Differential effects of atropine, procaine and dopamine in the rat ventral tegmentum on lateral hypothalamic rewarding brain stimulation

doi:10.1016/0166-4328(90)90024-9

Behavioural Brain Research

Volume 38, Issue 1, 16 April 1990, Pages 55-68

https://doi.org/10.1016/0166-4328(90)90024-9 Get rights and content

Abstract

Microinjections of the muscarinic antagonist, atropine, of dopamine, or of the local anesthetic, procaine, in the ventral tegmentum elevated frequency thresholds for lateral hypothalamic self-stimulation. The largest and most robust effects were observed following atropine (30 or 60 μg) microinjections. The most sensitive sites for the atropine effect were near dopamine cells. In order to determine if the effects of atropine can be reversed by pretreatment with a cholinergic agonist, carbachol (1–3 μg) was microinjected 15 min prior to atropine. Carbachol pretreatment attenuated the frequency threshold elevation of atropine by 47–95%. Since atropine is a local anesthetic, the effects of procaine on self-stimulation thresholds were tested as well. Procaine (100 or 250 μg) in ventral tegmentum elevated frequency thresholds by much less than atropine. Therefore, while atropine attenuates reward primarily through blockade of muscarinic receptors, the local anesthetic effect of atropine may enhance the threshold elevation. Dopamine (1–10 μg) also elevated frequency thresholds, but when dopamine injections were repeated daily, the threshold elevations were attenuated. This attenuation contrasted with the robust effects of atropine, and may reflect the development of autoreceptor subsensitivity. Hence, both dopaminergic and muscarinic receptors in ventral tegmentum are involved in lateral hypothalamic brain stimulation reward.

References (66)

G.K. Aghajanian et al.
Central dopaminergic neurons: neurophysiological identification and responses to drugs
A. Albanese et al.
Cholinergic and non-cholinergic forebrain projections to the interpeduncular nucleus
Brain Res.
(1985)
S. Arbilla et al.
Rapid desensitization of presynaptic dopamine autoreceptors during exposure to exogenous dopamine
Brain Res.
(1985)
C. Bielajew et al.
The effect of pulse duration on refractory periods of neurons mediating brain-stimulation reward
Behav. Brain Res.
(1987)
L.L. Butcher
Nature and mechanisms of cholinergic-monoaminergic interactions in the brain
Life Sci.
(1977)
K.A. Campbell et al.
A microcomputer-based method for physiologically interpretable measurement of the rewarding efficacy of brain stimulation
Physiol. Behav.
(1985)
R.J. Carey
Unilateral 6-hydroxydopamine lesions of dopamine neurons produce bilateral self-stimulation deficits
Behav. Brain Res.
(1982)
L.A. Chiodo et al.
Repeated tricyclic antidepressants induce a progressive ‘switch’ in the electrophysiological response of dopamine neurons to autoreceptor stimulation
Eur. J. Pharmacol.
(1980)
R. Cortes et al.
Quantitative light microscopic autoradiographic localization of cholinergic muscarinic receptors in the human brain: brainstem
Neuroscience
(1984)
A.J. Cross et al.
[³H]Quinuclidinyl benzylate and [³H]GABA receptor binding in rat substantia nigra after 6-hydroxydopamine lesions
Neurosci. Lett.
(1980)

H.C. Fibiger

The organization and some projections of cholinergic neurons of the mammalian forebrain

Brain Res. Rev.

(1982)

K.B.J. Franklin et al.

Pimozide-induced extinction in rats: stimulus control of responding rules out motor deficit

Pharmacol. Biochem. Behav.

(1979)

A.S. Freeman et al.

Firing properties of substantia nigra dopaminergic neurons in freely moving rats

Life Sci.

(1985)

C.R. Gallistel et al.

Pimozide and amphetamine have opposite effects on the reward summation function

Pharmacol. Biochem. Behav.

(1984)

C.R. Gallistel et al.

Does pimozide block the reinforcing effect of brain stimulation?

Pharmacol. Biochem. Behav.

(1982)

A.A. Grace et al.

Low doses of apomorphine elicit two opposing influences on dopamine cell electrophysiology

Brain Res.

(1985)

Z. Henderson et al.

Does the substantia nigra have a cholinergic innervation?

Neurosci. Lett.

(1987)

L.J. Herberg et al.

Self-stimulation and locomotor changes indicating ‘latent’ anticholinergic activity by an atypical neuroleptic (thioridazine)

Neuropharmacology

(1981)

W. Lichtensteiger et al.

A quantitative correlation between single-unit activity and fluorescence intensity of dopamine neurones in zona compacta of substantia nigra, as demonstrated under the influence of nicotine and physostigmine

Brain Res.

(1976)

D.C. Mash et al.

Autoradiographic localization of M1 and M2 muscarine receptors in the rat brain

Neuroscience

(1986)

E. Miliaressis et al.

The effects of pimozide on the reinforcing effect of central grey stimulation in the rat

Behav. Brain Res.

(1986)

P. Muller et al.

Presynaptic subsensitivity as a possible basis for sensitization by long-term dopamine mimetics

Eur. J. Pharmacol.

(1979)

R.D. Myers et al.

[⁴C]Dopamine microinjected into the brainstem of the rat: dispersion kinetics, site content and functional doses

Brain Res. Bull.

(1978)

S. Nakajima

Effects of intracranial chemical injections upon self-stimulation in the rat

Physiol. Behav.

(1972)

A. Rotter et al.

Muscarinic receptors in the central nervous system of the rat. II. Distribution of binding of [³H]propylbenzilcholine mustard in the midbrain and hindbrain

Brain Res. Rev.

(1979)

D.G. Spencer et al.

Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections

Brain Res.

(1986)

J.R. Stellar et al.

Effects of peripheral and central dopamine blockade on lateral hypothalamic self-stimulation: evidence for both reward and motor deficits

Pharmacol. Biochem. Behav.

(1983)

C.H. Vanderwolf et al.

Hypothalamic self-stimulation: the role of dopamine and possible relations to neocortical slow wave activity

Behav. Brain Res.

(1984)

R.Y. Wang

Dopaminergic neurons in the rat ventral tegmental area. II. Evidence for auto-regulation

Brain Res. Rev.

(1981)

R.Y. Wang

Dopaminergic neurons in the rat ventral tegmental area. III. Effects of d- and l-amphetamine

Brain Res. Rev.

(1981)

N. Woolf et al.

Cholinergic systems in the rat brain: II. Projections to the interpeduncular nucleus

Brain Res. Bull.

(1985)

J.S. Yeomans

The absolute refractory periods of self-stimulation neurons

Physiol. Behav.

(1979)

J.S. Yeomans et al.

Cholinergic involvement in lateral hypothalamic rewarding brain stimulation

Brain Res.

(1985)

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^∗: S.M. McGlynn published formerly under the name of S. Whitfield.

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Research reportDifferential effects of atropine, procaine and dopamine in the rat ventral tegmentum on lateral hypothalamic rewarding brain stimulation

Abstract

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Research report
Differential effects of atropine, procaine and dopamine in the rat ventral tegmentum on lateral hypothalamic rewarding brain stimulation