Regional specialization of motor functions in the rat striatum: Implications for the treatment of parkinsonism

Pmg. Neuro-Psychophormacol. k Biol. Psychiot. Printed In Great Brtlain. All tights reserved

1988. Vol. 12. pp. 217-224 Copyright

027~SR4WR8 $9.00 + SO IQ 1988 Pergamon Press plc

REGIONAL SPECIALIZATION OF MOTOR FUNCTIONS IN THE RAT STRIATUM: IMPLICATIONS FOR THE TREATMENT OF PARKINSONISM MICHELEPISA Department of Neurosciences McMaster University, Hamilton, Ontario, (Final

Canada

form, July 1987) Contents

1. 2. 3. 4. 5.

Abstract Introduction Nigro-putaminal system and parkinsonisn in primates Nigro-putaminal system and parkinsonism in rodents Mechanism of parkinsonian symptoms in primates and rodents Implications for treatment Acknowledgements References

217 217 218 218 221 222 222 223

Abstract Pisa, M.: Regional specialization fo;_:;; treatment of parkinsonism.

of motor functions in the rat striatum: implications Prog. Neuropsychopharmacol. & Biol.’ Psychiat. 1988, -12:

1. Behavioral studies of rats with ibotenic acid-induced lesions of distinctive regions of the rostra1 striatum demonstrated clearcut motoric impairments after lesions of the lateral striatum, but not after lesions of the medial striatum. 2. Differential effects of dorsolateral and ventrolateral lesions on segmental bodily movements indicated a somatomotor map in the lateral region. 3. Neurotoxic lesions of the lateral striatum produced deficits of motor energizing analogous to those of human parkinsonism. 4. These results support the hypothesis that neurodegenerative processes affecting the striatum (putamen) in humans may specifically account for parkinsonian lateral symptoms. 5. The implications of this hypothesis for the treatment of parkinsonism using the grafting technique are discussed. Keywords: caudate: dopamine: 6-hydroxydopamine; ibotenic acid: Huntington’s disease: motor control: neural grafts; Parkinson’s disease: putamen; somatotopy; substantia nigra; striatum. Abbreviations: dopamine (DA), L-3,4,-dihydroxyphenylalanine l- methyl-4(L-dopa) , phenyl-1,2,3,6, tetrahydropyridine (MPTP), Parkinson’s disease (PD), substantia nigra (SN), ventral tegmental area WTA). 1. Introduction The most

striking

of the dopaminergic (Hassler

1938;

innervation

pathological neurons of

feature the

Bernheimer et al 1973),

territories

of these

of Parkinson’s

substantia

with resulting

neurons

(Bernheimer

217

Disease

nigra-ventral depletion et al

(PD) is a degeneration

tegmental

area (SN-VTA)

of dopamine (DA) in the 1973; Price

et al 1979),

M. Pisa

210

which include

the striatum

other chemospecific 1985).

MPTP, a

parkinsonian et

al

by-product

degeneration

and

monkeys

et al 1983; Langston established

(Langston

et

the

et

al

of meperidine and tremor,

effect

of

the dopamine

innervation

changes

monoamine systems (Burns

taken

precursor the

causes a

with small or no chronic

results, of

derivatives,

at doses that produce a severe

neurons,

These

Many

in both humans (Langston

system and nondopaminergic

1983).

Bloom 1978).

however (Agid and Javoy-Agid

1983b),

al

dopaminergic

(Moore and

affected,

rigidity

nigrostriatal

dopaminergic

therapeutic

of

regions

preparations

akinesia,

of the dopaninergic

the mesolimbic

removal

limbic

of illicit

syndrome, including

1983a)

in both

and several

systems of the brain are also

together

L-dopa

striatum

with

the well

in PD, indicate

can

that

itself

by

cause

parkinsonism. 2. Nigro-Putaminal In

primates,

ventrolateral There is

the

neostriatum

region,

comprises

the putamen, divided

some evidence

more directly

System and Parkinsonism

related

that in

a

to parkinsonism

a

decrease

parkinsonian

of

[raF]G-fluorodopa

syndrome, process

degeneration:

Adams and Victor

neurons

loss

or

precipitate caudate

chiefly

of

the

dopaminergic

hypothesis

postural bilateral

pH=7.4)

dorsomedial repeatedly to onset

or

pellet

placed

movements number of

of either not

capsule.

1)

In

PD, the

et al 1979) and

of

the

in

patients

putamen

that either

loss

innervation,

2)

with a

(strionigral of putaminal

or

both,

could

the caudate neurons or the nigro-

cause

After

parkinsonian

This

disorders.

of or

either the

bites

in the rostra1

with

ug in

ventrolateral

striatum forelimb

of mash food: reaching

a tube:

buffered

.5 ul)

3)

into

reaching;

isotonic either

the

1) latency 2) maximal

maximal amplitude of

attempts before

postural

with

(N=lOl, and tested

grasping

4) number and duration

or without

forepaw

treated

measures were taken:

and conditioned

number of

were

rats

of rat on

reaching,

(phosphate

(7.5

These behavioral

striatum

forelimb

training,

vehicle acid

during licking and

in Rodents

conditioned motor

ibotenic

Day 30.

losses

biting,

between 16 and 34 mminside

pellets,

neurons

neuronal

tongue protrusion

tongue protrusion

reaching

hard-food

dorsolateral

of conditioned

internal

of the putamen is

caudate:

described

dopaminergic

loss

licking,

excitotoxin

up to postsurgical

amplitude of forelimb

the

the

been

System and Parkinsonism

injections

or the

the

These data suggest

would

and beam walking.

intrastriatal

saline,

of

the

(Pisa 1985, 1986, 1987a, 1987b; Pisa and Schranz 1987).

of regional

conditioned

fixation,

has

nigro-putaminal

in the rat

We examined the effects of

1985).

Nigro-Putaminal

3.

performance

affecting

innervation

was tested

by

pathology

and a

uptake (Garnett et al 1984) than the caudate:

In contrast,

parkinsonism.

other

the caudate,

(Bernheimer et al 1973; Price

L-dopa-resistant,

degenerative

each

region,

other primates

than pathology

putamen shows a more profound DA depletion a greater

dorsomedial

from

humans and

in Primates

fixation

a food

of bites

on

of the pellet-

219

Striatalregions and motor functions holding locomotor

forepaws,

its

amount of

speed and number of slips

Ibotenic attendant

and

food

and falls

acid produced axon-sparing, damage

selective

to remote

eaten

during a 5-min session

consistent

neurotoxic

effects

degenerative

neuronal

loss

(Schwartz et

reconstructed

in Fig 1 (see Pisa and Schranz 1987, for

in

5)

during walking on a narrow (5 cm) beam.

somatodendritic

brain regions,

of feeding:

representative

al 1979). rats

lesions

in the

striatum,

with the original The areas of further

each

with no

description

of striatum treatment

of

showing

group

are

details).

DMS

DLS

10.2

9.4

8.6

7.8

of areas of neuronal loss (black patches) in the striatum of Fig 1. Reconstructions injections into either the dorsomedial representative rats from groups with ibotenste (DMS) or the dorsolateral (DLS) or the ventrolateral (VLSI regions of the striatum. CON= Vehicle control. Numbers indicate frontal planes with reference to the stereotaxic atlas of Paxinos and Watson (1982).

220

M. Pisa

The main behavioral produced no lesions

increased

orofacial in

changes

are

execution orofacial

summarized

in any

the reaction

and forelimb

the

either

findings

chronic

in

1:

1)

dorsomedial

lesions

of the motor parameters measured: 21 ventrolateral

times and produced impairments in the execution

movements: 31 dorsolateral

of

Table

forelimb

lesions

movements than ventrolateral

movements or reaction

times;

of both

produced a more severe deficit

41 none

lesions,

of the

regional

without

altering

lesions

altered

beam walking performance. These results

indicate

not critically of the

related

lateral distinctive

in the rat,

to setting

striatum

movements. Furthermore, have

that,

the dorsal

motor

forelimbs

and execution

orofacial

movements.

physical

are critically

parameters of involved

and ventral

roles:

the

of forelimb

dorsal

reaching

In contrast,

movements and initiation

the neurons of the dorsomedial

of conditioned

movement, whereas

in

both initiation

regions

of the lateral

region

mediates postural

movements, with little

the ventral

region

responses,

striatum

the neurons

and execution striatum

of

appear to

fixation

of the

or no involvement

selectively

facilitates

in addition

are

in

orofacial

to influencing

forelimb

movements. Why did

ibotenate

lesions

of

the

rostra1

striatum

Richards and Taylor

(1982) provided

electrophysiological

organized

projection

the

sensory

forelimb

stimulation

stimulation

activated

to

activated

is distinctively

lack

disturbances

gait

therefore,

to sparing

of

neurons of the striatal

of the striatum of

striatum

neurons

of

the

fail

rat.

in

rats

with

of a caudal striatal

rostra1

region

orofacial

striatal

and

whereas hindlimb

suggest

control

Recently,

a somatotopically

striatum,

These findings

important in sensorimotor

gait?

for

Specifically,

rostra1

tail.

to alter

evidence

that the tail

of the hindlimbs.

lesions

that selectively

The

might be related, influences

hindlimb

movements. The finding role

of a

critical,

regionally

of the neurons

of the

rostrolateral

primates

showing,

specifically

i)

project

that putaminal

that

striopetal

specific

but

and

In a in either

separate

striatum

(Piss

and Schranz,

other investigators with selective studies,

the

and forelimb

rostra1

reaching

unpublished

who demonstrated

DA depletion

in

motor disturbances

however.

This relatively

that the

regional

the

in

striatum,

we

found

depletions

impairments

These results

striatum

(Sabol

longer present

was probably usually

et

two weeks

those of

reaching

in rats

19851.

In our

al., after

related

of DA of both

in the lateral

extended

impairment of forelimb

the striatum

ii)

physical

the movement-related

in rats with DA depletion

recovery

1975);

(Alexander and DeLong 1986).

observations).

were no

in

and motor cortex

to specific

6-hydroxydopamine-induced

only

lateral

that

iii)

motor

with studies

plan (Kunzle,

in relation

19841;

a chronic

rapid behavioral

DA depletions

fire

organized

study of rats with regional,

the medial or the lateral

tongue protrusion

to a somatotopic

DeLong,

neurons of the putamen are somatotopically

organized

rat agrees

of the somatosensory

not caudate neurons,

parameters of movement (Crutcher

somatotopically

in the

projections

to the putamen, according

neurons,

and

striatum

the lesions, to the finding

did not exceed 70%.

There is

considerable

evidence

behavioral et

al

disturbances

that

Striatal

regions and motor functions

only

profound

in rats

(Roberts

090%)

et al

221

DA depletions

1975;

Stricker

produce

and

long-lasting

Zigmond

1976;

Spyraki

in the

Rostra1

1982).

Table Chronic

Motor

Effects

of

Ibotenate-Induced Striatum

1 Regional of Rat

Site

Neuronal

of Neuronal

Loss

Loss

Dorsomedial Striatum

Dorsolateral Striatum

Ventrolateral Striatum

Onset of conditioned Licking

No change

No change

Delayed

Onset of conditioned forelimb reaching

No change

No change

Delayed

Maximal amplitude of tongue protrusion

No change

No change

Decreased

Duration

No change

No change

Increased

Steady forelimb fixations

No change

Decreaseda

No change

Unsteady fixations

No change

Increased

Increased

Maximal amplitude of of forelimb reaches

No change

Decreased

Decreased

Unsuccessful reaches

No change

Increaseda

Increased

No change

Decreased

Decreased

No change

No change

No change

No change

No change

No change

Measure

Feeding Locomotor

of bites

forelimb

forelimb

rate speed

Footslips during beam walking

N.B. Changes are relative to vehicle controls and statistically significant, at least (ANOVAwith post-hoc Newman-Keuls comparisons). a significant change also relative to ventrolateral lesion group, p t.05.

4. Mechanism Quantitative mechanism

approaches

of bradykinesia

of Parkinsonian have

Symptoms in Primates

considerably

in PD (Schultz

1984).

contributed Parkinsonian

E c.05

and Rodents to the

understanding

patients

are

of the

impaired

in

M. Pisa

222

initiation

of

volitional

of muscle activation execution

movements (Bloxham et al 1984; Evarts et al 19811, building

(Evarts

(Flowers

et

al

1976; Rallett

(Rallett

have

been

and Khoshbin 1980; Schultz

similarly

be

observations

and

and have severe of

the

execution

of large

striking

is a

problems

bradykinesia

in patients

It

is

of

apparent

veridical

with

Recent

studies

clearly

steps

and qualitative

rather

and

can

showed that these

conditioned

proximal

than in a single

responses,

distal

postural

musculature,

1987a, 1987b; Pisa and Schranz 1987).

nigro-putaminal

experimental

have

shown

can attenuate

(see

functions

Biorklund in

is related

and

patients

to the

then

system

removal

of

of the lateral

in

rats

and

the

and There

following

mechanism of

either

striatum

the intrinsic

neurons or the

in

can

the

rat

result

in

Stenevi

with

attempts have some success

from abortive of

placement of

could

or Huntington’s synaptic

disease.

been

location

made to

(Madrazo et al 1987).

whether or not the precise

placement

of

use grafts Further

between

the striatum

On the the

or cell

lesions

other or

graft

of the graft

are

is

graft

and host

may be expected

if

hand,

trophic

parkinsonian grafts

factors

may not

be

promote

(Kesslak et al critical.

needed,

however,

A few with

to examine

variable.

Acknowledgements The author was a Research

Scholar

of the Ontario

Mental Health

to

reviewed here suggest

in reversing

an important

of

recovery

for the treatment of parkinsonism,

studies

in

of motor

If behavioral

the studies

neuromodulators

striatal

produce recovery

connections within

in the caudate.

diffusible

or

It was proposed that implants

fetus

grafts

embryonic tissue

nigral

the putamen would be more effective

intrastriatal

already

homologous

outcome. More specifically,

in

releasing

19861, the precise

of

caused by

1984, for a review).

re-establishment

the precise implants

implants

Parkinson’s

symptoms than neural implants by

that

for Treatment

motor disturbances derived

the functional

that neural recovery

of

striatum

between the mechanism of motor disturbances

innervation

homologous neural tissue

influence

These

mechanism

models of parkinsonism.

suspensions

tissue,

incremental of

lateral

measurements

playback

initiation

Implications

rats

of an energizing

with PD.

that

dopaminergic

the

(Sanes 1985) of large

of the

Quantitative

coordination

therefore,

lesions

up

19801, single-burst

(Schwab et al 1954).

failure

with lesions

amplitude movements (Piss

degenerative

afferent

in rats

movements in

forelimbs,

analogy,

a

in slow motion video

perform reaching

fixation

motor acts

reflect

interpreted.

behavior

Khoshbin

1984).

observed

described of their

rats usually burst,

to

and

1980) and accuracy

of simultaneous

interpreted

The motor disturbances

Hallett

and Khoshbin,

amplitude movements, and control alterations

1981;

Foundation.

The work

Striatal regions and motor functions

was

supported

Jennifer

by

A. Schranz

the is

Medical gratefully

Research

Council

of Canada.

223

The collaboration

of Miss

acknowledged. References

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should

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