Increased rewarding properties of morphine in dopamine‐transporter knockout mice

Spielewoy, Cécile; Gonon, François; Roubert, Christine; Fauchey, Valérie; Jaber, Mohamed; Caron, Marc G.; Roques, Bernárd P.; Hamon, Michel; Betancur, Catalina; Maldonado, Rafaël; Giros, Bruno

doi:10.1046/j.1460-9568.2000.00063.x

Cited by 76 publications

(43 citation statements)

References 53 publications

(144 reference statements)

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“…Two possible adaptive changes of this kind are the dopamine transporter (DAT) and the D 2 dopamine autoreceptor (Spielewoy et al, 2000;Rouge-Pont et al, 2002). The DAT plays a central role in determining the duration and amplitude of DA action by rapidly recapturing extracellular DA into presynaptic terminals after release (Benoit-Marand et al, 2000).…”

Section: Morphine Induced a Change In The Firing Pattern In Vta Da Nementioning

confidence: 99%

“…The DAT plays a central role in determining the duration and amplitude of DA action by rapidly recapturing extracellular DA into presynaptic terminals after release (Benoit-Marand et al, 2000). Moreover, voltammetry studies have demonstrated that morphine in mice with a genetic disruption of the DAT produced a dramatic supernormal increase in the level of extracellular DA (Spielewoy et al, 2000). Thus, adaptive changes at the level of the DAT could produce the long-lasting changes in morphine-induced mesolimbic dopamine release observed (Spanagel et al, 1993) without altering the activity of VTA DA neurons (Budygin et al, 2004).…”

Section: Morphine Induced a Change In The Firing Pattern In Vta Da Nementioning

confidence: 99%

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No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

Georges¹,

Moine²,

Aston‐Jones³

2006

J. Neurosci.

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Substantial evidence indicates that the ventral tegmental area (VTA) of the mesocorticolimbic dopaminergic (DA) system has a key role in mechanisms of opiate dependence. Although DA neurons have been studied extensively, little is known about their activity and their response to acute morphine during morphine dependence. We recorded the activity of VTA DA neurons in five groups of anesthetized rats: drug-naive (naive) rats, morphine-dependent [(MD) implanted with pellets] rats, and three groups of withdrawn rats. Withdrawals either were precipitated by naltrexone or occurred spontaneously 24 h or 15 d after pellet removal. We confirmed that acute morphine in naive rats produced a marked increase in the firing of VTA DA neurons. We also found that the basal firing rate of VTA DA neurons was markedly higher in MD than in naive rats; however, in MD rats, acute morphine failed to increase DA activity. We confirmed inhibition of VTA DA activity in MD rats in response to precipitated withdrawal; however, this inhibition resulted only in a normalization of the firing rate to that of naive animals. In rats that had spontaneous withdrawal after 24 h or 15 d, the activity of VTA DA neurons was similar to that of naive rats, and an acute injection of morphine failed to alter their activity. Our results indicate that VTA DA neurons show long-lasting tolerance to the acute effect of morphine after withdrawal. These findings show that VTA DA neural activity is unlikely to be a factor in the altered behavioral responses that occur with acute morphine or naltrexone administration after chronic opiate exposure.

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Section: Morphine Induced a Change In The Firing Pattern In Vta Da Nementioning

confidence: 99%

Section: Morphine Induced a Change In The Firing Pattern In Vta Da Nementioning

confidence: 99%

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

Georges¹,

Moine²,

Aston‐Jones³

2006

J. Neurosci.

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“…Mutant mice (DAT-KO) exhibit extremely high levels of DA synthesis and turnover , with a greatly prolonged (300-fold) extracellular lifetime of DA (Giros et al, 1996), resulting in a five-to ten-fold increase in basal extracellular DA levels in the striatum and nucleus accumbens Spielewoy et al, 2000a;Shen et al, 2004). Besides their obvious hyperactivity, DAT-KO mice exhibit heightened rates of stereotypies and perseverative patterns of nongoal-directed behavior, distorting their motor, exploratory, and social behaviors Spielewoy et al, 2000b;Ralph et al, 2001;Rodriguiz et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Morice

Billard

Denis

et al. 2007

Neuropsychopharmacol

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101

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Dopamine-mediated neurotransmission has been implicated in the modulation of synaptic plasticity and in the mechanisms underlying learning and memory. In the present study, we tested different forms of activity-dependent neuronal and behavioral plasticity in knockout mice for the dopamine transporter (DAT-KO), which constitute a unique genetic model of constitutive hyperdopaminergia. We report that DAT-KO mice exhibit slightly increased long-term potentiation and severely decreased long-term depression at hippocampal CA3-CA1 excitatory synapses. Mutant mice also show impaired adaptation to environmental changes in the Morris watermaze. Both the electrophysiological and behavioral phenotypes are reversed by the dopamine antagonist haloperidol, suggesting that hyperdopaminergia is involved in these deficits. These findings support the modulation by dopamine of synaptic plasticity and cognitive flexibility. The behavioral deficits seen in DAT-KO mice are reminiscent of the deficits in executive functions observed in dopamine-related neuropsychiatric disorders, suggesting that the study of DAT-KO mice can contribute to the understanding of the molecular basis of these disorders.

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“…Studies using immunohistochemical detection of the Fos protein, product of the immediate early gene c-fos, show that acute or chronic morphine administration, or exposure to a morphine-associated context, induce Fos in DA-related structures (Nye and Nestler, 1996;Schroeder et al, 2000;Schroeder and Kelley, 2002). Deletion of the DA transporter results in increased morphine reward and morphine-induced c-fos in the NAc shell (Spielewoy et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Brain Regional Fos Expression Elicited by the Activation of μ- but not δ-Opioid Receptors of the Ventral Tegmental Area: Evidence for an Implication of the Ventral Thalamus in Opiate Reward

David

Matifas

Gavello-Baudy

et al. 2007

Neuropsychopharmacol

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Both m-opioid receptors (MORs) and d-opioid receptors (DORs) are expressed in the ventral tegmental area (VTA) and are thought to be involved in the addictive properties of opiates. However, their respective contributions to opiate reward remain unclear. We used intracranial self-administration (ICSA) to study the rewarding effects of morphine microinjections into the VTA of male and female MORÀ/À and DORÀ/À mice. In brains of mice tested for intra-VTA morphine self-administration, we analyzed regional Fos protein expression to investigate the neural circuitry underlying this behavior. Male and female WT and DORÀ/À mice exhibited similar selfadministration performances, whereas knockout of the MOR gene abolished intra-VTA morphine self-administration at all doses tested. Naloxone (4 mg/kg) disrupted this behavior in WT and DOR mutants, without triggering physical signs of withdrawal. Morphine ICSA was associated with an increase in Fos within the nucleus accumbens, striatum, limbic cortices, amygdala, hippocampus, the lateral mammillary nucleus (LM), and the ventral posteromedial thalamus (VPM). This latter structure was found to express high levels of Fos exclusively in self-administering WT and DORÀ/À mice. Abolition of morphine reward in MORÀ/À mice was associated with a decrease in Fos-positive neurons in the mesocorticolimbic dopamine system, amygdala, hippocampus (CA1), LM, and a complete absence within the VPM. We conclude that (i) VTA MORs, but not DORs, are critical for morphine reward and (ii) the role of VTA-thalamic projections in opiate reward deserves to be further explored.

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Increased rewarding properties of morphine in dopamine‐transporter knockout mice

Cited by 76 publications

References 53 publications

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Brain Regional Fos Expression Elicited by the Activation of μ- but not δ-Opioid Receptors of the Ventral Tegmental Area: Evidence for an Implication of the Ventral Thalamus in Opiate Reward

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