Effects of GBR 12909, a selective dopamine uptake inhibitor, on motor activity and operant behavior in the rat

doi:10.1016/0014-2999(89)90447-0

European Journal of Pharmacology

Volume 167, Issue 3, 29 August 1989, Pages 385-395

https://doi.org/10.1016/0014-2999(89)90447-0 Get rights and content

Abstract

GBR 12909, an aryl 1,4-dialkylpiperazine derivative, is a potent and selective inhibitor of the presynaptic dopamine uptake complex. The behavioral effects of this compound were studied in rats using several different paradigms. GBR 12909 (1, 10, 20 mg/kg i.p.) elicited a dose-dependent, long-lasting behavioral activation characterized by locomotion, rearing, sniffing and stereotypies at the highest dose. A second experiment investigated the consequences of subchronic treatment (one injection every 2 days for 14 days) with a high dose (20 mg/kg) of GBR 12909. Evidence was obtained for sensitization to GBR 12909, indicated by progressively more intense stereotypy induced by the high dose of GBR 12909, and also by an enhanced locomotor response to subthreshold doses of the drug, which lasted up to 7 weeks following the end of subchronic treatment. In a test of fixed-interval responding for food reward, GBR 12909 strongly enhanced lever pressing and lowered quarter-life. Low rates of responding were affected more than high rates. GBR 12909 also potentiated responding for a conditioned reinforcer (a stimulus which had previously been paired with food), suggesting that the rewarding impact of the stimulus was increased. It is concluded that the behavioral profile of GBR 12909 is similar to other dopamine-enhancing psychostimulants, and the sensitization may involve long-term changes in the dopamine uptake site.

References (35)

J.A. Bedford et al.
Comparative behavioral profile of cocaine and norcocaine in rats and monkeys
Pharmacol. Biochem. Behav.
(1980)
P. Berger et al.
Characterization of sodium-dependent [³H]GBR-12935 binding in brain: a radioligand for selective labelling of the dopamine transport complex
European J. Pharmacol.
(1985)
J.J. Bonnet et al.
GBR 12783, a potent and selective inhibitor of dopamine uptake: biochemical studies in vivo and ex vivo
European J. Pharmacol.
(1986)
P.B. Dews et al.
Rate dependency of the behavioral effects of amphetamine
M.L. Dubocovich et al.
Binding characteristics of the dopamine uptake inhibitor [³H]nomifensine to striatal membranes
Biochem. Pharmacol.
(1985)
R.E. Heikkila et al.
Behavioral properties of GBR 12909, GBR 13069 and GBR 13098; specific inhibitors of dopamine uptake
European J. Pharmacol.
(1984)
J.A. Javitch et al.
[³]-Mazindol binding associated with neuronal dopamine uptake sites in corpus striatum membranes
European J. Pharmacol.
(1983)
R.M. Post et al.
Drug-environment interaction: context dependency of cocaine-induced behavioral sensitization
Life Sci.
(1981)
M.E.A. Reith et al.
Saturable [³H]-cocaine binding in central nervous system of mouse
Life Sci.
(1980)
T.E. Robinson et al.
Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res. Rev.
(1986)

D.S. Segal et al.

Long-term administration of amphetamine: progressive augmentation of motor activity and stereotypy

Pharmacol. Biochem. Behav.

(1974)

B.H.C. Westerink et al.

Dopamine re-uptake inhibitors show inconsistent effects on the in vivo release of dopamine as measured by intracerebral dialysis in the rat

European J. Pharmacol.

(1987)

P.H. Andersen

Biochemical and pharmacological characterization of [³H]GBR 12935 binding in vitro to rat striatal membranes: labeling of the dopamine uptake complex

J. Neurochem.

(1987)

R.J. Beninger et al.

The acquisition of responding with conditioned reinforcement: effects of cocaine, (+)-amphetamine and pipradrol

Br. J. Pharmacol.

(1981)

C. Braestrup

Biochemical differentiation of amphetamine vs. methylphenidate and nomifensine in rats

J. Pharm. Pharmacol.

(1977)

M.N. Branch et al.

A detailed analysis of the effects of d-amphetamine on behavior under fixed interval schedules

J. Exp. Anal. Behav.

(1974)

J.L. Bruning et al.

Computational Handbook of Statistics

Cited by (73)

Modafinil acquires reinforcing effects when combined with citalopram
2022, Pharmacology Biochemistry and Behavior
Citation Excerpt :
GBR 12909 is a selective substance that inhibits DAT, so it increases only dopamine levels. It has been described as having fewer reinforcing and differential properties than drugs like cocaine (Kelley and Lang, 1989; Tella et al., 1996; Achterberg et al., 2016). Although GBR 12909 increases MA in a way similar to cocaine (Rothman and Grieg, 1998), it does not produce motor sensitization or tolerance (Melnick et al., 2001), perhaps because the neuroadaptations that it induces in the dopaminergic system are distinct from those of cocaine (Tella et al., 1996).
Modafinil (MOD) is a wakefulness promoter used to treat sleep disorders such as narcolepsy and obstructive sleep apnea. Its action mechanism consists in inhibiting dopamine (DAT) and norepinephrine (NET) transporters, but it has no affinity for the serotonin transporter (SERT). Modafinil's addictive potential is not yet clear, but one feature that differentiates it from potentially addictive drugs like cocaine revolves around affinity for SERT. The aims of the present study were to determine whether co-administration of MOD with the selective serotonin reuptake inhibitor citalopram (CIT) can increase MOD's psychostimulant effects on motor activity (MA), verify the effects of subsequent self-administration of MOD mixed with CIT, and document the presence of any symptoms of withdrawal. At 60 postnatal days (PD), male Wistar rats were treated chronically (16 days) with MOD at 30 or 60 mg/kg, with MOD+CIT at four dosage combinations administered to four groups (30MOD + CIT3, 30MOD + CIT5, 60MOD + CIT3, 60MOD + CIT5 mg/kg), or with a vehicle. After 40 min of daily drug administration, MA was measured on the open field test. MA increased only in the 60MOD group. The rats co-administered with 30MOD + 3CIT and 60MOD + 3CIT showed a decrease in the motivation to seek a pleasurable stimulus (lower consumption of sweet solution) after treatment concluded. The 60MOD and 60MOD + 3CIT groups showed MA sensitization after MOD intake. Additionally, higher self-administration of the mixture was observed in the groups pre-treated with 30MOD + 3CIT and 60MOD + 3CIT. Results suggest that serotonergic activity enhances modafinil's psychostimulant effects.
Potential role of tyrosine hydroxylase in the loss of psychostimulant effect of amphetamine under conditions of impaired dopamine transporter activity
2017, Behavioural Brain Research
Amphetamine and methylphenidate are known to have stimulatory effect in healthy subjects but not in humans with attention deficit hyperactivity disorder and in rodents with impaired dopamine transporter (DAT) function. This phenomenon is called the paradoxical calming effect of psychostimulants. It has been previously demonstrated that psychostimulants may regulate the enzymatic activity of tyrosine hydroxylase (TH). Hence, the objective of the present study was to determine whether the lack of activity-stimulating effects of amphetamine in hyperactive rats is associated with changes in TH activity. To model hyperactivity in rats, acute administration of DAT inhibitor GBR12909 was used. Changes in TH activity, assessed as L-DOPA accumulation and TH phosphorylation levels, were measured in amphetamine treated rats with or without pretreatment with GBR12909. Our results showed that amphetamine treatment alone increased locomotor activity in rats, whereas pretreatment of rats with GBR12909 counteracted this effect, a finding consistent with the paradoxical calming effect. GBR12909, while having no effect on its own, blocked amphetamine-induced elevation of TH activity in dorsal striatum and nucleus accumbens, measured as increased tissue L-DOPA concentration. However, the phosphorylation levels of TH were not affected by treatment with amphetamine, GBR12909 or the combination of both. Our findings indicate that other mechanisms than phosphorylation-regulated TH activity changes are responsible for the paradoxical calming effect of amphetamine under conditions of impaired DAT activity.
Electrical high frequency stimulation modulates GABAergic activity in the nucleus accumbens of freely moving rats
2015, Neurochemistry International
Citation Excerpt :
Behavioral scoring was performed on video recordings of the experiment. Different behavioral patterns were documented as previously described by various authors (Andersen et al., 1987; Kelley and Lang, 1989; Westerink et al., 1987). The behavioral activity was classified in three categories of arbitrary units scored from 0 to 2 (0 = absent, 1 = moderate, 2 = marked).
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective treatment option for those affected by obsessive compulsive disorder, who do not respond to pharmacological treatment strategies. Yet, little is known about the mechanism by which DBS achieve its therapeutic effects. Previous studies have shown an increase in GABA levels due to high frequency stimulation (HFS) in the rat caudate putamen. Here, the effect of high frequency stimulation in the nucleus accumbens of conscious and freely moving rats was characterized using unilateral but simultaneous microdialysis and HFS with a frequency of 124 Hz and 0.5 mA current. Extracellular levels of neurotransmitters – GABA, glutamate, dopamine, serotonin and their metabolites were quantified by means of HPLC with electrochemical detection. Basal levels of GABA were significantly increased in animals of the stimulation group compared to the control group without HFS. The levels of other neurotransmitters were unaffected. The influence of NMDA receptor antagonist, memantine (5 mg/kg) on the effect of HFS was investigated by subcutaneous administration of memantine on the day of the experiment. Memantine (without stimulation) enhanced basal GABA and dopamine levels. However, under the influence of both memantine and HFS, GABA levels were not affected by HFS whereas dopamine levels decreased during the stimulation period. The results of our study demonstrate that HFS in the nucleus accumbens of freely moving rats induces selective increase in GABA outflow and show a possible involvement of NMDA receptors in the mechanistic action of HFS.
Contribution of the mGluR7 receptor to antiparkinsonian-like effects in rats: A behavioral study with the selective agonist AMN082
2013, Pharmacological Reports
Citation Excerpt :
In contrast, selective DAT inhibitors abolish akinesia in this model [11, 33]; however, since the affinity of Met-1 for DAT is ca. 10 times lower than for SERT, a potential benefit of DAT inhibition may be masked by the effects induced by SERT blockade. Furthermore, DAT inhibitors are known to elevate extracellular DA levels in the striatum and to potentiate locomotion [13, 26]. Since AMN082 is unable to increase either striatal DA release [20] or locomotion (our study), its effect related to DAT inhibition also seems questionable.
Metabotropic glutamate receptors (mGluRs) have been shown to be potential targets for numerous neurological diseases, including Parkinson's disease (PD).We previously reported that ACPT-1, a non-selective group III mGluRs agonist, injected locally into the globus pallidus, striatum or substantia nigra pars reticulata (SNr), significantly attenuated the haloperidol-induced catalepsy in rats. N,N’-dibenzhydryl-ethane-1,2-diamine dihydrochloride (AMN082) is a potent, brain penetrating mGluR7 agonist, selective over other mGluRs.
The aim of the present study was to determine whether (1) activation of mGluR7 by systemic administration of AMN082 may produce antiparkinsonian-like effects in the haloperidol-induced catalepsy and reserpine-induced akinesia models in rats; (2) striatal and nigral mGluR7 is likely to contribute to such an effect.
We found that AMN082 (1 and 3 mg/kg) decreased the haloperidol (0.25 mg/kg)-induced catalepsy, but was not efficient in attenuating the reserpine (2.5 mg/kg)-induced akinesia. When given locally, AMN082 also significantly diminished catalepsy in rats; however, its effective striatal doses were 10-fold lower than those used in the SNr (2.5 and 7.5 pmol/0.5 μl/ side vs. 25 and 75 pmol/0.5 μl/side, respectively).
The above findings support the idea that the activation of mGluR7 can produce antiparkinsonian-like effects in rats. Furthermore, our results indicate contribution of both striatal and nigral mGluR7 to the anticataleptic effects of AMN082.
Behavioural characterisation of the effects of acute and repeated administration of GBR 12909 in rats: Further evaluation of a potential model of ADHD
2009, Neuropharmacology
Citation Excerpt :
The results suggest that acute GBR 12909-induced hyperactivity and increased rearing is possibly due to its' potent ability to selectively block the dopamine transporter and thus inhibit dopamine reuptake resulting in enhanced dopaminergic neuronal transmission at postsynaptic receptors. Indeed this is consistent with previous reports in adult rats (Heikkila and Manzino, 1984; Kelley and Lang, 1989; Hooks et al., 1994) where rats displayed enhanced locomotor responses to acute GBR 12909 sustained for up to 7 weeks following discontinuation of a 14 day treatment regime (Kelley and Lang, 1989). Considering the potency of GBR 12909 to inhibit DAT and the high dose of the drug used, it is probable that this repeated dosing regime caused alterations in the affinity of the drug for the DAT site and indeed it has been reported that GBR 12909 may produce conformational changes in the transporter protein (Stepanov and Järv, 2008).
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterised by excessive levels of hyperactivity, inattentiveness and impulsivity. Stimulant drugs which increase dopamine neurotransmission are treatments for ADHD. Hypodopaminergic fronto-striatal function with associated overactivity of the dopamine transporter (DAT) represents one possible neurobiological mechanism underlying ADHD. Few, if any, of the existing animal models of ADHD mimic the underlying neurobiology of the disorder. In this study we have further characterised the behavioural profile of a model of a hyperactive inattentive animal through manipulation of the DAT.
The behavioural effects of acute treatment and following withdrawal from sub-chronic treatment with GBR 12909 (30 mg/kg i.p.), a potent and highly selective DAT inhibitor, were examined in juvenile rats. GBR 12909 treatment was used to produce a compensatory up regulation following withdrawal. Acute treatment with GBR 12909 (30 mg/kg i.p.) resulted in a marked increase in locomotor and rearing behaviours on the first and fourth days during a 4 consecutive bi-daily drug treatment regime in postnatal weaned rats. Adolescent rats after 10, 20 and 30 days withdrawal from GBR 12909 pre-treatment maintained mild increases in locomotor activity and failed to discriminate a familiar over a novel object in the novel object discrimination task (using both 1 min and 3 h inter-trial intervals) indicating impaired learning and memory. Prepulse inhibition of acoustic startle was unaltered following withdrawal from GBR 12909 treatment.
These data reinforce the potential role of the DAT in the underlying neurobiology of ADHD. They also add further evidence to suggest that postnatal changes in the DAT following withdrawal from treatment with the DAT inhibitor, GBR 12909, may prove to be a useful animal model of ADHD with potential for examining the effectiveness of novel ADHD treatments.
Altered dopaminergic profiles: Implications for the regulation of voluntary physical activity
2009, Behavioural Brain Research
The biological regulating factors of physical activity in animals are not well understood. This study investigated differences in the central mRNA expression of seven dopamine genes (Drd1, Drd2, Drd3, Drd4, Drd5, TH, and DAT) between high active C57/LJ (n = 17) male mice and low active C3H/HeJ (n = 20) male mice, and between mice with access to a running wheel and without running wheel access within strain. Mice were housed with running wheels interfaced with a computer for 21 days with distance and duration recorded every 24 h. On day 21, the striatum and nucleus accumbens were removed during the active period (∼9 pm) for dopaminergic analysis. On average, the C57L/J mice with wheels ran significantly farther (10.25 ± 1.37 km/day vs. 0.01 ± 0.09 km/day, p < 0.001), longer (329.73 ± 30.52 min/day vs. 7.81 ± 6.32 min/day, p < 0.001), and faster (31.27 ± 3.13 m/min vs. 11.81 ± 1.08 m/min, p < 0.001) than the C3H/HeJ mice with wheels over the 21 day period. No differences in gene expression were found between mice in either strain with wheels and those without wheels suggesting that access to running wheels did not alter dopaminergic expression. In contrast, relative expression for two dopamine genes was significantly lower in the C57L/J mice compared to the C3H/HeJ mice. These results indicate that decreased dopaminergic functioning is correlated with increased activity levels in C57L/J mice and suggests that D1-like receptors as well as tyrosine hydroxylase (an indicator of dopamine production), but not D2-like receptors may be associated with the regulation of physical activity in inbred mice.

View all citing articles on Scopus

View full text

Effects of GBR 12909, a selective dopamine uptake inhibitor, on motor activity and operant behavior in the rat

Abstract

Pharmacol. Biochem. Behav.

European J. Pharmacol.

European J. Pharmacol.

Biochem. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Life Sci.

Life Sci.

Brain Res. Rev.

Pharmacol. Biochem. Behav.

European J. Pharmacol.

Biochemical and pharmacological characterization of [3H]GBR 12935 binding in vitro to rat striatal membranes: labeling of the dopamine uptake complex

J. Neurochem.

The acquisition of responding with conditioned reinforcement: effects of cocaine, (+)-amphetamine and pipradrol

Br. J. Pharmacol.

Biochemical differentiation of amphetamine vs. methylphenidate and nomifensine in rats

J. Pharm. Pharmacol.

A detailed analysis of the effects of d-amphetamine on behavior under fixed interval schedules

J. Exp. Anal. Behav.

Computational Handbook of Statistics

Biochemical and pharmacological characterization of [³H]GBR 12935 binding in vitro to rat striatal membranes: labeling of the dopamine uptake complex