Transcript Reward and Drug Addiction

Drugs, Addiction and Reward
Stimulants
• Behavioral Effect: increase activity, arousal, excitement,
etc.
• Primary Mechanism of Action: Activation of D2-D4
receptors, either directly or indirectly.
• Examples:
• Amphetamine: increases release of DA from presynaptic
terminal. Increases release of NE.
• Cocaine: Blocks reuptake of DA, NE and 5-HT (works on
same receptors as Ritalin)
• Why the crash?
• The cascade following an increase in release (increase DA
in the cleft. DA leaves the cleft faster than the presynaptic
terminal can resynthesize it. Also, excess DA in the cleft
sends feedback via autoreceptors to reduce further release
of DA.)
More Stimulants
• Caffeine:
• 1) Vasoconstrictor -- alters blood flow by
constricting vessels to the brain, increases blood
flow in the short term, but ultimately reduces blood
flow to the brain.
• 2) Disinhibition -- blocks adenosine, a transmitter
that ordinarily inhibits release of glutamate and DA.
• Nicotine:
• Stimulates nicotinic ACh receptors both in the CNS
and in the neuromuscular junction. Can also bind to
receptors that release DA in the nucleus
accumbens.
Depressants
• Behavioral Effect: depress CNS -- slower heart
rate, reduce tension, reduce anxiety, attentional
impairment, memory problems, etc.
• Examples:
• Alcohol: 1) alters cell membrane properties:
inhibits sodium flow across the membrane;
expands the membrane surface. 2) Decreases
5-HT activity 3) Makes the GABAa receptor
more responsive. (GABA agonist)
Hallucinogens
• Behavioral Effect: produce a dreamlike state,
altered reality, etc.
• Examples:
• LSD: Stimulates 5-HT receptors. Leads to an
increased number of 5-HT receptors at the postsynaptic site.
• PCP: Inhibits glutamate receptors (in nuc.
accumbens) leading to a net depression of
nucleus.
• MDMA (Ecstasy): Stimulates release of DA and
produces effects at 5-HT synapses.
Other Drugs of Abuse:
• Marijuana: Active ingredient THC is lipid
soluble, binds to cannabinoid receptors in
the hippocampus, basal ganglia, and
cerebellum. May also alter ACh receptor
function. Anandamide: "natural stash“.
• Morphine: Opiate receptors; endogenous
opiates: enkephalins, endorphins
FIGURE 4 Effects of cocaine on thresholds of brain stimulation reward and brain stimulation
detection. For measurement of detection threshold, the initial, noncontingent stimulus varied in
intensity (at subreward levels), whereas the second, or response-contingent, stimulus was held
constant at a rewarding intensity to maintain responding. Each point is the mean z score ± SEM, the
difference between the means of the thresholds after administration of vehicle and drug, divided by
the standard deviation of all thresholds after vehicle administration. A z score of 2 indicates
significant difference from vehicle treatment sessions. These results show that an acute
administration of cocaine can lower thresholds of brain stimulation (i.e., facilitate central reward).
The cocaine treatment does not affect the ability of the rat to discriminate because detection of a
nonrewarding stimulus is not altered (detection threshold). Error bars not shown indicate SEM less
than the diameter of the symbols in this illustration. Reprinted with permission from Kornetsky and
Bain (1982).
FIGURE 2 The cocaine dose–effect function shifts to the right following pretreatment with the dopamine (DA) D-1 receptor antagonists SCH23390
and SCH39166. (A) Effects of pretreatment with SCH23390 (0.01 mg/kg subcutaneous) on the dose–effect function of intravenously selfadministered cocaine (0.06–0.05 mg) measured using the within-session dose–effect paradigm (n=4). (B) Same as in A but for an individual rat.
Reprinted with permission from Caine and Koob (1995). (C and D) Effects of pretreatment with SCH39166 on cocaine self-administration in two
squirrel monkeys. Points are means based on the last three sessions at each dose of drug. Reprinted with permission from Bergman et al. (1990).,
Morphine Addiction
Chronic Administration of Morphine in the rat shrinks dopamine neurons in
the VTA
Alcohol Triggers Opioid Systems
Opiate Blockade via Naltrexone administration tends to eliminate “wanting”.
Glutamate and Cocaine addiction
Brief stimulation of Hippocampal Glutamate Fibers induce cocaine searching
Stimulation of the Medial Forebrain Bundle does not induce this searching
Effect.
Ecstasy
Evidence of short-term (B) and longer-term (C) in a monkey after substantive
Ecstasy exposure. Serotonergic axon loss is prominent in the anatomy.
FIGURE 8 Diagram describing the hypothetical spiraling distress-addiction cycle from a neurobiological
perspective. Small arrows refer to increased or decreased functional activity. The addiction cycle is
conceptualized as a spiral that increases in amplitude with repeated experience, ultimately resulting in
the pathological state of addiction. DA, dopamine; CRF, corticotropin-releasing factor. Reprinted with
permission from Koob and Le Moal (1997).
Serotonin Drugs