concepts to review

mesolimbic Dopamine system

microdialysis

SRTM (ref reg models)

BP images

PET BP images

SPM (voxel-wise t-tests)

meoslimbic dopamine system

3 lines to sample collector

intracranial -dialysis probe

infusate of aCSF and drug

Consider the effect of nicotine on dopamine

DA responses in nucleus accumbens of SD rats measured by microdialysis. Time course for effects of 0.32 mg/kg SC nicotine (open circles);

Figure is from Coe et al., J Med Chem. May 19 2005;48(10):3474-3477

SD rats

Dop

amin

e C

once

ntra

tion

n = 6 males

no trick

subjects apprised of drink type just before scan

is this different from Urban?

Is it different from Yoder?

how consistent is the “typical alcohol curve?”

what can be done to control it?

0

d0

dt

K

)t(DA1

k

'Bk

dt)t(F

)t(F

BP

11

BP1

BPV

DA

off

maxon

RAC

RAC

11

1

The free tracer is the “shutter”of the “dopamine-camera”

Free

11C-raclopride

FRAC(t)

The picture (BP) is “weighted” by the scenes when the shutter is open widest.

DA

time

Free

dopamine

DA(t)

But – what does that mean for detecting DA release with PET?

Free

tracer

FRAC(t)

DA

time

Free

dopamine

DA(t)

The pattern of shutter “opening” and “closing” is a function of the tracer parameters (K1, k2, kon, koff, etc)

This has consequences for experimental design (including choice of tracer).

compare to Urban who got 12% change in BP in VS in 11 males.

n = 11 males; 10 females, analyzed separately

design issues:

no baseline – what happens if DA goes DOWN with placebo – is this still a valid comparison? a valid interpretation?

how do we know they got to steady state? is that necessary for their analysis?

why might DA go down with ‘placebo’

drink is 3 drinks-worth; forced drinking in 5-10 minutes? aversive?

differences are masked by vodka smell – will this induce negative reward-prediction error?

DA release related to frequency of max-drinking day? what does this mean?

do men differ from women because they are demographically different?

blinded?

expectations?

order effects?

(need sham scan)

cue (visual and OLFACTORY)

n = 8 males

Experimental Setup

IV EtOH Clamp

visual cues (EtOH/neutral)

olfactometer

MirrorGoggles

olfactory cues

PET Gantry

Olfactometer (aka. the “smell-a-tron”)

Delivery of odors to subject is computer controlled and synchronized with presentation of visual cues.

Mirror goggle

PET scanner

Odors

Computer-controlled EtOH infusion

IV Alcohol Infusion

Arterial Cannula

Arterial Sampling (sometimes)

bolus study

order effects? why? can it be avoided?

not self admin

is iv alcohol like drinking? look at behavioral self reports

Conclusions- I• Data conform to

observations of dopaminergic function in reward prediction.

• Dopamine’s coding of expectation may be relevant to alcoholism (see Lapish, Seaman, & Chandler, 2006. ACER).

No CS

CS

CS

unexpectedreward

predictedreward

absence of predicted reward

from

: S

chul

tz,

Day

an,

& M

onta

gue,

199

7,

Sci

ence

.

is the Yoder design really analogous to the Schulz experiment in monkeys? Don’t we need prior conditioning? What is the author’s answer to this?**

would like to know if anyone’s BP went wrong way (DA down) in Urban study – if so, it would agree with Yoder.

BAC in Boileau study did not correlate with BP

(agrees with Urban -- claimed it didn’t correlate with)

**Yoder et al: probably claim that prioir drinking exposure IS conditioning. So when they see and hear alcohol cues – they expect to get reward.

Consider figure 3. Subjects said: “It was clear I was about to get drunk.”

Yoder: SHAS and AUDIT scores NOT correlated with BP

Boileau: SHAS scores did not correlate with BP

impulsiveness predicted BP change in VS