptors
coupled to Gs
locus coeruleus
major source of NE in the brain, neurons have TH and DBH
dorsal noradrenergic bundle (DNAB)
- originates from locus coeruleus
- major source of NE in the brain
- involved in cognition, arousal, and attention
ventral noradrenergic bundle (VNAB)
- originates from NE neurons in the medulla
- involved in aversive aspects of stress
role of NE in stress and arousal
responsible for many stress effects on memory and cognition
distribution of NE
- central nervous system (brain)
- major components of peripheral sympathetic nervous system “fight or flight” response
pharmacodynamics of amphetamine
amph, meth, and MDMA are all agonists of TAAR1 (intracellular GPCR)
distribution of cocaine in the human brain
matches that of DA transporters (DAT), which are densest in the striatum
DA is critical for…
the reinforcing and locomotor effects of cocaine and amphetamines
antagonists that disrupt amphetamine reinforcement (self-administration)
DA, but not NE
drugs not readily self-administered by animals or abused by people
- selective blockers of NET
- selective blockers of SERT
- other local anesthetics (Na+ channel blockers)
DAT blockade
appears to be the core mechanism by which cocaine and amphetamine are reinforcing
lesion studies
using 6-OHDA to lesion DA, but not NE, disrupts cocaine reinforcement (self-administration)
similar time course for amphetamine effects on:
- DA release in striatum
- locomotor effects
repeated amphetamine treatment
- produces sensitization of locomotor and reinforcing effects
- sensitization of DA levels in striatum
DAT knockout mice
- spontaneously hyperactive
- show increased locomotion
DAT knock-in mice
- mutation that makes them DAT insensitive to cocaine
- show loss of cocaine reinforcement (self-administration)
Stimulant-induced DA in nucleus accumbens (mesolimbic)
locomotion & reinforcement
Stimulant-induced DA in dorsal striatum (nigrostriatal)
stereotypies
reward cues and dopamine
- once learned, CS/reward-associated cues will elicit DA release
- drive motivation for reward
Cue-induced dopamine release in dorsal striatum
correlates with craving in addicts
in rats, cocaine-associated cues trigger…
drug seeking
treatments for stimulant addiction
- no clinically licensed treatment
- best treatments are psychosocial, CBT, relapse prevention therapy
neurotoxicity with amphetamines
Can cause depletion of monoamines and degeneration of nerve terminals
Amphetamine/methamphetamine neurotoxicity:
- high doses (10-50x)
- high extracellular DA necessary
- amphetamine: damage to DA terminals
- methamphetamine: damage to DA and 5-HT terminals
MDMA neurotoxicity
- only 2x normal street dose
- damage to 5-HT terminals
methamphetamine neurotoxicity in humans
Long-lasting decrease in DAT availability in abstinent methamphetamine and methcathinone users
methamphetamine neurotoxicity in baboons
Long-lasting decrease in DAT availability after meth
methamphetamine neurotoxicity in rats
Long-lasting decreases in TH and DAT after meth
acute adverse effects of MDMA
- reflect dehydration and hyperthermia
- subtle cognitive deficits
properties of sedative-hypnotics
- depress the CNS and behavior
- anxiolytic properties (downers)
- addictive effects
- cross-dependence and -tolerance
types of sedative-hypnotics
alcohol, barbiturates, benzodiazepines
structurally unrelated drugs similar to sedative-hypnotics
nonbenzodiazepines, methaqualone, GHB, opiates/opioids
properties of alcohol
- ethanol (ethyl alcohol) is consumed
- other forms are too toxic
- no current medical use
- not scheduled by the DEA
forms of alcohol: fermentation
- natural source
- yeast fermentation only produces concentrations up to 15%
forms of alcohol: distillation
- produces spirits or hard liquor
- concentration >15%
history of alcohol use
- incidence of alcohol abuse increased with distillation
- repeated attempts to ban it (temperance movement, prohibition)
- attempt to ban had opposite intended effects
alcohol molecules are ionized/non-ionized
non-ionized
% of alcohol absorbed and where
10% absorbed in stomach, 90% in small intestine
presence of food in stomach & it’s affect on alcohol absorption
- food in stomach slows gastric acid emptying and absorption
- more alcohol is degraded before being absorbed (first-pass metabolism)
small amounts of alcohol eliminated without being transformed
roughly 10% in sweat, tears, urine, and breath
breath levels are usually a good indicator of…
blood levels
how most alcohol is broken down
alcohol dehydrogenase (ADH) in stomach and liver
ADH (alcohol dehydrogenase) individual differences
- affects blood levels of alcohol
- 60% more gastric ADH in men
ALDH individual variation
- affects blood levels of acetaldehyde
- 50% of certain Asian groups have reduced ALDH function
alcohol excretion
zero-order kinetics, cleared at a constant rate
blood alcohol content (BAC/BEC)
grams of alcohol per 100 mL of blood
person with BAC of 0.2-0.3
quite drunk
person with BAC 0.45
LD50 (death), low margin of safety
cause of death from alcohol
respiratory centers in the brainstem shut down
alcohol effects on drunk driving
- increased probability of car accidents
- impaired reaction time and judgment
- increased aggression
alcohol effects: increased blood circulation
blood vessels dilated, feeling of warmth
alcohol effects: anti-diuretic hormone
ADH (anti-diuretic hormone) inhibited = increased urination and dehydration
alcohol effects: sleep
impairs REM sleep
alcohol effects: memory
blackouts/amnesia
alcohol effects on vestibular system
- alcohol makes blood less dense, which changes density of cupula compared to surrounding fluid
- sensation of movement triggers vestibular-ocular reflex
cupula
in semicircular canals (part of vestibular system in inner ear), senses movement
alcohol withdrawal: hangover
seen as a mini-withdrawal
alcohol withdrawal: chronic use
- can be fatal
- seizures, hallucinations, tremors, autonomic disruption
- treated using benzos because of cross-dependence
acute tolerance of alcohol
- aka tachyphylaxis
- ascending and descending BAC
metabolic tolerance of alcohol
- increased expression of ADH
- induction of liver enzymes of cytochrome P450 family
other types of alcohol tolerance
behavioral, pharmacodynamic, cross-tolerance with benzos/barbs
negative effects of chronic heavy alcohol use
- liver damage (~10-20%)
- brain damage, including Korsakoff syndrome
fetal alcohol syndrome
- alcohol readily crosses placenta
- lower birth body weight
- craniofacial malformations
- neurological problems
- binge drinking and high BAC have been implicated in FAS
risks for alcoholism
- stress
- lifetime anxiety
- early-life stress
- increased novelty seeking
- family history of alcoholism
self-administration of alcohol in animals
- most animals will drink only a little alcohol
- selective breeding –> populations that drink more alcohol or abstain completely
forms of barbiturates
- comes from barbituric acid (synthetic)
- barbital and phenobarbital were first drugs to be marketed
barbiturate uses (overall)
- anxiolytics, hypnotics, and anticonvulsants
- “truth serum”
medical use for barbiturates
- anesthesia
- sedation
- epilepsy
risks of barbiturates
significant addiction potential and overdose risk
drug that replaced barbs
benzos
retired uses of barbs
- sleep induction
- anxiety
- alcohol withdrawal (too dangerous)
DEA schedule for barbs
II, III, IV
side effects of barbs
- reduced REM sleep and slow wave sleep
- reduced cognitive function
- dangerous with alcohol
- tolerance –> dose escalation –> reduced margin of safety
- dependence and withdrawal (seizures)
barbiturate abuse
used recreationally to relieve anxiety, decrease inhibition
barbiturate effects at high doses
respiratory centers in the brainstem shut down, common means of suicide
use of benzodiazepines
- anxiolytics
- sedatives
- anticonvulsants
- treatment for alcohol withdrawal
- surgical sedation/amnesia
duration of action for benzos
varies for different benzos due to
- depot binding
- metabolic pathways (active vs inactive metabolites)
properties of nonbenzodiazepines
- similar benefits, side effects, and risks
- different chemical structure from benzos
use for nonbenzos
sleep disorders
pharmacodynamic properties of nonbenzos
act at the binding site of GABAa receptors
medical uses of benzos
- schedule IV
- anxiety
- emotional stress
- relief from agitation and alcohol withdrawal
- sedation
- pre-surgery relaxation & anterograde amnesia
- anticonvulsant
- amnesia (roofies)
safety of benzos compared to barbs
- less metabolic tolerance
- lower dependence and abuse
- higher therapeutic index; do not affect respiratory centers in brain
- much harder to take a lethal overdose of benzos
reversal agent for benzos
Flumazenil, competitive antagonist for benzos
abuse of benzos
less liable to be abused by humans than barbs
dependence/withdrawal of benzos
- milder form of alcohol/barbiturate withdrawal symptoms
- persistent emotional disturbances following withdrawal
other forms of abuse for benzos
Rohypnol (date rape drug)
DUI dangers of benzos
- sleep medications (Ambien) can leave people drowsy in the morning
- possibility of “sleep driving”
anxiolysis of barbs/benzos
- both are anxiolytic in animals and humans
pharmacodynamics of sedative-hypnotics
enhance chloride influx through GABAa receptors (ionotropic)
pharmacodynamics of barbs/benzos
unique binding sites on GABAa receptors
pharmacodynamics of alcohol
unknown mechanism at GABAa receptor
similarities of alcohol to barbs/benzos
- similar spectrum of behavioral effects
- similar increase in chloride currents
- cross-tolerance and cross-dependence
quaaludes
originally used as a hypnotic, sedative, or muscle relaxant
use of GHB
- decreased use now due to abuse potential
- subjective effects of GHB mostly resemble alcohol
- mild stimulant-like effects
- Xyrem for narcolepsy/cataplexy
abuse of GHB
club drug and date-rape drug
mechanism of action for GHB
acts as an agonist for GHB receptor and GABAb receptor (both GPCRs)
GABAb vs GHB receptor in response to GHB
GABAb receptor primarily involved in behavioral effects of GHB
GHB: GABAb knockout mice
do not display typical behavior or physiological effects to GHB
GHB: GHB receptors in mice
normal mice don’t respond to a selective agonist for GHB receptor
GABA in the brain
- most important inhibitory neurotransmitter in the adult, vertebrate brain
- found throughout brain in high concentrations (many neurons and nuclei)
- important role in regulating excitation
GABA synthesis
GABA is formed from glutamate (immediate precursor) via enzyme glutamic acid decarboxylase (GAD)
VGAT stands for…
vesicular GABA transporter
GABA transporters
GAT-1, GAT-2, GAT-3 (on neurons and glia); transports GABA out of synapse
GABA metabolism/degradation
via the enzyme GABA amino-transferase (GABA-T)
GABAa receptors
- ionotropic
- ligand-gated Cl- channels
- 5 subunits (2 alpha, 2 beta, 1 gamma)
GABAb receptors
- metabotropic
- need two different subunits
- autoreceptor
GABA binding to GABAa
increased Cl- conductance –> hyperpolarization and IPSPs
mechanism of action for barbs/benzos
- act at different site of GABAa receptors
- act at a different site than GABA
mechanism of action for all sedative-hypnotics
enhance chloride influx through GABAa receptors
benzo effects of GABA transmission
- cause GABAa channels to open more frequently
- need GABA; benzos have no effect alone, benzos are positive allosteric modulators
barb effects of GABA transmission
- cause GABAa channels to stay open for longer durations
- barbs have some direct agonist effects without GABA
benzo binding site
- discovered in 1977
- benzo binding correlates with anxiolytic effects
benzo inverse agonists (beta-carbolines)
- beta-carbolines negatively modulate GABAa receptor
- found in psychedelic drug ayahuasca
GABAa subunits: benzo behavioral effects
GABAa receptors with different subunits are differentially involved in various behavioral effects of benzos
alpha2 subunit: anxiolytic effects on benzos
anxiolytic effects require alpha2-conditioning GABAa receptors
alpha1 subunit: rewarding effects of benzos
- rewarding effects require alpha1-containing GABA receptors
- increase firing of VTA dopamine neurons via disinhibition
low to moderate effects of alcohol
specific, acute effects
high doses of alcohol
nonspecific effects
acute effects of alcohol on glutamate mechanisms
- inhibits glutamate transmission
- reduces effectiveness of glutamate actions at NMDA receptor
- results in memory loss
chronic effects of alcohol on glutamate mechanisms
- upregulation of NMDA receptors
- hyperexcitability during withdrawal
acute effects of alcohol on GABA mechanisms
increases GABA-induced Cl- influx at GABAa receptor
chronic effects of alcohol on GABA mechanisms
- reduces GABAa-mediated Cl- influx
- hyperexcitability during withdrawal
acute effects of alcohol on DA mechanisms
- increases DA transmission
- alcohol self-administration reduced, but not blocked, by DA antagonist or 6-OHDA lesions
chronic effects of alcohol on DA mechanisms
- reduction in DA transmission
- withdrawal-induced negative affect and reduction in DA
acute effects of alcohol on opioid mechanisms
- increases endogenous opioids
- Alcohol self-administration decreased by opioid antagonist or μ opioid receptor knockout
chronic effects of alcohol on opioids mechanisms
reduces opioid production
alcohol treatment: detoxification
benzodiazepine replacement
alcohol treatment: psychosocial
self-help groups
