# Presentation: 540630

## Neurobiological Substrates of Stimulant Action and Reward

**Elliot A. Stein, Ph.D.**
**Neuroimaging Research Branch**
**NIDA-IRP**

## Outline

**The problem of drug abuse**
**Acute CNS effects of nicotine **
**Behavioral and neuropharm-**
**	****acological actions of acute cocaine and methylphenidate  **
**Inhibitory control mechanisms**
**Cocaine and IC**

## The Problem of Substance Abuse   

**	****Essence of addiction is the **_**compulsive**_** self-administration of drug. Multiple hypotheses, each with different degrees of emphasis on MCL DA system: **
**drugs are **_**positively reinforcing**_**- they feel good**
**drugs **_**fix a negative state**_**, either pre-existing or due to withdrawal from use**
**drugs of abuse ‘**_**hijack’ normal reward circuits**_
**drug-induced DA release leads to **_**over-learning of reward/drug association**_
_**Key point:**_** drug abuse is a recurring, relapsing brain disease with underlying *****pharmacological***** and *****behavioral***** mechanisms**

## Mechanisms???

**Mechanisms???**

## 	“A cigarette is the perfect type of a perfect pleasure. It is exquisite and leaves one unsatisfied. What more could one want”	

**	****	****	****	****	****	****Oscar Wilde**

**“****Nicotine is the drug in tobacco that causes addiction. The pharmacological and behavioral processes that determine tobacco addiction are similar to those **
**that determine addiction to drugs such **
**as heroin and cocaine.” **
**Surgeon General, 1988**

## Nicotine as an Addictive Agent

**Capable of producing tolerance, physical dependence and withdrawal symptoms (increased irritability, anxiety and depression) upon cessation of use**
**Animals and humans SA nicotine, which shares behavioral properties with other drugs of abuse, most notably the psychomotor stimulants**
**Humans report IV nicotine as pleasant, often preferring it to cigarettes **
**Human cocaine abusers identify IV nicotine as similar, and in many cases, identical to IV cocaine****   **

## Objectives

***   ******To determine the CNS sites and mechanisms of action of acute nicotine in human cigarette smokers using ******	******	******	******	******functional magnetic resonance ******	******	******	******imaging (fMRI)***

## Nicotine (1.5 mg)

***Stein, E.A. et al*** ***Am. J. Psych, 1998***

## fMRI Analysis-binary decision model

**Parameters defined from known pharmacokinetics and empirically via visual inspection**
***Bloom et al. Human  Brain Map ***_***8***_***: 235-244, 1999***

**fMRI Analysis-****binary decision model**

**cing**

**IFG**

**OFG**

**insula**

**Lat orb gyr**

***Stein, E.A. et al***. ***Am. J. Psych ***_***155:***_*** 1009-1015, 1998***

## Nicotine: regional activation

_**CORTEX**_
**Orbital**** ****(posterior, lateral)**
**Cingulate**
**Frontal**** ****(inferior, medial, superior)**
**Temporal**** ****(inferior, medial, superior)**
**Insula**
**Visual**** ****(****medial, inferior, lateral occipital; cuneus, precuneus, lingual****)**

_**SUBCORTICAL**_
**  ****Thalamus:** **VA, MD, LD, PL, VL, anterior n.**
**  ****Basal Ganglia**: **putamen, caudate, NAcc, globus pallidus**
**  ****Limbic**: **amygdala, hypothalamus**
**  ****Colliculus**: **superior, inferior**

## Slide 12

## Cocaine

**More reinforcing than amphetamines or opiates-monkeys SA cocaine>8000x/single injection**
**Given choice-prefer cocaine to food, water or sexual contact**
**Prefer cocaine+shock to low (or no) cocaine without shock**
**Given unlimited access-monkeys and rats SA to death**

## Cocaine: CNS effects

***Breiter HC et al, Neuron, 19:591-611 (1997)***

**Cocaine:**** ****CNS effects**

## Experimental Procedure

**Experimental Procedure**

**Day 1 (GCRC): each subject received IV cocaine (40mg/70kg) for safety toleration. Subjects were also trained on VAS behavioral assessment scales for *****HIGH, Pleasant, Nervous, CRAVING and Sour *****(1/min).**
**Day 2, 3, and 4: subjects underwent 4 consecutive fMRI scans each day (GE-EPI, TR=6s, TE=40ms, 1.5T GE Signa) and were injected  with saline and one of the 3 doses cocaine (10, 20, 40 mg/70 kg; the order & dose of injections were blind to the subjects) **

## Finger-tapping

**Before**
**Cocaine **

**After**
**Cocaine **

**0**

**10**

**20**

**40**

***Stein et al Unpublished data***

## Methylphenidate

**IV cocaine - baboons and cocaine users**
**IV MP – healthy volunteers and cocaine users**
**Pharmacokinetics, Cardiovascular, Behavior, Distribution**
**	**
**	**
**	**
**Other neuroimaging - IV cocaine in humans**
**PET: London et al (1990)- global CMRglu decreases**
**fMRI: Breiter et al (1997)- mostly MCL regional activation**

**Methylphenidate**

- 11C-Cocaine

- 11C-MP

**Time (mins)**

**Time (mins)**

## Experimental Design

**Experienced cocaine users**
**IV drug injections in 3 scanning sessions on separate days**
**	****20mg/70kg cocaine (n=13); 10 mg MP (n=11); 20mg MP (n=13)**
** ****2 x 38 min runs per scan = 1 saline + 1 drug**
** ****Dose and drug/saline order single blinded**

## BOLD Time Series

**BOLD Time Series**

**Time (min)**

*Dirckx,et al 2004*

## Summary

**Summary**

_**20mg cocaine, 20mg MP and 10mg MP**_
** ****Signal ****Increases**** in LEFT**
**ventromedial orbitofrontal cortex**
**prefrontal cortex**
**anterior cingulate **
**caudate: head/body**
**dorsomedial thalamus**
**Insula**
**Signal ****Decreases**** in LEFT**
**nucleus accumbens**
**subcallosal gyrus **
** **_**Saline**_
** ****No significant changes (small LEFT NAc increase in 20MP saline condition)**
**	****	**

## Dirckx,et al 2004

***Dirckx,et al 2004***

## Conclusions

**BOLD can used to follow time-and dose-dependent regional alterations in neuronal activity following acute drug administration**
**Abused drugs appear to exert similar activation/ deactivation effects (****e.g. negative in NAcc and positive in ACC) ****on similar groups of structures (e.g. MCL regions)**
**fMRI can be applied to follow ‘real-time’ CNS pharmacokinetic and pharmacodynamic aspects of drug actions**
**Given similar sites (so far), the different abuse liabilities of cocaine and MPh may be rooted in their differing pharmacokinetics (Volkow et al)**

## Right Hemisphere Dominance of Inhibitory Control: an Event Related functional MRI Study 

***Garavan, Ross and Stein***
***PNAS (USA) 96: 8301-8306, 1999***

## Significance of Inhibitory Control

**Suppression of irrelevant/interfering stimuli or impulses: fundamental executive function essential for normal thinking**
**IC deficits implicated in ADHD, Tourette’s, OCD, other disinhibition syndromes-including drug abuse**
**Characteristic of frontal lobe development**

## Inhibitory Control Task

**Inhibitory Control Task**

- L

**Respond**
**(Target 1)**

**Respond**
**(Target 2)**

- Y

- A

- Y

- M

- T

- A

- X

- P

- G

**500 msec**

**1000 Letters (150 Targets - 25 Lures)**

## Frontal-Parietal co-Activation

***Garavan et al PNAS (USA) 96: 8301-6, 1999***

**IFG/OFG**

**Post **
**parietal**

**Med Fr Cx**

**L        ****	****       R**

## Inhibitory Control

**Target RT**

**Mean % AUC**

**Inf. Parietal Lob**

- r=-0.67

**Inhibitory Control**

***Garavan, Ross and Stein PNAS (USA) 96: 8301-8306, 1999***

**1**

**4**

**3**

**2**

**IFG-OFC**
**MGF-dlpfc**
**Insula**
**Post Parietal lobe**

## Inhibitory Control Conclusions

**Confirms a role for orbital frontal, parietal, and cerebellar regions in inhibitory control**
**Implicates a preferential role for right hemisphere in response inhibition**
**Baseline to compare with drug abuse **_**Ss **_**(on and ****off**** drug)**

## IC and Cocaine Abuse

**Pharmacological effects of cocaine on MCL DA system **_**insufficient**_** to explain cognitive deficits often seen in chronic drug abusers (e.g. impaired attention, memory and IC reported)**
**Failure to develop and/or loss of IC can profoundly impact ability to gate pre-potent, yet inappropriate and dangerous behaviors, e.g. cocaine use**
**Cocaine users show decreased frontal, cingulate, insula and superior temporal gray matter**
**Cocaine users show decreases in cingulate and OFC metabolism**
**     ****Functional consequences not well understood**

## Inhibitory Control Task

**Inhibitory Control Task**

**1180 Go and 80 NoGO stimuli over 4 runs, enabling the study of both response inhibition and error-related processes. **
**Task difficulty varied to equate behavioral performance**

***Kaufman et al J Neurosci 23: 2003***

## Inhibitory Control

**Failed Inhibitions**

**Users**** ****(n=13)**

**Controls ****(n=14)**

**Inhibitory Control**

_**Errors**_**: ****U<C:**** R. MFG/preSMA, ACC, L. insula, L. IFG **

_**Stops**_**: ****U<C: ****ACC, Rt. insula**

***Kaufman et al J Neurosci 23: 2003***

## Inhibitory Control

**Failed Inhibitions**

**Users**** ****(n=13)**

**Controls ****(n=14)**

**Inhibitory Control**

_**Errors**_**: ****U<C:**** R. MFG/preSMA, ACC, L. insula, L. IFG **

_**Stops**_**: ****U<C: ****ACC, Rt. insula**

***Kaufman et al J Neurosci 23: 2003***

## ACC, area critical for cognitive control esp. in urgent inhibitions, and activated by all abused drugs tested, less responsive in cocaine USERS for STOPS and ERRORS

STOP related hypoactivity in R insula and rostral ACC, emotional processing areas, not in other IC areas, suggests hypoactivity not ubiquitous but specific

ACC also hypoactive in Scz and hyperactive in OCD-consistent with problems in error monitoring system (failure to monitor and integrate in Scz; overactive monitoring in OCD)

**STOP related hypoactivity in R insula and rostral ACC, emotional processing areas, **_**not in other IC areas**_**, suggests ****hypoactivity not ubiquitous but specific**
**ACC also hypoactive in Scz and hyperactive in OCD-consistent with problems in error monitoring system ****(****failure to monitor and integrate in Scz; overactive monitoring in OCD****)**

**Cocaine and Response Inhibition**

## 1H-MRS in Cocaine Abuse

**Basal ganglia**

**Thalamus**

**Cocaine (****n=21****)**

**Control (****n=13****)**

***Li et al Biol Psych 1999***

**NAA/Cr**

**No change**
**NAA/Cr**

**1****H-MRS in Cocaine Abuse**

**Dec # or viability of neurons**
**Dec synaptic density**
**Neuronal dysregulation/**
**	****dysfunction**
**Monoamine depletion**

_**Thalamus**_

_**Basal ganglia**_

## Hypoactivity in USERS: reduced IC, diminished action monitoring, reduced responsivity to self errors-may, at minimum, serve to prolong drug abuse

Suggests USERS may be compromised in endogenous and volitional control of behavior; thus behavior disproportionately determined by environmental contingencies, cues (drug craving cues) and automatized or habitual behaviors leading to reduced capacity to inhibit external influences

May inform optimal therapeutic interventions and help identify casual users most at risk for becoming dependent

**Suggests USERS may be compromised in endogenous and volitional control of behavior; thus behavior disproportionately determined by environmental contingencies, cues (drug craving cues) and automatized or habitual behaviors **_**leading to reduced capacity to inhibit external influences**_
**May inform optimal therapeutic interventions and help identify casual users most at risk for becoming dependent**

**Clinical Implications**

## The folks in the lab who REALLY did the work

**The folks in the lab who REALLY did the work**

**Tom Ross**
**Hugh Garavan**
**BettyJo Salmeron**
**Rob Risinger**
**John Pankiewicz**
**Natalia Lawrence**
**Alan Bloom**
**Stacy Engelbart**
**Jackie Kaufman**
**Veronica Dixon**
**Qiwen Mu**
**Sharon Dirckx**
**Shi-Jiang Li**