Addiction: Wise: Drug dependence-- cluster of cognitive, behavioral and physiologic symptoms indicating the person has impaired control of drug use, and continues to use the drug despite adverse consequences. Physical dep.-- adaptive state to the drug, with physical withdrawal symp. Psychol dep.-- “pleasure”, high---- pos. reinf. Neg. reinf.---- drug intake terminates aversive effects of abstinence ( withdrawal ). Craving-- memory

ADDICTIONS Wise (1989, 1996): physical vs. psychological dependence tolerance, withdrawal Periaqueductal gray (PAG), VTA, n. accumbens, raphe n., hypoth., amygdala, hippocampus, cingulate, prefrontal cortex Endogenous opiates (enkephalin, endorphin) –morphine, opium, heroin (mu, kappa, delta receptors) DA- cocaine, amphetamine, nicotine, caffeine Marijuana (THC)- anandamide( “internal bliss”), 2-AG, noladin ether, virodhamine (4 ligands) Alcohol - “steady” vs. “binge”, somatization (girls) Blum et al (1990, 1996); Spear (2000): Reward deficiency syndrome Nader et al. (2002)

Addicts become accustomed to high levels of dopamine, which plays an important role in the regulation of pleasure. Dopamine is manufactured in nerve cells within the ventral tegmental area and is released in the nucleus accumbens, limbic areas and the frontal cortex.

1. After being released into the synapse, dopamine binds to receptors on the next neuron. 2. Dopamine is either quickly reabsorbed (reuptake) or broken down by the enzyme monoamine oxidase (MAO).

Cocaine blocks reuptake of dopamine plus added release Cocaine blocks reuptake of dopamine plus added release. As a result, dopamine accumulates in the synapse, where it stimulates the receiver cell.

Amphetamines stimulate excess release of dopamine, overwhelming the processes of reuptake and enzymatic breakdown.

Nicotine stimulates the release of dopamine, while another substance in cigarette smoke blocks the action of MAO.

5-HT – in hypothalamus from raphé n. Reward-Deficiency-Syndrome(Blum et al., 1996) ICSS cascade: DA – VTA to n. accumbens, amygdala, hippocampus, septum, cingulate, prefrontal cortex 5-HT – in hypothalamus from raphé n. Enkephalin – in VTA from hypothalamus, in n. accumbens GABA – in VTA, n. accumbens GABAa/BZD - in amygdala BZD = Benzodiazepine

REWARD CASCADE Hypoth VTA N. Accumbens Raphé Amygdala Hippoc 5-HT ENK GABA GABA ENK Raphé DA D1/2 D2 Amygdala DA Reinforce Hippoc GABA (after Blum et al., 1996) GABAa (BZD) P300-wave (EEG) Frontal Cortex D2 + D4 ??? Anxiety Reduced

Spear (2000): Reward-deficiency syndrome in adolescence. Nader et al. (2002): D2 activity and social status in monkeys. ICSS & ADDICTION---- Rev. Olds, Delgado, Deutsch, Stein, Crow, Gallistel, Gibson et al., Rolls, Shizgal, Wise, Stein & Belluzzi, Henry, Blum et al., Spear, Nader et al. Video: Addiction