medications and behavior: scheduled psychoactive drugs

Controlled Substances Act of 1970: Drug Schedule

schedule one

drugs have high potential for abuse, have no medically accepted use, + lack safety information regarding their use

schedule two

drugs have high potential for abuse, have accepted medical uses, but their use may lead to severe dependence

schedule three

drugs have potential for abuse, have accepted medical uses, + may lead to low or moderate dependence

schedule four

drugs have low potential for abuse, have accepted medical uses, + have lower risk of dependence than do schedule 3 drugs

schedule five

drugs have low potential for abuse, have accepted medical uses, + have lower risk of dependence than do schedule 4 drugs

examples of drugs from each schedule

schedule one mmphl

heroin, LSD, mescaline, psilocybin, marijuana

schedule two

morphine, codeine, cocaine, amphetamine, methamphetamine, nabilone (synthetic THC)

schedule three

anabolic steroids, pentobarbital, Marinol (synthetic THC)

schedule four 

benzodiazepines, phenobarbital, Ambien + similar sleep aids 

schedule five 

codeine + opiate preparations for cough or diarrhea 

pharmacology of cocaine

rate of absorption depends on administration route 

fast metabolism

• 1-1.5 hours

• metabolites can be detected in blood/tissues for several weeks

crack cocaine 

dissolve cocaine in ammonia or heat w/ baking soda so that it can be vaporized (inhalation)

*makes cracking sound + results in cocaine rocks 

Cocaethylene

cocaine combined w/ alcohol; more potent w/ longer half-life (2.5 hrs); very cardiotoxic »» hypertension, arrhythmia, decreased blood flow

Cocaine mechanisms

slide one

• binds to dopamine transporter (DAT) + blocks reuptake of DA

• at least 47% of DATs must be blocked to perceive euphoric effects

  • typically 60-80% occupied

slide two

• cocaine also blocks reuptake NE and 5HT reuptake which may contribute to reinforcing + euphoric effects

• knockout mice (DAT gene deleted) tested to see if DA is primarily responsible

• PPC place preference conditioning

  • dual-chamber apparatus in which mice can explore side w/ cocaine access + side w/o cocaine access

is blocking DAT sufficient (for whattttt - preventing cocaine overdose)?

no, methylphenidate also blocks DAT

• speed of administration is a factor

• methylphenidate - oral form typically much slower to enter brain + block DATs

DAT knockout mice

still prefer cocaine side 

• cocaine maintains reinforcing effects in absence of DAT blockade (which would normally provide the increased synaptic DA)

• theory: 5-HT “upstream” in VTA »» contributes to increased DA release in NAC 

cocaine: local anesthetic

• dulls pain

• constricts blood flow

mechanism

• disrupts propagation of AP by blocking voltage-dependent NA channels

psychostimulants

• amphetamine

• methamphetamine

*Ephedrine - aka “ma huang” in Chinese medicine

amphetamine 

• 1st synthesized in 1887

• used widely by US military in both world wars 

• many deaths due to cardiotoxicity

examples 

• Benzedrine - mid 1930s, antihistamine inhalant 

• Dexedrine - soon after, for narcolepsy, attention disorders, nasal congestion, obesity

methamphetamine

• synthesized from ephedrine in 1983 - aka “crystal meth” (crystal form)

• 1980s boom in popularity

• high lipid solubility »» powerful euphoric effects

• typically preferred over amphetamine

pharmacology of amphetamines

• half-life = 10-15 hrs

• peak plasma levels

  • PO (oral) = 2-3 hrs

  • inhalation (snorting/insufflation) or smoking = within 3-5 min

  • IV = seconds to minutes

• excreted by kidneys

amphetamine mechanisms of action

1. increased release of NE + DA from presynaptic vesicles »» more DA + NE in synaptic cleft 

2. DA released into presynaptic cytoplasm (becoming “free”)

• dopamine transporter (DAT) acts in reverse 

• more DA in synaptic cleft 

3. blocking reuptake transporter for NE »» more NE in synaptic cleft 

amphetamine mechanisms of action continued

• Da up-regulation in mesolimbic and mesocortical systems »» euphoria + cortical arousal

• DA activity increased in nigrostriatal system »» motor stimulating effects

• at high doses amphetamines induce psychosis

• DA + NE activity increased in RAS »» increased cortical arousal, vigilance, + attention

  • expression of CART (cocaine & amphetamine-regulated transcript) in hypothalamus »» anorectic (appetite suppression) effects (wt loss)

other amphetamines -Ecstasy aka Molly 

• methylenedioxymethamphetamine (MDMA)

• gained popularity in 1970s w psychotherapy + early 200s w/ heavy recreational use

• effects: euphoria, increased self-perception, enhanced sensations, “promotes intimacy”

• side effects: elevated HR/BP, bruxism (w/ broken teeth), neurotoxicity, esp reduced attention, concentration, memory

• mostly 5HT agonist; but DA linked w/ euphoria 

Psychedelics: LSD

most potent of all psychoactive drugs, discovered by Abbie Hoffman, synthesized in a labratory

psychedelics: Psilocybin

similar to LSD but from mushrooms in Pacific Northwest

common response to psychedelics

vivid visual hallucinations w/ color + movement elaboration

uncommon response to LSD + Psilocybin

1. synesthesia

2. flashbacks (“bad trip”) - unpleasant hallucinations that recur - likely from the memory + not residual drug effects

LSD and Psilocybin effects + actions 

effects of both

• increased HR/BP, pupil dilation, dizziness, increased temp

actions of both

• primarily partial 5HT agonists; secondarily DA agonists 

Marijuana (MJ)(Cannabinoids) history

• was used pharmacologically in US mid-1800s for psychoactive effects + medicinally

• Marijuana Tax Act (1937)

  • used prohibitive taxes to decrease cannabis use + research

• Controlled Substances Act (1970)

  • listed it as Schedule 1 drug, an illicit substance

• recently legalized in many states

marijuana pharmacokinetics (and administration route info)

• active compound: tetrahydrocannabinol (THC)

• concentration of THC varies widely 

• fast metabolism w/ typical effects lasting approx 2 hrs 

administration rate 

• smoking is most effective administration route 

  • reaches brain within seconds of inhalation

  • peak plasma levels reached within a few minutes

• oral administration takes longer to absorb

use detection

• single use detected for app 2 weeks

• regular use detected for approx 4 weeks

marijuana pharmacodynamics 

• cannibinoid receptors located in basal ganglia, cerebellum, hippocampus, amygdala, thalamus, + cortex along w/ lymphatic tissues in immune system

• effects: both inhibitory + excitatory

  • inhibitory effects on ACh + glutamate in hippocampus

  • disinhibitory effects on glutamate + DA in PFC

  • disinhibitory effects on DA in VTA

medical marijuana (PANG)

• nausea/vomiting for cancer treatment (inhibit vomiting by acting on receptors in area postrema of brainstem)\

• appetite loss in AIDS patients 

• pain (chronic)

• increased intraocular pressure (glaucoma) are also treated 

*pts report oral is not as effective as smoking marijuana + more difficult to regulate levels in general

psychoactive effects: marijuana

mild euphoria, distortions in time, sedation, can cause anxiety/depression

memory + cognition

• STM interference

• disrupted LTM retrieval (recall more than recognition)

• weak state-dependent retrieval effects

• interference w/ knowledge acquisition

• in general:

  • fragmented speech

  • forgetting what user or others have asid

  • loosening of associations

  • perception of great insights (but w/o analysis + after intoxication insights are not really so great)

marijuana motor control effects 

• impaired motor control, coordination, + performance 

• glutamate inhibited in basal ganglia + disrupted cerebellum activity

  • paradoxically, also therapeutic effects for degenerative motor diseases

• less detrimental than alcohol for driving but still a causal factor in accidents 

  • actually makes drivers more cautious + try to compensate but can’t do it well enough

marijuana cardiovascular effects 

• initially

  • increase in BP and HR

• repeated use

  • decrease in BP from vasodilation

    • to compensate, HR increases »» problems in those w/ cardiac hx or susceptibility

    • but - no evidence that it’s associated directly w/ cardiovascular events

tolerance and dependence: marijuana 

tolerance noted after repeated administration of high doses in mice 

• mechanism = apparent decrease in cannabinoid receptor activation

*most users do not use such high doses!

dependence + withdrawal are noted w/ chronic use (cravings, depression, aggressiveness, irritability)

• CONTROVERSY

• proponents say no, opponents say yes 

tolerance and dependence self-administration experiments

lever pressing for direct drug administration

squirrel monkeys showed high abuse potential demonstrated by continued lever pressing

tolerance and dependence w/ addictive drugs

addictive drugs produce sensitization in DA neurons in mesolimbic reward system in mice

• observed as behavioral sensitization + increased locomotor activity

• cannabinoids can - under certain conditions - produce tolerance and dependence in both animals and humans