PSYCHOPHARMACOLOGY OF DOPAMINE: THE CONTRIBUTION OF COMPARATIVE STUDIES IN INBRED STRAINS OF MICE

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Abstract

Comparative studies of behavioral responses to centrally acting drugs in inbred strains of mice which show differences in brain neurotransmitter activity represent a major strategy in the investigation of the neurochemical bases underlying behavioral expression. Moreover, these studies represent a preliminary stage in behavioral genetic research since they allow quantitative scales to be established and suggest correlations to be tested in recombinant inbred strains. The present review evaluates results obtained in mice of the C57BL/6 (C57) and DBA/2 (DBA) inbred strains which have been used for studies of the behavioral pharmacology of dopamine (DA) and investigated for the functional and anatomical characteristics of their brain DA systems. Differences between C57 and DBA strain involve susceptibility and sensitivity as well as qualitative differences in the type or direction of the behavioral effects of DA agonists. Moreover, data on strain-dependent differences for DA metabolism, release and receptor densities and distribution provide important indications about the relationship between behavioral and central effects of DA agonists and, more generally, about the involvement of brain DA in behavior.

Comparative studies in C57 and DBA mice have also revealed differences in susceptibility to context-dependent, context-independent and stress-induced behavioral sensitization to psychostimulants. Consequently, they support the view that the term “behavioral sensitization” may define different phenomena in which different, independent genotype-related factors play a major role. Finally, studies on the behavioral and central effects of stressful experiences in C57 and DBA mice together with psychopharmacogenetic analyses, indicate that different symptomatological profiles may derive from genotype-dependent adaptation of brain DA receptors to environmental pressure. © 1997 Elsevier Science Ltd. All Right Reserved.

Section snippets

INTRODUCTION

The use of inbred strains of mice offers great advantages to studies aimed at investigating the role played by neurotransmitter systems in the effects of psychotropic drugs. An inbred strain is a set of animals that is produced by at least 20 consecutive generations of sister × brother or parent × offspring mating and that can be traced to a single ancestral pair in the 20th or subsequent generations. Animals of an inbred strain are almost fully homozygous, which thus provides a well-defined

Strain-Dependent Sensitivity to Amphetamine-Induced Locomotion: Role of Differential Susceptibility to Psychostimulant-Induced Mesoaccumbens Dopamine Release

The best known behavioral effect of indirect DA agonists is psychomotor stimulation. In the rat, amphetamine stimulates locomotion when administered at low to intermediate doses, whilst at higher doses it promotes increasingly focused stereotypies. By using the neurotoxine 6-hydroxydopamine (6-0HDA), which selectively destroys neurons containing DA and noradrenaline (NA), Creese and Iversen (1975)found that focused stereotypies promoted by high doses of amphetamine were blocked by local

Strain-Dependent Hyperdefensiveness and Catalepsy Promoted by Selective D2-Like Receptor Agonists

As already discussed, D2-like receptor agonists promote motor inhibition in mice when administered at low doses, and coadministration of high doses of selective agonists of D2- and D1-like receptors promotes hyperlocomotion (Belzung et al., 1992) and stereotypies (climbing). Similar effects have been reported in rats (Braun and Chase, 1986; Braun et al., 1986). However, in this species enhanced locomotion and stereotypies are also promoted, although to a lesser extent, by high doses of

Strain-Dependent Susceptibility to Behavioral Sensitization

As already discussed (Introduction), enhanced behavioral response to psychostimulants, i.e. behavioral sensitization, is promoted by repeated systemic injections of different types of psychostimulants, either explicitly paired or unpaired with the test environment, and by chronic or repeated stress experiences. Moreover, some data appear to suggest the possibility of cross senstization between stressors and pychostimulants (see Antelman and Chiodo, 1983; Robbins et al., 1990for review).

CONCLUSIONS

The data reviewed indicate marked strain-dependent differences between C57 and DBA strain for the effects of DA agents which are not limited to susceptibility or sensitivity. Indeed, qualitative differences in behavioral responses elicited by DA agonists as well as opposite effects on memory consolidation have been reported. The observation that stimulation of DA receptors can elicit different or even opposite behavioral outputs in individuals characterized by different genetic constitutions

Acknowledgements

The work described in the present review has been supported throughout the years by Italian CNR (DO) and MURST (60%), and by CNR grants (Com.04; 11).

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    Copyright © 1997 Elsevier Science Ltd. All rights reserved.