Cocaine: Discussion on the Role of Dopamine in the Biochemical Mechanism of Action

Scheel-Krüger, Jørgen; Bræstrup, Claus; Nielson, Mogens; Gołembiowska, Krystyna; Mogilnicka, E

doi:10.1007/978-1-4684-3087-5_19

Cited by 117 publications

(48 citation statements)

References 54 publications

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“…In this study, pretreatment with haloperidol reduced the locomotion-activating effects induced by repeated administration of DEP and EtOH + DEP. Indeed, there are many studies showing that the locomotor stimulation produced by psychostimulants can be reversed by DAergic antagonists, like haloperidol, pimozide, SCH-23390 and metoclopramide (23)(24)(25). In addition, it is known that the decrease of vesicular DA by reserpine, or the blockage of DA synthesis by a -methyl-p-tyrosine, reduces the stimulant effects of psychostimulants, as well as of low doses of EtOH (26)(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

1999

Braz J Med Biol Res

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The widespread consumption of anorectics and combined anorectic + alcohol misuse are problems in Brazil. In order to better understand the interactive effects of ethanol (EtOH) and diethylpropion (DEP) we examined the locomotion-activating effects of these drugs given alone or in combination in mice. We also determined whether this response was affected by dopamine (DA) or opioid receptor antagonists. A total of 160 male Swiss mice weighing approximately 30 g were divided into groups of 8 animals per group. The animals were treated daily for 7 consecutive days with combined EtOH + DEP (1.2 g/kg and 5.0 mg/ kg, ip), EtOH (1.2 g/kg, ip), DEP (5.0 mg/kg, ip) or the control solution coadministered with the DA antagonist haloperidol (HAL, 0.075 mg/ kg, ip), the opioid antagonist naloxone (NAL, 1.0 mg/kg, ip), or vehicle. On days 1, 7 and 10 after the injections, mice were assessed in activity cages at different times (15, 30, 45 and 60 min) for 5 min. The acute combination of EtOH plus DEP induced a significantly higher increase in locomotor activity (day 1: 369.5 ± 34.41) when compared to either drug alone (day 1: EtOH = 232.5 ± 23.79 and DEP = 276.0 ± 12.85) and to control solution (day 1: 153.12 ± 7.64). However, the repeated administration of EtOH (day 7: 314.63 ± 26.79 and day 10: 257.62 ± 29.91) or DEP (day 7: 309.5 ± 31.65 and day 10: 321.12 ± 39.24) alone or in combination (day 7: 459.75 ± 41.28 and day 10: 427.87 ± 33.0) failed to induce a progressive increase in the locomotor response. These data demonstrate greater locomotion-activating effects of the EtOH + DEP combination, probably involving DA and/or opioid receptor stimulation, since the daily pretreatment with HAL (day 1: EtOH + DEP = 395.62 ± 11.92 and EtOH + DEP + HAL = 371.5 ± 6.76; day 7: EtOH + DEP = 502.5 ± 42.27 and EtOH + DEP + HAL = 281.12 ± 16.08; day 10: EtOH + DEP = 445.75 ± 16.64 and EtOH + DEP + HAL = 376.75 ± 16.4) and NAL (day 1: EtOH + DEP = 553.62 ± 38.15 and EtOH + DEP + NAL = 445.12 ± 55.67; day 7: EtOH + DEP = 617.5 ± 38.89 and EtOH + DEP + NAL = 418.25 ± 61.18; day 10: EtOH + DEP = 541.37 ± 32.86 and EtOH + DEP + NAL = 427.12 ± 51.6) reduced the locomotor response induced by combined administration of EtOH + DEP. These findings also suggest that a major determinant of combined anorectic-alcohol misuse may be the increased stimulating effects produced by the combination.

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Section: Discussionmentioning

confidence: 99%

Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

1999

Braz J Med Biol Res

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“…

The behavioral effects of cocaine in rodents include the stimulation of locomotor activity and stereotypy as well as convulsions at higher doses (Scheel-Kruger et al 1977;McCreary and Marsden 1993). Cocaine also serves as a positive reinforcer for operant behavior (de Wit and Wise 1977) and elicits interoceptive stimulus effects easily discriminable from saline .

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confidence: 99%

“…Cocaine also serves as a positive reinforcer for operant behavior (de Wit and Wise 1977) and elicits interoceptive stimulus effects easily discriminable from saline . The locomotor stimulant effects have been linked to the inhibition of dopamine (DA) reuptake (Koe 1976) and a subsequent enhancement of DA activation via both DA D 1 and D 2 receptors (Scheel-Kruger et al 1977;McCreary and Marsden 1993;White et al 1998). The elevated DA neurotransmission, particularly within the mesoaccumbens pathway originating from DA soma in the ventral tegmental area (VTA) and terminating in the nucleus accumbens (NAc), is especially important in mediating the locomotor, discriminative stimulus and reinforcing effects of cocaine (for review, Amalric and Koob 1993).…”

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“…20, NO. 6 cocaine-induced hyperactivity or to unmask more intense DA stereotypies such as gnawing and biting in rats (Scheel-Kruger et al 1977;Berman et al 1982), although the 5-HT 2/1A/1D antagonist methysergide did not alter cocaine behaviors in mice (Reith 1990). Herges and Taylor (1998) have recently reported that methysergide potentiated, while the 5-HT 2A/2C antagonist ketanserin differentially increased (0.1 mg/kg) and decreased (1 mg/kg) cocaine-induced locomotor hyperactivity, consistent with the reduction seen after a high dose of the 5-HT 2 antagonist ritanserin (10 mg/kg; Peltier et al 1994).…”

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confidence: 99%

“…Both mCPP (Nader and Barrett 1990) and the 5-HT 2 antagonist ritanserin (Meert and Janssen 1992;Howell and Byrd 1995) altered rates of responding for cocaine in self-administration tasks. The ability of selective 5-HT 2C antagonists to affect hyperactivity induced by cocaine has not been analyzed, however, non-selective 5-HT 1/2 antagonists have been shown to enhance cocaine-induced hyperactivity (Scheel-Kruger et al 1977;Berman et al 1982;Herges and Taylor 1998; but see Reith 1990 andPeltier et al 1994). Since 5-HT 2C antagonists appear to increase the activity of a subpopulation of VTA DA neurons (Prisco et al 1994;Prisco and Esposito 1995;Ashby and Minabe 1996;Lejeune et al 1997) and 5-HT 2C agonists induce hypomotility (Lucki et al 1989;Kennett 1993;Kennett et al 1996), a 5-HT 2C antagonist would be predicted to increase the locomotor activation observed after cocaine administration.…”

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confidence: 99%

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Effects of the 5-HT2C/2B Antagonist SB 206553 on Hyperactivity Induced by Cocaine

McCreary

Cunningham²

1999

Neuropsychopharmacology

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The behavioral effects of cocaine in rodents include the stimulation of locomotor activity and stereotypy as well as convulsions at higher doses (Scheel-Kruger et al. 1977;McCreary and Marsden 1993). Cocaine also serves as a positive reinforcer for operant behavior (de Wit and Wise 1977) and elicits interoceptive stimulus effects easily discriminable from saline . The locomotor stimulant effects have been linked to the inhibition of dopamine (DA) reuptake (Koe 1976) and a subsequent enhancement of DA activation via both DA D 1 and D 2 receptors (Scheel-Kruger et al. 1977;McCreary and Marsden 1993;White et al. 1998). The elevated DA neurotransmission, particularly within the mesoaccumbens pathway originating from DA soma in the ventral tegmental area (VTA) and terminating in the nucleus accumbens (NAc), is especially important in mediating the locomotor, discriminative stimulus and reinforcing effects of cocaine (for review, Amalric and Koob 1993).Despite the pronounced involvement of DA in its in vivo effects, cocaine is not a selective DA reuptake inhibitor as it binds to 5-hydroxytryptamine (5-HT) and norepinephrine (NE) transporters and inhibits the reuptake of 5-HT and NE with at least equal potency and efficacy as that of DA reuptake (Koe 1976). Recent studies of the locomotor stimulant, reinforcing and stimulus effects of cocaine suggest that enhanced 5-HT transmission and subsequent stimulation of 5-HT receptors play a modulatory role in the in vivo effects of cocaine (for reviews, see Cunningham and Callahan 1994;Walsh and Cunningham 1997).The exact contribution of specific 5-HT receptors to the behavioral profile of cocaine has not yet been fully elucidated, largely due to the multiplicity of 5-HT receptors in mammalian systems and the lack of selective Received May 13, 1998; revised August 20, 1998; accepted September 3, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 6 5-HT 2C Receptors and Cocaine Hyperactivity 557 ligands for each of the respective receptor subtypes. At least 14 5-HT receptor subtypes have been shown to exist, although the operational characteristics are unknown for some receptors (Hoyer and Martin 1997). The 5-HT 2C receptor subtype (formerly 5-HT 1C ) has received attention as a possible therapeutic target in psychiatric conditions such as psychoses and anxiety (Kennett 1993) and evidence suggests that this receptor is important in the serotonergic regulation of the mesolimbic DA system. The transcript for the 5-HT 2C receptor is richly expressed in DA somatic and terminal field regions, including the VTA and NAc (Hoffman and Mezey 1989;Eberle-Wang et al. 1997).Although not yet established for the VTA, 5-HT 2C mRNA was localized in ␥ -aminobutyric acid (GABA), but not DA, neurons in the substantia nigra suggesting that the influence of 5-HT 2C receptors on DA cell bodies may be indirect (Eberle-Wang et al. 1997). In keeping with the distribution of mRNA, ligand binding studies have demonstrated labeling of 5-HT 2C receptors in the VTA and NAc (Pazos and Palacios 1985;M...

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Cocaine-Induced Redoppuction of Glucose Utilization in Human Brain

London

Cascella

Wong

et al. 1990

Arch Gen Psychiatry

291

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We examined the effects of cocaine hydrochloride (40 mg intravenously) on regional cerebral metabolic rates for glucose and on subjective self-reports of eight polydrug abusers in a double-blind, placebo-controlled, crossover study. The regional cerebral metabolic rate for glucose was measured by the [fluorine 18]-fluorodeoxyglucose method, using positron emission tomography. With eyes covered, subjects listened to a tape that presented white noise, "beep" prompts, and questions about subjective effects of cocaine or saline. Cocaine produced euphoria and reduced glucose utilization globally (mean reduction, 14%). Twenty-six of 29 brain regions (all neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain) showed significant decrements (5% to 26%) in the regional cerebral metabolic rate for glucose. No significant effects of cocaine were observed in the pons, the cerebellar cortex, or the vermis. Right-greater-than-left hemispheric asymmetry of regional cerebral metabolic rates for glucose occurred in the lateral thalamus. The findings demonstrate that reduced cerebral metabolism is associated with cocaine-induced euphoria.

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Cocaine: Discussion on the Role of Dopamine in the Biochemical Mechanism of Action

Cited by 117 publications

References 54 publications

Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

Effects of the 5-HT2C/2B Antagonist SB 206553 on Hyperactivity Induced by Cocaine

Cocaine-Induced Redoppuction of Glucose Utilization in Human Brain

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