# Presentation: 934936

## ?

***Why Does ***
***the Brain Become***

**Nora D. Volkow, M.D.**
**Director**
**National Institute on Drug Abuse**

**ADDICTED**

***?***

## Slide 2

## Brain Dopamine System

**DA**

**DA**

**DA**

**DA**

**DA**** **

**DA**** **

**DA**

**signal**

**Dopamine Cell**

**DA Transporters**

**DA Receptors**

**Metabolism**

**Brain Dopamine System**

## Effect of Cocaine Abuse on Dopamine D2 Receptors

**normal subject**

**cocaine abuser (*****1 month post*****)**

**cocaine abuser (*****4 months post*****)**

**Effect of Cocaine Abuse on Dopamine D2 Receptors**

## DA D2 Receptors in Controls and

**Cocaine Abusers**

**Normal Controls**

**DA D2 Receptors**

**(Bmax/Kd)**

**Age (years)**

**DA D2 Receptors in Controls and**
** ****in Cocaine Abusers (NMS)**

## Dopamine D2 Receptors are Lower in Addiction

**DA**

**DA**

**DA**

**DA**

**DA**** **

**DA**** **

**DA**

**Reward Circuits**

**DA**** **

**DA**** **

**DA**** **

**DA**** **

**DA**** **

**Reward Circuits**

**DA**

**DA**

**DA**

**DA**

**DA**** **

**DA**

***Drug Abuser***

***Non-Drug Abuser***

## Addiction

**Addiction**

**DRUG**

**Environment**

**Biology/Genes**

## DA D2 Receptors in Controls and Cocaine Abusers  ([11C] Raclopride)

**Normal Controls**

**Cocaine Abusers**

## DA D2 Receptors and Response to 

**DA D2 Receptors and Response to **
**Intravenous MP in Controls**

**pleasant**

**DA D2  receptor availability**

*** = p < 0.004**

**pleasant**

**unpleasant**

**neutral**

- *

**DA D2 Receptors**
**(Bmax/Kd)**

**unpleasant**

**pleasant**

***Subjects with low receptors report MP as ***
***pleasant and those with high receptors as unpleasant***

## Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors

**2nd D2R Vector**

**Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**Percent Change in D2R**

**4**

**6**

**8**

**10**

**24**

**p < 0.0005**

**p < 0.0005**

**p < 0.005**

**p < 0.10**

**p < 0.005**

**1st D2R Vector**

**0**

**Null Vector**

**-100**

**-80**

**-60**

**-40**

**-20**

** ****0**

**Time (days)**

**4**

**6**

**8**

**10**

**24**

**p < 0.001**

**% Change in Alcohol Intake**

**p < 0.001**

**p < 0.001**

**p < 0.01**

**p < 0.01**

**0**

**Overexpression of  **
**DA D2 receptors **
**reduces alcohol**
**self-administration**

***Source: Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.***

**DA**

**DA**

**DA**

**DA**

**DA**

**DA **

**DA**

**DA**

## Addiction

**Addiction**

**DRUG**

**Environment**

## *

**Dominant**

**Subordinate**

**Individually**
**Housed**

**Group**
**Housed**

*****

*****

**S**

**.003**

**.01**

**.03**

**.1**

**0**

**10**

**20**

**30**

**40**

**50**

** ****Reinforcers (per session)**

**Cocaine (mg/kg/injection)**

***Morgan, D. et al. Nature Neuroscience, 5: 169-174, 2002.***

## What is the Functional Significance of the Decreases in DA D2 Receptors?

**DA**

**DA**

**DA**

**DA**

**DA**** **

**DA**** **

**DA**

**signal**

**DA SYNAPSE**

**Metabolism**

***What is the Functional Significance of the Decreases in DA D2 Receptors?***

## Brain Glucose Metabolism 

**in Cocaine Abusers (n=20) and Controls (n=23)**

**micromol/100g/min**

**micromol/100g/min**

**CG**

**OFC**

**CG**

***P < 0.005***

***P < 0.01***

## Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism

**Striatum**

**CG**

**PreF**

**OFC**

**30**

**35**

**40**

**45**

**50**

**55**

**60**

**65**

**1.8**

**2**

**2.2**

**2.4**

**2.6**

**2.8**

**3**

**3.2**

**3.4**

**DA D2 Receptors (Ratio Index_x0008_)**

**OFC**

**    ****umol/100g/min**

**r = 0.7, p < 0.001**

**OFC**

**umol/100gr/min**

**DA D2 Receptors**

**(Bmax/kd)**

**Cocaine **
**Abusers**

**r = 0.7, p < 0.005**

**METH**
**Abusers**

**Salience Attribution**

**Inhibitory Control**

##        Would these responses   

***    ******differ between controls                               ***
***and addicted subjects?***

**CA**

**PUT**

**Striatum**

**VTA/SN**

**CG**

**PreF**

**OFC**

**nucleus**

**accumbens**

***Would increasing DA***
***     ******enhance activity***
***      ******in the OFC?***

**Compared the response to ****IV MP**** (2 sequential **
**doses of 0.5 and 0.25 mg/kg) in 15 controls and **
**21 cocaine abusers using FDG and PET to **
**measure regional brain glucose metabolism**

## Self Reports of Drug Effects After MP in Controls and in Cocaine Abusers

**baseline**

**First MP**

**Second MP**

**Self Report Craving**

**(0-10)**

**Self Report High**

**(0-10)**

**Self Reports of Drug Effects After MP in Controls and in Cocaine Abusers**

**P < 0.001**

**P <0.001**

## MP-induced Increases in Metabolism 

**Baseline**

**MP**

**Rectal Gyrus/Brain**

**Craving**

**Rectal  Gyrus**

**(MP - Placebo)**

**p < 0.005**

**Abusers > Controls  *****p = 0.001***

**p < 0.01**

## Brain Circuits Involved in 

**PFC**

**ACG**

**OFC**

**SCC**

**REWARD**

**INHIBITORY **
**CONTROL**

**MOTIVATION/**
**DRIVE **

***  ******Alter reward/motivational systems   ***
***  ******Interfere with conditioned responses***
***  ******Promote plasticity of dysfunctional brain circuits***

** ****Treatments Being Studied**
**Include Those That: **

**Brain Circuits Involved in **
**Drug Addiction**

**MEMORY/**
**LEARNING **

## ADDICTION Requires a

**genome**

**protein expression**

**neuronal circuits**

**DRUGS OF ABUSE**

**social**

**behavior**

**ADDICTION Requires a**
**Systems Approach**