• Voluntary Drug Taking
• Essential for models of addiction because it involves different neurochemical responses and adaptations than passive drug exposure
• self-administration is the golden standard for measuring the reinforcing properties of drugs

• less useful for addiction studies 
• useful for 
  • Studying effects of prenatal and early adolescent drug exposure on propensity for drug seeking / taking behavior in adulthood
  • Facilitate the acquisition of self-administration by prompting development of tolerance to adverse effects and establishing a state of drug dependence.

• unconditioned stimulus: drug
• unconditioned response: environmental context 
  • can be no confounding reason for subject to preference or bias environment
  • ex. one environment cannot contain more food, water, or some other preferable or subversive stimulus - both environments must be identical (w/ exception of drug presence, location of prior drug exposure, etc.)
• conditioned stimulus: drug-free choice of environment
• conditioned response: time spent in drug-paired environment
• Pros
  • can demonstrate rewarding or aversive effects
  • High predictive validity for detecting drugs with abuse potential
  • Time-efficient and convenient for assessing hedonic effects of drugs and drug withdrawal
• Cons
  • Limited to passive drug exposure
  • Rewarding effects of drugs that do not produce euphoria can be masked by anxiogenic or aversive effects
• CPP = conditioned place preference
• CPA = conditioned place aversion
• Caution when interpreting a failure to acquire CPP
  • Could be due to absence of detectable rewarding effects of the drug
  • Could indicate an impairment in the ability to make associations – i.e. failure to learn

[image]

• Conditioned stimulus paired with a food reward
• Sign-trackers maintain more contact with a reward-predictive CS
• Goal trackers tend to orient towards the reward location
• Characteristics correlated with differences in sensitivity to cocaine-induced neuroadaptations and propensity for drug seeking

[image]

• assesses animal's hedonic state
  • affective or emotional state
• instrumental responses reinforced with brief electrical stimulation of brain tissue
• Reward threshold (the minimum frequency at which intra-cranial stimulation reinforces instrumental responding)
  • Used to measure changes in hedonic state following administration of drugs of abuse
  • Chronic drug administration can increase reward threshold and decrease rewarding effects of drugs
  • Thought to mimic anhedonia in chronic drug users
  • Also can show the emergence of aversive affective states during drug withdrawal
  • Very sensitive to changes in affect
  • Limited by rate-altering effects of drugs (stimulant or sedative effects on behavior)
• drug of abuse lowers reward threshold
• withdrawal raises reward threshold

[image]

• Drug exposure is contingent upon entry into the goals box
• Olfactory stimuli in the start box can be conditioned to signal drug availability
• Arrow indicate “retreats” – interpreted to indicate aversive drug effects
• Drug of abuse in this example decreases start latency and run time – measures of the motivational effects of DOA
• Start latency predicts the magnitude of escalation in cocaine intake during subsequent self-administration
• This procedure can detect reinforcing and aversive effects of DOA and the development of tolerance to anxiogenic and other aversive drug effects.

[image]

• models that use operant learning and scheduling to assess drug reinforcement effects 
• drug self-administration (operant learning) demonstrates reinforcing nature of drugs.
• Basis
  • By definition, a reinforcer is a stimulus that increases the frequency of the behavior it is contingent upon
  • Rats respond on an “operanda” (i.e. nose poke or level push) to receive injection of drug
• Terms
  • operandum - response apparatus
  • reinforcement schedule - prescribed contingency between instrumental responding and reinforcements
  • schedule demand - number of response(s) required to receive reinforcing stimulus 
  • schedule completion - performance of the set of responses required for a delivery of reinforce
  • extinction - instrumental responses are no long reinforced (e.g. no drug is administered) or the CS-US relationship is eliminated
• types to know
  • fixed ratio
  • progressive ratio
  • concurrent schedule
  • chain schedule
  • second-order schedule

• presentation of the reinforcer is contingent upon the performance of a fixed number of instrumental responses
• continuous or FR1 - one response required for presentation of reinforcer
• Pros
  • easy for subjects to acquire
  • identifies reinforcing property of self-administered drugs
  • produces strong response-drug associations and high drug intake
• Cons
  • generate U-shaped dose effect curves for drugs of abuse
    • may sound like positive thing but descending limb of curve indicates decrease in instrumental responding due to aversive and/or rate-altering effects of drugs at high doses

[image]

• overcomes limitations of fixed-ratio scheduling
• schedule demand is gradually increased after each schedule completion until responding ceases
• linear relationship between dose and break point - most demanding schedule subject will complete
• limitation - there may be drug-induced performance impairments early in the session
  • Cause misinterpretation by underestimating break point
  • Especially concerning when comparing the reinforcing effects of different drugs

[image]

[image]

• can be optimized to compare relative reinforcing effect of different drugs
• 2 or more reinforcing schedules are implemented simultaneously via distinct operanda
• This permits to observation of choice behavior (unequal distribution of responses on different operanda)
• Also can be used to detect changes in the motivational effects of a drug relative to a natural reinforcer after chronic drug exposure

[image]

• can be used to study the difference between drug seeking and drug taking
• Chain schedules have 2 or more reinforcement schedules implemented in a fixed sequence.
• Schedule completion on a “seeking” lever (initial link) provides access to the “taking” lever (terminal link).  When both are completed drug reinforcement occurs.
• Progression between the links is dependent on schedule completion, and completion of the terminal link results in primary reinforcement

• when drugs are taken in excess, escalation effect may be observed(especially over longer periods of time)
  • subject increases drug intake over extended access to drug self-administration
• mechanisms
  • tolerance builds to rewarding effects of drug leading subject to take increasingly large amounts of drug
  • Neuroadaptations that potentiate drug-induced motivation, promote negative reinforcements and/or expedite habitual or compulsive drug-seeking behavior

[image]

• creates deprivation effect over time
  • Increased responses and intake of drug following period(s) of forced abstinence.
  • Experimenter imposes period where animal cannot access drug

[image]

• Model of cue-induced drug seeking
• Second-order reinforcement schedule involves extended periods of drug seeking maintained by drug-associated conditioned stimuli.
• 2 sets of schedule completions
  • Conditioned reinforcement: completion produces the CS (cue) – measure of cue-induced motivation
  • Completion of the second order schedule is required from primary reinforcement (drug)

• model of cue-induced drug seeking
• Process
  • During self-administration training, drug delivery is paired with the presentation of a CS or occurs in a distinct environment during drug training
  • Subjects then receive extinction training in the absence of the CS or environmental context
  • Reinstatement effect = increase in the magnitude of drug-seeking behavior at test
• Reinstatement of drug seeking behavior can be triggered by stress or passive drug exposure
• abstinence model
  • Animals are kept in an alternative context without access to the operandum
  • The ability of drug, stress, or CS to induce drug seeking behavior is then tested.
  • [image]

A=drug-paired context     B=alternative context

• Extinction training is not a good model for abstinence in a human user
  • Typically addicts don’t undergo extinction training!
  • Addicts stop using because of increasingly negative consequences (health, financial, social)
• Extinction training causes brain plasticity mechanisms that inhibit future drug seeking
• Model requires response contingent presentation of the cue (conditioned stimulus)
  • In reality, cues typically evoke drug seeking behavior whereas in the model the cue is reinforcing behavior that already occurred
• Passive presentation of the cue is not effective at triggering drug seeking behavior

• model for cue-induced drug "craving"
• Pavlovian CS-drug conditioning and instrumental response-drug training are done separately
• After training, passive CS presentation increases instrumental response rate suggesting that the conditioned cue is provoking a state of “wanting” or “craving” indicated by increased drug seeking behavior

(last one in image)

[image]

• hedonic impact
  • pleasure we experience from action
  • liking something
  • palatability is hedonic impact of food
• incentive salience
  • our actual motivation to obtain something we like
  • primarily a product of other motivations
  • wanting something
• salt depletion example

• hedonic impact
  • pleasure we experience from action
  • liking something
  • palatability is hedonic impact of food
• incentive salience
  • our actual motivation to obtain something we like
  • primarily a product of other motivations
  • wanting something
• salt depletion example

• formed by Robinson and Berridge in 1993
• a model to explain drug craving
  • craving is manifestation of incentive salience that becomes stronger w/ repeated use due to sensitization of mesolimbic dopamine system to drug effects
  • repeated presentation of reinforcer causes stimuli associated w/ it to also have greater incentive salience

• self-stimulation paradigms
  • rodents would push lever to electrically stimulate certain portions of brain indicating increased motivation for action[image]

• Virtually all abusable drugs enhance basal neuronal firing or basal neurotransmitter release in these reward circuits
• Many of drugs of abuse alter transmission within the dopamine system arising from the VTA and projecting to the nucleus accumbens
• five major regions
  • VTA - ventral tegmental area
  • nucleus accumbens
  • hippocampus/amygdala
  • basal ganglia
  • prefrontal cortex
• These areas work together as a motivation control system. 
  • Contributes to fitness and survival of organisms
  • Even invertebrate brains have a dopamine system similar to our reward system!! 

• mesolimbic dopamine circuit = VTA → NAc
  • the reward synapse
  • VTA releases dopamine in the NAc
  • NAc releases an opiate-like neuropeptide into the VTA to create a complete circuit
• Ventral Tegmental Area
  • source of dopamine cell bodies sending axon projections to the nucleus accumbens
• Nucleus Accumbens
  • receives dopamine inputs (axon terminals) from the VTA
  • all addictive drugs produce an increase of dopamine here

• increases motor output through connection to thalamus to produce overall increase in behavior
• receives input from both cortex and nucleus accumbens
• communicates w/ thalamus and thalamus communicates w/ cortex

• tells the nucleus accumbens where we are and what is happening around us (our “context”)
• Gives environmental stimuli “incentive salience”
• forms circuit w/ cortex and receives information from nucleus accumbens
• hippocampus
  • particularly ventral subiculum of hippocampus
  • responsible for spatial and contextual control
• amygdala
  • particularly basolateral amygdala
  • responsible for conditioned association and affective drive (emotional drive)

• provides the nucleus accumbens with several options for behavior
• acts as sort of initial and final initiator of action
• communicates w/ basal ganglia, nucleus accumbens, and hippocampus/amygdala
• executive control (response inhibition and task switching)

• source of dopamine cell bodies sending axon projections to the nucleus accumbens
• purpose: dopamine modulation of NAc
  • 60-65% of neurons in VTA are DA
  • Heterogeneous population 
• Input to the VTA is widespread, not from distinct nuclei
  • A distributed ‘band’ of neurons that stretches from the PFC to medullary brainstem
  • Innervation is direct and indirect through intermediary structures

• DA neurons fire in burst when animal encounters behaviorally salient stimulus. 
  • stimulus that predicts a reward.
  • Induction of burst firing depends on glutamate activation of NMDA receptors
  • This input comes from PPTg/LDT
    • pedunculopontine tegmental nucleus
    • laterodorsal tegmental nucleus
• Interestingly, DA neurons must be in a spontaneously firing state in order to be induced to fire a burst.
• Process
  • Glutamate from PPTg gives information about the behavioral signal
  • The vSub provides amplification factor by determining population activity
  • Taken together this system regulates context-dependent responses by modulating the amplitude of DA response

• part of ventral striatum
  • caudate and putamen of basal ganglia are dorsal striatum
• made up of 90% medium spiny projection neurons and 10% local circuit interneurons
• has two main parts w/ different projections and neurochemical characteristics
  • core - contributes to motivated behaviors like cue-conditioning and drug seeking 
    • more distal from central fissure
  • shell - contributes to drug reward
• Site of integration of cortical afferents
• Under modulatory influence of DA from the VTA
• Regulates activity/excitability in DA neurons
  • through opiate-like neuropeptides
• Receives excitatory input from limbic and limbic associated cortical areas including (but not limited to)
  • mPFC, lPFC, entorhinal cortex, ventral subiculum of the hippocampus, basolateral amygdala
• Modulatory inputs from DA neurons in the VTA and peptide-containing neurons from the hypothalamus

[image]

• Excitatory inputs
  • ventral subiculum
    • receives input from dorsal hippocampus, prefrontal cortex, basolateral amygdala
    • integrates spatial and affective memory
  • basolateral amygdala
  • prefrontal cortex
• For VTA to cause burst in NAc, it must tonically release dopamine (be spontaneously active)
  • VTA neurons usually inhibited by ventral pallidum
  • Population activity refers to the proportion of DA neurons that are spontaneously active
• Ventral Pallidum is inhibited by NAc which disinhibits VTA allowing for increase in population activity
• Pathway
  1. Vsub excites NAc
  2. NAc inhibits VP
  3. VP disinhibits VTA
  4. VTA population activity increases
• Fits with the limbic (hippocampus) role of providing context information, allows the state of DA neurons to modulate animal’s attention

• rapid, large-amplitude shifts in membrane potential of ~20mV
• spontaneous action potentials can only occur during up state
• up states driven by Vsub input, thus it is providing affective info of locations in space – important for context-specific processes

• Receives inputs from:
  • dorsal hippocampus
  • prefrontal cortex
  • basolateral amygdala
• integrates spatial and affective information
• D1 agonists increase vSub drive of NAc neurons 
• occurs through phasic release of DA during bursts of spikes
• bursting of DA neurons occurs upon exposure to a rewarding event
• Thus, rewarding event can facilitate vSub→NAc activity indicating involvement in reward-related behavior
• Disconnection of vSub and NAc disrupts the acquisition of learned behavior

• Drugs that increase vigilance and alertness
• Heighten mood
• Reduce need for sleep
• Most also increase the activity of the sympathetic nervous system:  sympathomimetics
• Include cocaine, amphetamine, caffeine, nicotine, and others
• because of their increase of stress response, they increase physical stress on body if used during times of stress

• its use hails from the ephedra sinica 5000 years ago in China
  • typically consumed in ma huang teas
• ephedrine molecule concentrated in 1880's from ma huang
  • used in treatment of asthma
  • sympathomimetic qualities led to dilation of airways
• until recently, actually found in diet pills (suppresses hunger)
• pseudoephedrine (Sudafed) came to replace it as common OTC decongestant due to overuse of ephedrine to make more addictive drugs

• amphetamines synthesized by Romanian scientist in 1887
• methamphetamine discovered in 1919
• Amphetamine was re-discovered in the 1920’s in the search for a synthetic substitute of ephedrine after which point it became used
  • Structure similar to epinephrine – known stimulant of sympathetic nervous system
  • Two structural analogues were produced:  amphetamine and methamphetamine
• amphetamines sold as OTC cough suppressant for first time in 1932
• dextroamphetamine (adderall) became commonly available in 1940s
• by 1950s, amphetamines were used to treat depression and weight loss

• amphetamine and methamphetamine were both re-discovered around same time
  • Methamphetamine synthesized by pharmacologist in Japan while amphetamine synthesized by American around 1920s
• Methamphetamine is more potent – why??
  • Methyl group makes it more nonpolar allowing it to pass far more easily through BBB
  • Higher potency, faster onset, faster fall-off, stronger high = more addictive
• other derivatives
  • Methamphetamine (Desoxyn, Methedrine)
  • Methylphenidate (Ritalin - used for ADHD)
  • Dextroamphetamine (Dexatrim) - adderall
  • 3,4,-Methylenedeoxymethamphetamine (MDMA, Ecstasy, X)

• most commonly used recreationally for ability to produce euphoria
  • CRANK, CRYSTAL, SPEED, METH, C.R., GO, GO FAST, GEEK, GACK, GEET, RED ROCK, TWEAK, SHABU, HIRRPOPON, BATU, AMP, PEANUT BUTTER, PROPE DOPE, P2P, POOR MAN'S COKE, PINK GLASS, CHALK, ZIP
  • SMOKERS:  LOKER, BULB BABY, BULBER, CHORE BOY, HITTER
  • SNORTERS: GACKERS, GEETERS, TWEAKERS, RAILS, TRAIN TRACKS, RAILING DOWN, LIGHTNING BOLTS, SNORTING FAT ROCKS
• Instrumental:  Medical uses not as common.
  • Once used as an antidepressant
  • Originally used to treat Asthma
  • Narcolepsy
  • ADHD

• Oral (very well absorbed via G.I. tract; blood levels may be kept constant over time).
  • -Crosses the blood brain barrier; concentrated in spleen , kidneys and brain; high lipid solubility allows it to pass efficiently, but also allows it to collect in certain organs
• Intravenous (gets to the brain in seconds).
• Inhalation - most amphetamines are not volatile enough to vaporize when smoked however ....
  • A form of methamphetamine hydrochloride can be inhaled by smoking.
  • Inhalation allows for very rapid onset of effects (similar to smoking cocaine)

• @ low doses
  
  • Loss of appetite
  • Dilated pupils
  • Rapid breathing and increased heart rate
  • Increased blood pressure (vasoconstrictor)
  • Arrhythmias (change in BP can be enough in some to cause arrhythmia or even stroke)
  • Facilitates athletic activities requiring bursts of energy (sprinting etc.) 
  • Not good for more coordinated sports
• @ high doses
  •  Fever
  • Sweating
  • Headaches
  • Blurred vision
  • Dizziness
  • Toxicity:  Direct lethal effects are unusual, but when they occur are caused by stroke or internal bleeding.

• @ low doses
  • Elevates mood/ euphoria. Effects last for 3-6h and are followed by a feeling of depression. 
  • Increases alertness, decreases fatigue
  • Increases focus and attention
  • Subjects report “a desire to get to work and accomplish things”
• @ high doses or w/ chronic use
  • Dysphoria: dissatisfaction, anxiety, restlessness
  • Social Withdrawal
  • Depression
  • Irritability, anxiety
  • Aggression
  • Hallucinations
  • Paranoid psychosis
  • Stereotypy - repetitive or ritualistic movement like body rocking 

• Low doses of amphetamine induce tolerance over 4-6 weeks of medical use, but high doses induce tolerance over course of 1 day binge
  • cross-tolerance can occur w/ cocaine
• sensitization is uniquely reported (opposite of tolerance)
  • cross-sensitization can occur w/ cocaine
  • unique effect of psychostimulants
• dependence is less physiological (although there are still symptoms
• strong psychological dependence
  • preoccupation w/ obtaining drug
  • Cravings
  • Physical dependence can lead to psychological dependence in hopes of suppressing withdrawal symptom
  • Animal self administration
• withdrawal symptoms include hunger, lethargy, exhaustion, and depression

• South American plant used by people of Andes mountain for 4500 yrs w/out problem
• Pure cocaine was first extracted from the leaf of the Erythroxylon coca bush, which grows primarily in Peru and Bolivia
• Europeans knew of coca leaves at the time of the conquest, but cocaine did not gain widespread attention until the mid 1800’s
• A French chemist, Angelo Mariani, imported tons of coca leaves and extracted the drug to put in lozenges, teas and wines. Made him a wealthy man.
• J.C. Pemberton began to develop cocaine as we know it today through his line of sodas
  • alcohol removed from coca wine and replaced w/ kola nut (caffeine source)

• The use of cocaine in psychiatry was promoted by Sigmund Freud (primarily for treatment of addiction and depression). 
  • Also prescribed to women who were hysterical and for anxiety
• Cocaine used as a local anesthetic since the late 1800’s.
• Still used as a local anesthetic (Schedule II drug).  It has been largely replaced by other drugs like novocaine.
• Almost all use of cocaine today is recreational

• methylphenidate (ritalin) used 
• stimulants arous CNS allowing more sensory information to reach thalamus and cortex
• The modulatory action of RAS efferents help direct attention and arousal
• Thus in ADHD children, the RAS may be depressed and stimulants can reset it to the appropriate level so that the appropriate sensory input is received.
• side effects include decrease in appetite, weight, and height
  • why some parents only let children use during school year

• Forms of Cocaine
  • Leaves - chewing on leaves of coca plant allows for slow absorption through mucous membranes and GI tract.  Lower blood levels and slower onset 
  • HCl salt - cocaine power.  Dissolves in water - can be taken intravenously or snorted
  • Freebase refers to a compound that has not been neutralized by an acid to make the hydrochloride salt. The freebase form of cocaine is smokable.
    • Freebase is produced in a more expensive process.
  • Speedball - mixed with heroin and injected intravenously
• Routes of Administration
  • Oral - slow absorption and onset
  • Mucous membrane (snorting cocaine HCl or on gums) 
  • Intravenous - cocaine HCl injection or speedball
  • Inhalation -freebase and crack produce very intense high that fades quickly

• @ low doses
  • very similar to amphetamine differing only in time-course
    • 3-4 hrs for amphetamine; 45 mins cocaine
  • Users report being swept away by a wave of well-being.  They feel self confident, alert, energetic, outgoing, fidgety and talkative
  • cross-tolerance and cross-sensitization w/ amphetamine
• @ high doses
  •  Irritability
  • Anxiety
  • Psychotic behavior
  • Suicidal thoughts
  • Rebound depression
  • Anxiety
  • Paranoid ideation
  • Hallucinations (visual and somatosensory)
  • Aggression

• @ low doses
  • Constricts blood vessels
  • Increases heart rate
  • Raises blood pressure
  • Arrhythmias
  • Increases body temperature
  • Headaches
• @ high doses/cocaine toxicity
  • Loss of consciousness
  • Seizures
  • Damage to nasal membranes (snorting)
  • Liver damage with chronic use
  • Can cause sudden death by triggering arrhythmia, respiratory arrest, cerebral hemorrhage, convulsions.  
  • Most likely to be fatal via I.V. injection

• “Best high is the first high”:  Tolerance occurs with acute use. (pretty much immediately)
  • Cocaine spree is an attempt to overcome increasing tolerance
  • During a binge, extremely high blood levels of cocaine are reached over a period of 1-2 days.
  • Results in sleeplessness, tremors, nausea, and psychotic behavior - cocaine psychosis.
• Sensitization to motor or convulsive effects
• essentially to unwanted/toxic effects
• Dependence:  May be greater for cocaine than amphetamine because the subjective crash is greater for I.V. and smoking users
  • Subjective crash more intense and often reported in cocaine users than amphetamine users
• A very strong psychological dependence.
• Mild physical dependence
• Withdrawal effects: following a binge, cocaine leads to increased appetite, sleepiness, depression - very similar to amphetamine.

• structurally similar to catecholamines but don't interact directly w/ catecholamine receptors
  • they do, however, work through enhancing catecholamine transmission
• Mechanisms
  • Competitive inhibition of DAT
  • Phosphorylation of DAT results in internalization
  • Inhibits DA uptake by VMAT-2 & collapses vesicular pH gradients resulting in DA flowing out of the vesicle into the cytoplasm
  • Intracellular DA causes reverse transport of DA by DAT
  • High AMPH concentrations inhibit MAO
• similar process occurs in noradrenergic neurons

[image]

• Reinforcing properties due to VTA – NA pathway
• Also encodes the relationship between drug effects and predictive environmental stimuli (cue)
• DA signaling in NAc (and specifically the DAT) is necessary for self-administration of psychostimulants in rodents.
• Mesolimbic system is markedly dysregulated following chronic psychostimulant administration
• Thought to underlie the increased motivation to obtain psychostimulants in abusers.

• experiments conducted in mouse striatal synaptosomes show that dopamine uptake is unaffected w/out DAT
• experiments also show decreased locomotor activity and response to psychostimulants in mice w/out DAT
• Animals that express an intact dopamine transporter that has decreased cocaine binding are insensitive to the rewarding effects of cocaine – as measured by conditioned place preference
• Drugs that bind to only the DAT transporter have similar rewarding (DPP) and reinforcing (self-administration) effects as drugs that bind all three monoamine transporters 

• Similar to amphetamine in its ability to block DA uptake.  However, it does not enter the cell, thus does not induce DA release.
• Tolerance:  autoreceptor activation leads to neurotransmitter depletion (#4 in image)
• Amphetamine lasts longer (2-3 hours vs. 30 min for cocaine).  This may be due to the releasing effects of AMPH and that high doses of AMPH can also inhibit the DA degradation monoamine oxidase (MAO)
  • Likely due to fact that it does more things to affect dopamine transmission and has intracellular mechanism
• Amphetamine and cocaine produce indistinguishable subjective feelings and reinforcing properties, their different MOA can result in different long-term effects on tolerance, addiction, neuronal damage and cravings.
  • Subjective reinforcing effects seem to be due to active blockade of transporter as it is shared between them
  • Different mechanisms of action in other areas means that other effects may be different even though high is same

• Chronic use depletes DA
• In response to depleted DA, postsynaptic neurons compensate by upregulating receptor numbers and increasing sensitivity
• When cocaine is taken again, the effect of the drug can be enhanced due to the increase in receptors.