The weaver mutant mouse: a model to study the ontogeny of dopamine transmission systems and their role in drug addiction

https://doi.org/10.1016/S0301-0082(00)00061-7Get rights and content

Abstract

Dopaminergic neurons and their projection-systems are important in some fundamental human activities like locomotion, feeding and sex, essential for survival and procreation, and are relevant to pathologies like Parkinson's disease and drug abuse. Three main dopaminergic projection-systems, namely the nigrostriatal, mesocortical and mesolimbic pathways are the major targets of the neuropharmacological actions of psychomotor stimulants such as cocaine and amphetamine. Studies on knockout mice for dopamine or its receptors provide substantial information but fail to reveal the role of individual dopaminergic projection-systems. Mutant animals with defects specific to one or more projection-systems might be useful for studying the role of individual dopaminergic projection-systems. We propose the weaver mutant mouse, with a defective nigrostriatal dopaminergic projection-system and dopamine depletion in the dorsal striatum but with intact mesocorticolimbic projection-systems, as a suitable model to study the role of individual dopaminergic systems in diverse biological processes including Parkinson's disease and drug abuse.

Introduction

Dopaminergic neurons have become the subject of intense research because of their pharmacological and therapeutic properties. Indeed dopaminergic neurons are said to be the missing link between psychiatric problems and behavioral modifications, selective molecular therapy and pathogenic hypothesis of psychotic states (Le Moal and Simon, 1991). There are several reasons for the importance of dopamine. The discovery, that Parkinson's disease has an anatomopathological basis, (i.e. a lesion of dopaminergic cells within the substantia nigra) gave rise to intense basic and clinical investigations on the dopaminergic nigrostriatal transmission and attempts to treat Parkinson's disease have been made by transplantation of dopaminergic cells (Herman and Arbous, 1994). Dopamine seems to be involved in schizophrenia but knowledge on its role in etiology and therapy of this pathology is scarce (Seeman et al., 1993). Secondly, dopaminergic neurons play an important role in neurophysiological functions and behavior. They are endowed with particular physiological and anatomical properties that distinguish them from the sensory and motor neurons or others subserving more integrative functions (Koshland et al., 1982).

The dopaminergic systems have been recognized fundamental in functions such as movement, eating, drinking, sex and pleasure, related to survival of an individual and propagation of the species. In recent years, the role of dopamine has become evident in acute rewarding effects of psychomotor stimulants like cocaine and amphetamine (Cheng, 1993). Low doses of dopamine receptor antagonists, when administered systemically, increase self-administration of amphetamine and cocaine (Davis and Smith, 1975, De Witt and Wise, 1977). Opiate actions are mediated through specific receptors but involve certain dopaminergic mechanisms as well (Koob and Le Moal, 1997, Nestler and Aghajanian, 1997). A large body of literature exists on dopamine, its receptors, and on neuroanatomy and physiology of dopaminergic neurons, yet knowledge on the fundamental properties of these important neurons is incomplete.

Section snippets

The dopaminergic networks

Neuroanatomical studies have indicated three major functional networks of the dopaminergic systems (Björklund and Lindvall, 1984):

  • 1.

    The nigrostriatal system, the largest of the three, originates mainly in the pars compacta of the substantia nigra (SNC) and innervates the dorsal striatum including the caudate putamen (CP) and globus pallidus (GP). Degeneration of this pathway leads to Parkinson's disease.

  • 2.

    The mesolimbic system, arises mainly in the ventral tegmental area (VTA) and innervates the

Pharmacological methods are not adequate to understand the role of dopamine

A large number of functional investigations are biased by the use of pharmacological techniques. However attractive the psycho-pharmacological approach may be, it is difficult to interpret the results from a physiological point of view, especially when a drug has been administered peripherally and simple behavioral assays are used to evaluate their functional effects. The reactivity of dopaminergic neurons and the use of dopamine after pharmacological treatments, lesions, behavioral situations,

The dopamine-deficient mice

More recently, the attractive experimental system of dopamine-deficient (knockout) mice, has been studied (Zhou et al., 1995). These mice, unable to synthesize dopamine, specifically in dopaminergic neurons, were born at expected frequency, but became hypoactive and stopped eating a few weeks after birth. Nonetheless, the midbrain dopaminergic neurons, their projections and several characteristics of their striatal target-neurons of these mice, appeared normal (Zhou and Palmiter, 1995).

The mice lacking dopamine receptors

Pharmacological studies identified two major classes of dopamine receptors termed Dl-like and D2-like, based on different ligand-binding properties (Missale et al., 1998). The cellular localization of these receptor types in the brain, is highly controversial. The most accepted view is that physiologically significant levels of D1 and D2 receptors are localized to largely non-overlapping populations of neurons in the dorsal and ventral striatum. Neurons bearing Dl-like receptors express certain

The mesencephalic dopaminergic neuronal loss in the weaver mutant

Weaver (wv), an autosomal recessive mutation in the mouse, has been intensively studied because of its effects on the cerebellum (Sidman, 1968, Sidman et al., 1965). The wv disease is mainly expressed in the cerebellum early in postnatal life when most granule cells die in their proliferative zones, after failing to migrate to the internal granule layer (Smeyne and Goldowitz, 1989). Interestingly, the wv mouse also displays dopamine deficiency in the forebrain (Roffler-Tarlov and Graybiel, 1984

The weaver mutant as a model to study the dopaminergic projection-systems

A detailed analysis of the dopaminergic system in this mutant mouse would not only explain what is lacking in the wv mouse, but also enlighten how the dopamine mechanism works in normal mouse and explain the factors involved in the abnormalities and indicate methods to rectify. Herein we discuss recent studies on the dopaminergic systems of the wv mutant mice and suggest future experimental investigations to understand the role of dopaminergic projection-systems in normal and wv animals and

Dopaminergic neurons and their projections

A basic knowledge on the ontogeny of the dopaminergic neurons and their projections, particularly on those innervating the striatal region along with the development of the striatum itself, is essential to understand the functional and regulatory roles of the dopaminergic systems. The organizational role played by the dopaminergic system in the forebrain can become evident through studies on the developing brain both in normal and wv mice. Since the striatum is a compartmentalized structure as

Distribution of dopamine and opioid receptors in wv mice

Several lines of evidence indicate the existence of interaction between opioid peptides and midbrain dopaminergic neurons. Earlier studies (German et al., 1993, Speciale et al., 1993) have demonstrated area-specifı̀c distribution of mu opioid receptors (MORs) in dopaminergic neurons of the retrorubral field, substantia nigra and ventral tegmental area and related nuclei. Particularly MORs are very less in retrorubral region. In the rostral position of SN there are abundant MORs

Influence of abused drugs on the dopaminergic projections

Among the different dopaminergic projections of the mammalian brain, the mesocorticolimbic dopaminergic systems have been implicated in drug-reinforcement. In these systems axons from the ventral tegmental area project to forebrain, mainly to the nucleus accumbens, olfactory tubercle, frontal cortex, amygdala and septal area (Heimer et al., 1995). They are also said to modulate the activity of other areas of the ventral striatum — a region thought to be involved in converting emotion into

Possible protection of the nigrostriatal dopaminergic system in weaver mutant by the application of dopaminotrophic agents

The possibility, that dopaminergic and striatal cell loss in wv mouse is caused by insufficient dopaminotrophic support, is suggested by the study on the influence of dopaminotrophic factors in wv brain. Several growth factors are reported to influence dopaminergic neurons (Beck et al., 1993, Jones et al., 1994, Beck et al., 1995, Berhow et al., 1995, Bowenkamp et al., 1996). GDNF has a trophic influence on grafted fetal mesencephalic dopaminergic neurons (Beck et al., 1995) suggesting that (1)

Acknowledgements

This work was supported by the Italian National Research Council (CNR) strategic program on ‘Biological sensors and projection of biosensors.’

References (50)

  • U. Schmidt et al.

    Activation of dopaminergic D1 receptors promotes morphogenesis of developing striatal neurons

    Neuroscience

    (1996)
  • C. Strazielle et al.

    Distribution of dopamine transporters in basal ganglia of cerebellar ataxic mice by (125I) RTI-121 quantitative autoradiography

    Neurochem. Int.

    (1998)
  • R.D. Todd

    Neural development is regulated by classical neurotransmitters: dopamine D2 receptor stimulation enhances neurite outgrowth

    Biol. Psychiatry

    (1992)
  • C. Verney et al.

    Early postnatal changes of the dopaminergic mesencephalic neurons in the weaver mutant mouse

    Dev. Brain Res.

    (1995)
  • P. Voorn et al.

    The pre- and postnatal development of the dopaminergic cell groups on the ventral mesencephalon and the dopaminergic innervation of the striatum of the rat

    Neuroscience

    (1988)
  • M. Xu et al.

    Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice

    Cell

    (1994)
  • M. Xu et al.

    Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and dopamine-mediated behavioral responses

    Cell

    (1994)
  • Q.Y. Zhou et al.

    Dopamine-deficient mice are severely hypoactive, adipsic and aphagic

    Cell

    (1995)
  • J.H. Baik et al.

    Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors

    Nature

    (1995)
  • K.D. Beck et al.

    Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain

    Nature

    (1995)
  • A. Björklund et al.

    Dopamine-containing systems in the CNS

  • R.E. Boeme et al.

    Dopamine receptor binding in inbred mice: strain differences in mesolimbic and nigrostriatal dopamine binding sites

    Proc. Natl. Acad. Sci. USA

    (1983)
  • K.E. Bowenkamp et al.

    6-hydroxydopamine induces the loss of the dopaminergic phenotype in substantia nigra neurons of the rat

    Expl. Brain Res.

    (1996)
  • R.S. Burns et al.

    A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine

    Proc. Natl. Acad. Sci. USA

    (1983)
  • S.B. Caine et al.

    Effects of dopamine D1 and D2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat

    J. Pharmacol. Expl. Ther.

    (1994)
  • Cited by (23)

    • Generation and vulnerability of deep cerebellar nuclei neurons in the weaver condition along the anteroposterior and mediolateral axes

      2016, International Journal of Developmental Neuroscience
      Citation Excerpt :

      Moreover, the cornu ammonis 3 region of the hippocampus and the dentate gyrus, areas involved in memory formation, present morphological abnormalities (Sekigucchi et al., 1995). All these sensory modalities are impaired in multiple drug abuse as seen in wv/wv mice due to point mutation in the inward rectifying K+ conductance (Maharajan et al., 2001; Sharma et al., 2004; Sharma and Ebadi, 2005). In addition, brain regional metallothioneins (MTs) are down-regulated in the weaver homozygotes (Sharma and Ebadi, 2014), whereas over-expression of MTs significantly attenuated progressive neurodegeneration, which confirmed the free radical theory and highlighted the significance of intra-mitochondrial calcium over load leading to Charnoly Body formation implicated in apoptosis and progressive neurodegenetration.

    • GIRK Channels: A Potential Link Between Learning and Addiction

      2015, International Review of Neurobiology
      Citation Excerpt :

      Based on these phenotypes, the weaver mouse model has been used to investigate the role of SN dopamine neuron loss in Parkinson's disease, a disorder characterized by movement impairments and cognitive dysfunction, including impaired working memory and response inhibition (Matsumoto, 2015); however, it should be noted that the weaver GIRK mutation is not part of Parkinson's pathology in humans (Bandmann, Davis, Marsden, & Wood, 1996) and there are important differences in the overall neurological changes observed in the two models (Derenne et al., 2007). Alternatively, weaver mice have been proposed as a potential tool to differentiate the roles of distinct dopamine signaling pathways (Maharajan, Maharajan, Ravagnan, & Paino, 2001), as the mesolimbic dopamine projections are largely unaffected in this model. Having established that GIRK-mediated signaling is sensitive to modulation by multiple drugs of abuse and that GIRK channels play an important role in the neuronal plasticity that underlies long-term behavioral changes, we now turn our attention to the third criteria supporting a role of GIRK channels in addiction development: the ability of drug-induced alterations in GIRK channel-dependent signaling to support the development and maintenance of addictive behaviors.

    • Structural manipulation on the catecholic fragment of dopamine D <inf>1</inf> receptor agonist 1-phenyl-N-methyl-benzazepines

      2014, European Journal of Medicinal Chemistry
      Citation Excerpt :

      Dopamine (DA) is one of the major cerebral neurotransmitters and plays an essential role in the pathophysiology of many neurobehavioral and neuropsychiatric disorders. DA exerts its agonistic actions primarily through its five major DA receptors (D1–D5), among which, D1,–D3 receptors are the most studied DA receptors [1–3] and are the primary targets of current clinically prescribed dopaminergic drugs [4,5]. Although the D1 receptor was discovered very early with high abundance in the mammalian brains, clinically useful D1 receptor agonists and antagonists are very limited [4–6].

    • Pitx3-deficient aphakia mice display unique behavioral responses to psychostimulant and antipsychotic drugs

      2010, Neuroscience
      Citation Excerpt :

      Although there are numerous genetic models to investigate many aspects of the DA system, there are currently few animal models available to dissect the contribution of individual DA neuronal groups to behavior. Currently available mice with naturally occurring genetic mutations which show interesting region-specific dopamine phenotypes include the coloboma (Wilson, 2000; Jones et al., 2001), reeler (Nishikawa et al., 2003; Lalonde and Strazielle, 2007) and weaver mice (Schmidt et al., 1982; Maharajan et al., 2001). Our group and others have demonstrated severe and gross abnormalities of the A9 DA circuits relative to A10 circuits in ak mice: this includes selective loss of A9 DA content as measured by HPLC, A9 cell loss measured by nissl staining, loss of the DA markers AADC, TH, and DAT, loss of retrograde labeling from the striatum, as well as nigrostriatal-mediated behavioral deficits (Hwang et al., 2005).

    • Weaver mutant mice exhibit long-term learning deficits under several measures of instrumental behavior

      2007, Physiology and Behavior
      Citation Excerpt :

      Homozygous weaver mutant mice (wv/wv) are one of a number of animal models that exhibit characteristics analogous to human Parkinsonism. Specifically, an amino acid mutation in the G protein-activated, inwardly-rectifying potassium channel GIRK2 leads to a number of neurochemical changes characteristic of human Parkinsonism, such as the destruction of cells in the substantia nigra and the ventral tegmental area, and the reduction of striatal and cortical dopamine and tyrosine hydroxylase activity [1–12]. Outwardly, wv/wv mice resemble humans with Parkinson's disease insofar as they manifest ataxia, unstable gait, and motor tremors [12–16].

    View all citing articles on Scopus
    View full text