Repeated administration of methamphetamine causes hypersensitivity of D2 receptor in rat ventral tegmental area

doi:10.1016/S0304-3940(03)00673-6

Neuroscience Letters

Volume 347, Issue 2, 21 August 2003, Pages 89-92

https://doi.org/10.1016/S0304-3940(03)00673-6 Get rights and content

Abstract

To elucidate whether the methamphetamine (MAP)-induced hypersensitivity to dopamine occurs in the ventral tegmental area (VTA), patch clamp studies were performed using brain slice preparations. MAP or physiological saline was administered to 8–10-day-old rats daily for 5 days. On day 5, patch clamp studies were performed on VTA dopamine neurons which were identified by morphological and electrophysiological characteristics. Dopamine (1–100 μM) and talipexole (a dopamine D2 receptor agonist, 1–100 μM) produced a dose-dependent hyperpolarization in these neurons; treatment with SKF 38393 or PD128907 (Dl and D3 receptor agonists, respectively) had no effect. The extent of hyperpolarization was significantly greater in the MAP group compared to the saline controls, suggesting that repeated MAP administration causes a hypersensitivity to dopamine that is D2 receptor-dependent. This hypersensitivity reduces the excitability of VTA dopamine neurons, thus decreasing dopamine release in the nucleus accumbens area. This may compensate for the MAP-induced elevation of dopamine levels and modulate the dopamine-induced signal transduction cascades, leading to reverse tolerance in nucleus accumbens neurons.

Section snippets

Acknowledgements

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, by a Grant-in-Aid from the Ministry of Health and Welfare, Japan and by the Sankyo Foundation of Life Science. This work was carried out with equipment of the Research Facilities for Laboratory Animal Science and Research Center for Molecular Medicine, Hiroshima University School of Medicine.

References (17)

M.E Gnegy et al.
Phosphorylation of neuromodulin in rat striatum after acute and repeated, intermittent amphetamine
Brain Res. Mol. Brain Res.
(1993)
A.A Grace et al.
Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. 1. Identification and characterization
Neuroscience
(1983)
A.A Grace et al.
Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. 2. Action potential generating mechanisms and morphological correlates
Neuroscience
(1983)
A.A Grace et al.
Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. 3. Evidence for electrotonic coupling
Neuroscience
(1983)
M Hara et al.
Acute effects of methamphetamine applied microiontophoretically to nucleus accumbens neurons in rats
Neurosci. Res.
(1987)
P.W Kalivas et al.
Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity
Brain Res. Brain Res. Rev.
(1991)
S Masuko et al.
Dissociated high-purity dopaminergic neuron cultures from the substantia nigra and the ventral tegmental area of the postnatal rat
Neuroscience
(1992)
T.E Robinson et al.
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res. Rev.
(1993)

There are more references available in the full text version of this article.

Cited by (11)

Reduction of dopamine and glycogen synthase kinase-3 signaling in rat striatum after continuous administration of haloperidol
2021, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Considering that the GRK6/ARRB2 system prevents G protein-dependent early signaling and induces AKT/GSK-3 signaling, both the GRK6/ARRB2 system and the AKT/GSK-3 signaling alteration may contribute to a reduction of post-DRD2 signaling in DSS. As a similar concept to DSS, the dopamine hypersensitivity state (DHS) is generally known to be induced by repeated psychostimulant administration (Amano et al., 1996; Amano et al., 2003). Several studies have reported that DHS rats exhibited behavioral supersensitivity to dopamine, similarly to DSS rats (Klawans and Margolin, 1975; Amano et al., 2002; Shuto et al., 2006).
Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats.
Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions.
In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/β and an increase in the pGSK-3β/GSK-3β ratio, whereas AKT was not changed.
Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS.
Tipepidine activates VTA dopamine neuron via inhibiting dopamine D<inf>2</inf> receptor-mediated inward rectifying K<sup>+</sup> current
2013, Neuroscience
Citation Excerpt :
We adjusted the resting membrane potential to approximately −50 mV with injecting currents. This resting membrane potential is observed in DA neurons in slice preparations including VTA (Amano et al., 2003). In this condition, the application of 10−7 M DA immediately hyperpolarized the cell membrane followed by the reduction of firing rate (Fig. 6A).
We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine (DA) neurons via inhibiting G protein-coupled inwardly rectifying potassium (GIRK) channels. In this study, we investigated the action of tipepidine on DA D₂ receptor-mediated GIRK currents (I_DA(GIRK)) and membrane excitability in DA neurons using the voltage clamp and current clamp modes of the patch-clamp techniques, respectively. DA neurons were acutely dissociated from the ventral tegmental area (VTA) in rats and identified by the presence of the hyperpolarization-activated currents. Tipepidine reversibly inhibited I_DA(GIRK) with IC₅₀ 7.0 μM and also abolished I_DA(GIRK) irreversibly activated in the presence of intracellular GTPγS. Then tipepidine depolarized membrane potential and generated action potentials in the neurons current-clamped. Furthermore, the drug at 40 mg/kg, i.p. increased the number of cells immunopositive both for c-Fos and tyrosine hydroxylase (TH) in the VTA. These results suggest that tipepidine may activate DA neurons in VTA through the inhibition of GIRK channel-activated currents.
Serotonergic modulation of neuronal activity in the nucleus accumbens following repeated methamphetamine administration in rats
2013, Journal of Pharmacological Sciences
Electrophysiological studies were performed to determine whether serotonergic modulation in the nucleus accumbens (NAcc) was affected after repeated methamphetamine (MAP) administration. NAcc slices (400 μm) from Wistar rats administered MAP (5 mg/kg) or saline once daily for 5 days were prepared 1, 5, or 10 days after the final injection. Population spikes (PS) induced by local stimulation of NAcc were recorded. PS inhibition by serotonin was significantly attenuated in the MAP group at 5 days but did not differ at 1 or 10 days. We next analyzed the effects of serotonin receptor subtype (5-HT_1A,2,3,4,6,7)-selective agonists of PS. Differences between saline and MAP groups in 5-HT_1A,2,3,4,6 receptor agonist–induced changes of PS were small or not significant. Interestingly, 5-HT₇ receptor agonists significantly enhanced PS in the MAP group. Changes in the secondary messenger system related to 5-HT₇ receptors were also investigated. Adenylate cyclase activator–induced PS enhancements were significantly larger in the MAP group. However, dibutyryl-cAMP–induced PS enhancement was not significantly different. In conclusion, 5-HT–induced inhibition of PS in NAcc was attenuated 5 days after repeated MAP treatment: the change in the effect of 5-HT was probably due to enhancement of the excitatory modulation via the 5-HT₇ receptor with adenylate cyclase signal transduction systems. [Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.13100FP]
Eating high-fat chow enhances sensitization to the effects of methamphetamine on locomotion in rats
2011, European Journal of Pharmacology
Citation Excerpt :
Among those dopamine receptors, D1 and D2 receptors are thought to be particularly important in the development of sensitization (Kuribara and Uchihashi, 1993; Shuto et al., 2008). Although the number of dopamine D2 receptors is not changed in animals displaying behavioral sensitization to methamphetamine, there is a significant increase in the high affinity state of dopamine D2 receptors that parallels the development of sensitization (Amano et al., 2003; Seeman et al., 2002). Moreover, eating high-fat chow increases sensitivity to effects of direct-acting agonists that are mediated by dopamine D2 receptors (e.g. Baladi and France, 2009).
Eating high-fat chow can modify the effects of drugs acting directly or indirectly on dopamine systems and repeated intermittent drug administration can markedly increase sensitivity (i.e., sensitization) to the behavioral effects of indirect-acting dopamine receptor agonists (e.g., methamphetamine). This study examined whether eating high-fat chow alters the sensitivity of male Sprague Dawley rats to the locomotor stimulating effects of acute or repeated administration of methamphetamine. The acute effects of methamphetamine on locomotion were not different between rats (n = 6/group) eating high-fat or standard chow for 1 or 4 weeks. Sensitivity to the effects of methamphetamine (0.1–10 mg/kg, i.p.) increased progressively across 4 once per week tests; this sensitization developed more rapidly and to a greater extent in rats eating high-fat chow as compared with rats eating standard chow. Thus, while eating high-fat chow does not appear to alter sensitivity of rats to acutely-administered methamphetamine, it significantly increases the sensitization that develops to repeated intermittent administration of methamphetamine. These data suggest that eating certain foods influences the development of sensitization to drugs acting on dopamine systems.
Feeding conditions differentially affect the neurochemical and behavioral effects of dopaminergic drugs in male rats
2008, European Journal of Pharmacology
The high co-morbidity of eating disorders and substance abuse suggests that nutritional status can impact vulnerability to drug abuse. These studies used rats to examine the effects of food restriction on dopamine clearance in striatum and on the behavioral effects of amphetamine (locomotion, conditioned place preference), the dopamine receptor agonist quinpirole (yawning), and the dopamine receptor antagonist raclopride (catalepsy). Amphetamine increased locomotion and produced conditioned place preference. Food restriction reduced dopamine clearance, which was restored by repeated treatment with amphetamine or by free feeding. Food restriction also decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy; normal sensitivity to both drugs was restored by free feeding. The same amphetamine treatment that normalized dopamine clearance, failed to restore normal sensitivity to quinpirole or raclopride, suggesting that in food-restricted rats the activity of dopamine transporters and dopamine receptors is differentially affected by pathways that are stimulated by amphetamine. These studies show that modest changes in nutritional status markedly alter dopamine neurotransmission and the behavioral effects of direct-acting dopamine receptor drugs (agonist and antagonist). These results underscore the potential importance of nutritional status (e.g., glucose and insulin) in modulating dopamine neurotransmission and in so doing they begin to establish a neurochemical link between the high co-morbidity of eating disorders and drug abuse.
Differential impact of inhibitory g-protein signaling pathways in ventral tegmental area dopamine neurons on behavioral sensitivity to cocaine and morphine
2021, eNeuro

View all citing articles on Scopus

View full text

Repeated administration of methamphetamine causes hypersensitivity of D2 receptor in rat ventral tegmental area

Abstract

Section snippets

Acknowledgements

Brain Res. Mol. Brain Res.

Neuroscience

Neuroscience

Neuroscience

Neurosci. Res.

Brain Res. Brain Res. Rev.

Neuroscience

Brain Res. Rev.