Basic Behavioral Neurobiology of Drug Addiction

1. Basic Behavioral Neurobiology of Drug Addiction J. David Jentsch, Ph.D. Assistant Professor of Psychology (Behavioral Neuroscience)

2. Theoretical Frameworks for Studying Addiction • Examining individual differences that represent risk factors for addiction • Examining behavioral factors that contribute to impulsive and compulsive drug seeking • Examining physiologic changes produced as a function of drug exposure (particularly long-term intake) • Examining physiologic changes associated with withdrawal, successful abstinence and/or recidivism

3. Phases of Substance Abuse • Sampling • Liking (reinforcing stimulus effects of drugs support instrumental act to consume) • Wanting (stimuli associated with drug intake provoke the desire for drugs and facilitate the instrumental drug-taking act) • Needing (sometimes physical dependence occurs which results in a somatic state which supports avoidance behavior)

4. Sampling • Availability • Individual differences • Risk-taking behavior/pleasure-seeking/impulsive personality types • Co-morbidity with psychiatric disorders • Experience with other substances

5. Liking • Positive reinforcing stimulus effects of the drug (unconditioned stimulus [US]) effects support instrumental behavior • Measured with acquisition of self-administration/conditioned place preference in animals • Many drugs also, of course, produce aversive US effects that can function to inhibit the acquisition of instrumental conditioning • Taken together, all the super-imposed US effects represent the “discriminative” stimulus properties of the drug

6. Establishing Drug-Taking • Requires dopamine to be released into the striatum (ventromedial parts, in particular). • This dopamine, on net, inhibits activity within the striatum. • Depiction of decreased striatal activity in a monkey learning to volitionally take cocaine. From Porrino et al. (2002) J Neurosci, 22: 7687-94.

7. Circuit • Basolateral amygdala – nucleus accumbens: involved in acquisition and maintenance of instrumental behavior.

8. Duration of Experience Plays a Role • Clearly, with increasing duration of intake, several things occur. • At the behavioral level, drug effects can change (sensitization or tolerance). • Use patterns may be changing (escalation). • At the neuronal level, physiological effects of the drug may be altered. • Neurochemical or molecular changes.

9. Experience Modifies Drug Effects on Circuitry • After many days of intake, baseline activity of the striatal neuron is lowered and the effects of cocaine on the neuron are increased. • Electrophysiological recording of single unit activity within the striatal complex of rats self-administering cocaine. Figure from Peoples et al. (1999) Brain Res, 822: 231-6.

10. Factors • In theory, experience with the drug may be facilitating future drug consumption rates, etc. • This is not a phenomenon that depends upon drug TAKING because animals passively exposed to stimulants show greater rates of acquisition of self-administration and/or place preference in the future. • So, some direct effect of the drug on the brain modifies the response of an organism to that and other drugs in the future.

11. Experience Effects and Individual Difference Effects May Overlap • For example, delta-FOS-B is a transcription factor that is upregulated in brain in response to chronic cocaine administration. • Direct over-expression of this protein in drug-naïve transgenic mice “pre-sensitizes” them to cocaine. • Data from Kelz et al. (1999) Nature, 401: 272-6

12. Molecular Alterations • So, drugs do at least two things. • First, they act as USs to support instrumental conditioning. • Second, they, via direct pharmacological effects, alter signaling within neurons required for learning about drug effects.

13. Drug Addiction is More Than Just Instrumental Conditioning • Stimuli associated with drug intake acquire incentive properties via Pavlovian learning mechanisms. • Those incentive stimuli can in turn evoke drug-seeking behavior via Pavlovian mechanisms (so-called Pavlovian to Instrumental Transfer). • These effects require not just the accumbens, but also amygdala and its inputs to the striatum.

14. Cocaine Experience “Sensitizes” Appetitive Pavlovian Learning • The acquisition of a CS-US association (revealed by CS evoked magazine approach) is increased in animals with a history of cocaine exposure. • Therefore, the mechanisms by which drug-associated stimuli acquire significance is facilitated. • Therefore, drugs both act as USs and (by altering neurochemistry) enhance the normal processes of CS-US learning. • Data from Taylor and Jentsch (2001) Biol Psychiatry, 50: 137-43.

15. Circuit So Far • Basolateral amygdala – nucleus accumbens: involved in acquisition and maintenance of instrumental behavior. • Central nucleus of the amygdala: involved in the acquisition of Pavlovian relationships between cues and rewards.

16. Cues Associated with Drugs Act as Incentives • Berridge and Robinson discuss, at length, the role for incentives in addiction. • The describe how, by virtue of Pavlovian mechanisms, CSs associated with drugs gain incentive value. • These CSs can then activate a motivational state in which drugs are “wanted”.

17. Drug Cues Stimulate Craving • Showing cocaine addicts pictures of things that remind them of cocaine (syringes, white powder, etc) dramatically increases blood flow in the amygdala. • So, in addition to the striatum, this brain nucleus is important. • Data from Childress et al. (1999) Am J Psychiatry, 156: 11-8.

18. Incentive Sensitization • Pavlovian-Instrumental transfer is a behavioral situation in which reward-associated cues, when presented non-contingently, facilitate operant responding for the reward to which they were paired. • Prior sensitization to amphetamine increased the PIT effect, providing evidence that incentive effects can be “sensitized” by drugs. • Data from Wyvell and Berridge (2001) J Neurosci, 21: 7831-40.

19. The Circuit So Far • Basolateral amygdala – nucleus accumbens: involved in acquisition and maintenance of instrumental behavior. • Central nucleus of the amygdala: involved in the acquisition of Pavlovian relationships between cues and rewards. • Basolateral amygdala – nucleus accumbens: involved in the PIT effect. • All potentiated by cocaine.

20. What About Other Memory Systems? • Prefrontal cortex sends a dense projection to the nucleus accumbens and amygdala, amongst other places, and this projection normally mediates the control over reward-related behavior by higher order memory processes. • Inhibition of pre-potent responses/tendencies. • For example, frontal lobe lesions “un-gate” reward-related behavior like cocaine self-administration. • Might be a circuit mediating the “cognitive” control over impulsive behavior.

21. Chronic Exposure to Cocaine Erodes Cognitive Flexibility • Cocaine treated and normal animals are trained to learn a new discrimination and then reverse it (measures PFC function). • When drug-experienced animals have to shift responding away from something now inappropriate (reversal learning), they are impaired. • Data from Jentsch et al. (2002) Neuropsychopharmacol., 26: 183-190.

22. Drugs… • Act as USs to support instrumental learning • Support conditioned incentive properties of associated cues • Alter the physiology of brain circuits mediating these types of learning, thereby accelerating or sensitizing their function • Erode the function of brain circuits that normally inhibit reward-related behavior • Seize control of a system by stomping on the gas while cutting the brakes