Anomalous effect of mazindol on dopamine uptake as measured by in vivo voltammetry and microdialysis

Ng, Jeffrey P.; Menacherry, Stanley; Liem, Ben; Anderson, D.C.; Singer, Michael C.; Justice, Joseph B.

doi:10.1016/0304-3940(92)90523-a

Cited by 16 publications

(18 citation statements)

References 14 publications

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“…Unfortunately, the lack of a quantitative measure of dopaminergic or noradrenergic metabolism (in our patients) makes it impossible to know whether the dose of mazindol used in the present study was appropriate. While comparable to that used in earlier open-labeled trials (Seibyl et al 1991), the dose of mazindol used in the present study (3 mg/day), is considerably lower than that typically used in preclinical studies (10-25 mg/kg) (Ng et al 1992). Failure to achieve a significant enhancement in extracellular DA levels could explain the discrepancy between our results and previous studies demonstrating a reduction in negative symptoms following d-amphetamine.…”

Section: Discussioncontrasting

confidence: 57%

“…In addition, mazindol has been reported to paradoxically increase V max of the DA transporter, which could contribute to its comparatively modest effects in increasing basal DA levels (Ng et al 1992). Thus, it seems reasonable to assume, even in the absence of an explicit measure of drug-induced changes in neurotransmitter levels, that the increase in DA levels produced by mazindol in the present study would be less than that achieved in patients receiving amphetamine.…”

Section: Discussionmentioning

confidence: 99%

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Mazindol Treatment of Negative Symptoms

Carpenter

2000

Neuropsychopharmacology

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Hypodopaminergic and hyponoradrenergic pathophysiology may be a basis for primary and/or secondary negative symptoms in schizophrenia. The hypothesis that enhanced neurotransmission in these systems would be therapeutic for negative symptoms was tested by comparing mazindol and placebo in a double-blind, cross-over design trial. Outcome following mazindol supplementation was comparable to placebo supplementation (F(1,30) Many mental and physical states can temporarily reduce an individual's ability to experience pleasure, gratification, and reinforcement. However, when Rado (1956) described anhedonia as a core feature of schizophrenia, he referred to an enduring or trait reduction in capacity rather than a transitory or state impairment. Meehl (1962) elaborated this concept in the context of a trait neurointegrative disability associated with schizophrenia. Stein and Wise (1971) subsequently introduced the hypothesis that neurotoxic damage to the noradrenergic reward system was present in schizophrenia. This latter theory, while not capable of accounting for the broad range of clinical manifestations of the disease, seemed a highly cogent hypothesis for anhedonia per se (Strauss and Carpenter 1972).Negative symptoms of schizophrenia are defined more broadly than anhedonia, but the core features of reduced social drive, restricted emotional experience and expression, alogia, and a diminished capacity for the experience of pleasure are hypothesized to emerge from pathophysiology in the neural circuits concerned with drive, emotion, and reward. Dopaminergic and noradrenergic neurons are central to the mediation of these experiences (Schultz 1997).These considerations suggest a therapeutic hypothesis, that enhanced neurotransmission in noradrenergic and/or dopaminergic systems would be therapeutic for negative symptoms. In particular, the dopaminergic mesocortical projections and noradrenergic circuitry involved with reward are seen as possible neural substrates for the negative symptoms of schizophrenia (Weinberger 1987;Davis et al. 1991). Developing a treatment based on either of these presumptions is not straightforward, however, since the hyperdopaminergic mesolimbic hypothesis would predict that a drug that reduces negative symptoms would have the potential liability of increasing positive symptoms.An approach to enhancing mesocortical dopaminergic activity, while having little effect on other projections, is the use of dopamine reuptake inhibitors. This approach is based on the observation that dopamine NO . 4 turnover rates in the mesocortical projection are two to four fold higher than in the mesolimbic or nigrostriatal systems (Agnati et al. 1980;Bannon et al. 1981;Thierry et al. 1976). Accordingly, a reuptake blocker should result in a faster accumulation and higher concentration of synaptic dopamine in cortical regions than in other dopamine terminal fields. Direct support for this hypothesis is provided by preclinical studies in which drugs that block amine transporters increase dopamine levels in ...

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Mazindol Treatment of Negative Symptoms

Carpenter

2000

Neuropsychopharmacology

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“…This dose of mazindol was subthreshold for the elicitation of observable locomotor activation, but is a dose that has been reported to increase extracellular DA concentrations in rat striatum (Ng et al 1992). These doses of fluvoxamine were reported to increase extracellular levels of 5-HT in frontal cortex without altering extracellular levels of DA or NE (Jordan et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Role of 5-HT2A and 5-HT2B/2C Receptors in the Behavioral Interactions Between Serotonin and Catecholamine Reuptake Inhibitors

McMahon

2001

Neuropsychopharmacology

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Dysfunction of monoamine neurotransmission seems to contribute to such pathopsychological states as depression, schizophrenia, and drug abuse. The present study examined the effects of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and antidepressant fluvoxamine on locomotor activity in rats following administration of the catecholamine reuptake inhibitor mazindol. Mazindol (1 mg/kg) did not alter locomotor activity; whereas, fluvoxamine (20 mg/kg) given alone induced a brief period of hypomotility. Hyperactivity was elicited in a doserelated manner when fluvoxamine (5-20 mg/kg) was combined with mazindol (1 mg/kg). The hyperactivity elicited by fluvoxamine (20 mg/kg) Several lines of evidence suggest that dopamine (DA) and serotonin (5-hydroxy tryptamine; 5-HT) interact in the central nervous system and that dysfunction of these neurotransmitters may contribute to such pathopsychological states as depression, schizophrenia, and drug abuse (Kahn and Davidson 1993;Kosten et al. 1998). The 5-HT-containing cell bodies of the dorsal raphe nucleus project to DA cell bodies of the ventral tegmental area (VTA) and substantia nigra (SN), and to their terminal fields in the prefrontal cortex (PFC), nucleus accumbens (NAc), and striatum (Hervé et al. 1987;Steinbush et al. 1981; Van der Kooy and Hattori 1980). The precise nature of the interaction between 5-HT and DA has been difficult to elucidate, with both inhibitory and excitatory roles for 5-HT identified with respect to the neural activity of DA neurons and the release of DA. For example, electrophysiological studies in vivo suggest an inhibitory influence of 5-HT on DA cell bodies of the VTA and SN (Prisco et al. 1994;Kelland et al. 1990), and 5-HT inhibits DA release from striatal slices (Ennis et al. 1981;Westfall and Tittermary 1982). On the other hand, in vivo microdialysis studies consistently demonstrate that local infusion of 5-HT increases DA efflux in the PFC, NAc, and striatum (Benloucif et al. NO . 3 1993; Gobert and Millan 1999; Iyer and Bradberry 1996;Parsons and Justice 1993), possibly through stimulation of one or more of the 14 5-HT receptor subtypes characterized to date (Barnes and Sharp 1999).The behavioral importance of 5-HT and DA interactions has been difficult to define. Much of this research has focused on modifications of behaviors evoked by enhanced DA neurotransmission consequent to psychostimulant administration. In early studies, reductions and enhancements of the locomotor stimulatory effects of cocaine (Scheel-Kruger et al. 1976) and amphetamine (Geyer et al. 1976) were reported following increased 5-HT synthesis or depletion of 5-HT, respectively. These and similar findings generated the hypothesis that 5-HT plays an inhibitory role in DA-mediated behavior. On the other hand, systemic administration of selective serotonin reuptake inhibitors (SSRIs) potentiated hyperactivity induced by amphetamine or cocaine in rats (Herges and Taylor 1998;Sills et al. 1999aSills et al. , 1999b, but not in mice (Arn...

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“…Medium spiny neurons in both the striatum and Acb release GABA. One class of medium spiny neurons contains ENK and the D2 class of DA receptors [48, 49]. The other class contains DYN and predominately expresses the D1 DA receptor.…”

Section: Substrates Of Drug and Alcohol Addictionmentioning

confidence: 99%

Targeting Endogenous Mu- and Delta-Opioid Receptor Systems for the Treatment of Drug Addiction

Shippenberg¹,

LeFevour²,

Chefer³

2008

CNSNDDT

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Drug addiction is a chronic, relapsing disorder that is characterized by a compulsion to take drug regardless of the adverse consequences that may ensue. Although the involvement of mesoaccumbal dopamine neurons in the initiation of drug abuse is well-established, neuroadaptations within the limbic cortical- striatopallidal circuit that occur as a consequence of repeated drug use are thought to lead to the behavioral dysregulation that characterizes addiction. Opioid receptors and their endogenous ligands are enriched in brain regions comprising this system and are, thus, strategically located to modulate neurotransmission therein. This article will review data suggesting an important role of mu-opioid receptor (MOPr) and delta opioid receptor (DOPr) systems in mediating the rewarding effects of several classes of abused drugs and that aberrant activity of these opioid systems may not only contribute to the behavioral dysregulation that characterizes addiction but to individual differences in addiction vulnerability.

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Anomalous effect of mazindol on dopamine uptake as measured by in vivo voltammetry and microdialysis

Cited by 16 publications

References 14 publications

Mazindol Treatment of Negative Symptoms

Mazindol Treatment of Negative Symptoms

Role of 5-HT2A and 5-HT2B/2C Receptors in the Behavioral Interactions Between Serotonin and Catecholamine Reuptake Inhibitors

Targeting Endogenous Mu- and Delta-Opioid Receptor Systems for the Treatment of Drug Addiction

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