Analysis of information sources in references of the Wikipedia article "Hypoactivity" in English language version.
The TAAR1-selective antagonist EPPTB blocked methamphetamine- and bupropion-stimulated chloride conductance in Xenopous oocytes co-expressing mouse TAAR1 and the human cystic fibrosis transmembrane conductance regulator in a concentration-dependent manner with IC50's of 2.3±0.3nM and 4.3±0.7nM, respectively. [...] EPPTB displayed no affinity for mouse biogenic amine transporters nor did it produce a significant phenotype in wildtype or taar1-/- mice. In contrast, at the highest dose tested (100 mg/kg, i.p.) EPPTB inhibited approximately 70% of methamphetamine-stimulated (3 mg/kg, i.p.) activity in wildtype mice while having no effect on similarly treated [TAAR1] knockout mice. Intraperitoneal co-administration of methamphetamine (3 mg/kg) and bupropion (50 mg/kg) to wildtype mice produced greater activity than either drug alone, an effect absent from [TAAR1] knockout mice. [...] The existence of a methamphetamine-activated G protein-coupled receptor that is also activated by bupropion [...]
In the present experiments, two monoamine releasers, l-MA and PAL-329, were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous. For example, the subjective effects of l-MA in human studies are similar in some respects to those of d-MA. However, the subjective effects of the two isomers also differ in potentially important ways. While both l-MA and d-MA produce subjective ratings of "drug liking" and "good effects" in experienced stimulant users, only l-MA produces concomitant ratings of bad or aversive drug effects (Mendelson et al 2006), a factor which may limit its abuse liability.
Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),4 thereby enabling rapid and extensive transport across the blood–brain barrier.19
The stereoisomers of methamphetamine produce markedly different dopamine, norepinephrine, and serotonin responses in various brain regions in rats.41,42 d-Methamphetamine (2 mg/kg) is more potent in releasing caudate dopamine than l-methamphetamine (12 and 18 mg/kg). By use of in vitro uptake and release assays, d-methamphetamine (50% effective concentration [EC50], 24.5 ± 2.1 nmol/L) was 17 times more potent in releasing dopamine than l-methamphetamine (EC50, 416 ± 20 nmol/L) and significantly more potent in blocking dopamine uptake (inhibition constant [Ki ], 114 ± 11 nm versus 4840 ± 178 nm).12,13
When considered with neurochemical data that l-MA is similarly potent in releasing norepinephrine (NE) but 15- to 20-fold less potent in releasing dopamine (DA), as compared to d-MA (Kuczenski et al., 1995; Melega et al., 1999), l-MA may appear to carry lower abuse liability than d-MA.
Consistent with our past results, in response to 2 mg/kg D-AMPH, mean caudate extracellular DA increased approximately 15-fold to a peak concentration of 688 ± 121 nM during the initial 20 min interval, then returned to baseline over the next 3 hr. Similarly, in response to 2 mg/kg D-METH, DA increased to a peak concentration of 648 ± 71 nM during the initial 20 min interval and then declined toward baseline. In contrast, in response to both 6 mg/kg L-AMPH and 12 mg/kg L-METH, peak DA concentrations (508 ± 51 and 287 ± 49 nM, respectively) were delayed to the second 20 min interval, before returning toward baseline. [...] Similar to our previous results, 2 mg/kg D-AMPH increased NE to a maximum of 29.3 ± 3.1 nM, about 20-fold over baseline, during the second 20 min interval. L-AMPH (6 mg/kg) produced a comparable effect, increasing NE concentrations to 32.0 ± 8.9 nM. In contrast, D-METH promoted an increase in NE to 12.0 ± 1.2 nM which was significantly lower than all other groups, whereas L-METH promoted an increase to 64.8 ± 4.9 nM, which was significantly higher than all other groups.
The configuration of the α-methyl group is also an important determinant of the stimulant activity. The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).
There have been no studies directly comparing the pharmacodynamics and pharmacokinetics of the methamphetamine enantiomers in mice. It is often suggested that dmethamphetamine exerts more potent physiological and pharmacological effects than l-methamphetamine does, and that the stimulating effects exerted by l-methamphetamine on the central nervous system are 2–10 times less potent than those of d-methamphetamine (Mendelson et al. 2006). The results of the present study indicated that psychostimulant effects induced by l-methamphetamine are lower than those elicited by one-tenth the dose of d-methamphetamine. In addition, plasma pharmacokinetic parameters and striatal concentrations of methamphetamine following administration of l-methamphetamine at 10 mg/ kg (which did not induce psychomotor activity) were approximately 11 and 16 times as high, respectively, as those following administration of 1 mg/kg d-methamphetamine. Despite the fact that there are differentiable psycho-stimulating effects between two enantiomers, no significant difference in plasma pharmacokinetic parameters was detected at 1 mg/kg.
{{cite book}}: |journal= ignored (help)The role of DA in the abuse-related effects of psychostimulants is well established in animal models. Still, deletions of DA D1, D2, and D3 receptor genes in mice had minimal impact on MDMA-induced locomotor activity,97 and DAT inhibition did not affect neurocognitive effects of MDMA in cynomolgus monkeys.98 In humans, D2 receptor antagonists reduced amphetamine-induced and MDMA-induced euphoria only at doses that produced dysphoria on their own.99 Therefore, it seems likely that systems unrelated to DA may be principally responsible for the acute effects of MDMA.40
There is also evidence to support our finding that administration of SB 242084 alone induces stimulant-like effects, because administration of a high dose of SB 242084 (1.0 mg/kg) significantly increased basal locomotor activity in rats (Zaniewska et al., 2009). [...] This discrepancy may be accounted for by highlighting the tested dose range within each experiment. For example, the dose of SB 242084 used for reinstatement experiments in the previous rodent study (0.5 mg/kg) also failed to induce significant locomotor effects (Fletcher et al., 2002). However, increasing the dose of SB 242084 to 1.0 mg/kg did produce a modest, but significant, effect on locomotor activity in a separate study (Zaniewska et al., 2009).
In addition to enhanced dopamine release, TAAR1-KO mice show enhanced hyperlocomotion in response to psychostimulant drugs including amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) [19,20,41,55], as well as to drugs that increase monoamine levels, such as MAO inhibitors [56]. By contrast, TAAR1-OE animals are hyposensitive to the stimulatory effects of amphetamine [54] in comparison to wild-type animals. [...] Three TAAR1 full agonists, RO5166017, RO5256390, and SEP-363856, were all able to prevent psychostimulant-induced hyperlocomotion in wild-type but not TAAR1-KO mice [47,78,79].
Most notably, Caron & Gainetdinov (personal communication) have recently observed that group-housed TA1 KO mice show enhanced sensitivity to the locomotor stimulating effects of both amphetamine and b-PEA relative to group-housed WT littermates, as well as normal habituation to an open field.
Psychostimulants like cocaine and d-amphetamine interact with the DA transporter (DAT) to elevate extracellular DA concentration. In rodents, this translates into excessive [locomotor activity (LMA)] (Figures 2A, B; Figure S3A, B in Supplement 1), the reversal of which can be used to predict the potential antipsychotic activity of drugs (22). RO5203648 given orally reduced hyperlocomotion in both rats and mice treated with cocaine (Figure 2A, B), although not at the highest dose in mice (10 mg/kg). RO5203648 reduced d-amphetamine-induced hyperlocomotion by one half at a high dose (30 mg/kg) in rats, whereas in mice it had no effect at the doses tested (Figure S3A, B in Supplement 1).
[...] EPPTB's effect on the spontaneous locomotor activity in a familiar environment displayed by WT and taar1-deficient mice chronically exposed to 3 mg/kg METH (i.p.) over a range of doses was examined. The results of this study (Grandy, 2014; SfN abstracts) support the interpretation that EPPTB prevents to a significant degree METH-stimulated locomotor activity but only in WT mice with a history of chronic METH exposure.
It was found that visual stimulation of rats with white-light of 82 lux intensity induced locomotor activity and increased extracellular 5-HT and dopamine (DA) levels in the visual cortex (Müller et al., 2007a; Müller and Huston, 2007) and 5-HT in the medial prefrontal cortex (Pum et al., 2008). The 5-HT and DA increase were also seen in anesthetized animals (Pum et al., 2008). Cocaine, which induces serotonergic and dopaminergic activation (Izenwasser et al., 1990; Müller and Homberg, 2015), potentiates [light-induced locomotor activity (LIA)] (Pum et al., 2011).
In the present experiments, two monoamine releasers, l-MA and PAL-329, were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous. For example, the subjective effects of l-MA in human studies are similar in some respects to those of d-MA. However, the subjective effects of the two isomers also differ in potentially important ways. While both l-MA and d-MA produce subjective ratings of "drug liking" and "good effects" in experienced stimulant users, only l-MA produces concomitant ratings of bad or aversive drug effects (Mendelson et al 2006), a factor which may limit its abuse liability.
Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),4 thereby enabling rapid and extensive transport across the blood–brain barrier.19
The stereoisomers of methamphetamine produce markedly different dopamine, norepinephrine, and serotonin responses in various brain regions in rats.41,42 d-Methamphetamine (2 mg/kg) is more potent in releasing caudate dopamine than l-methamphetamine (12 and 18 mg/kg). By use of in vitro uptake and release assays, d-methamphetamine (50% effective concentration [EC50], 24.5 ± 2.1 nmol/L) was 17 times more potent in releasing dopamine than l-methamphetamine (EC50, 416 ± 20 nmol/L) and significantly more potent in blocking dopamine uptake (inhibition constant [Ki ], 114 ± 11 nm versus 4840 ± 178 nm).12,13
When considered with neurochemical data that l-MA is similarly potent in releasing norepinephrine (NE) but 15- to 20-fold less potent in releasing dopamine (DA), as compared to d-MA (Kuczenski et al., 1995; Melega et al., 1999), l-MA may appear to carry lower abuse liability than d-MA.
Consistent with our past results, in response to 2 mg/kg D-AMPH, mean caudate extracellular DA increased approximately 15-fold to a peak concentration of 688 ± 121 nM during the initial 20 min interval, then returned to baseline over the next 3 hr. Similarly, in response to 2 mg/kg D-METH, DA increased to a peak concentration of 648 ± 71 nM during the initial 20 min interval and then declined toward baseline. In contrast, in response to both 6 mg/kg L-AMPH and 12 mg/kg L-METH, peak DA concentrations (508 ± 51 and 287 ± 49 nM, respectively) were delayed to the second 20 min interval, before returning toward baseline. [...] Similar to our previous results, 2 mg/kg D-AMPH increased NE to a maximum of 29.3 ± 3.1 nM, about 20-fold over baseline, during the second 20 min interval. L-AMPH (6 mg/kg) produced a comparable effect, increasing NE concentrations to 32.0 ± 8.9 nM. In contrast, D-METH promoted an increase in NE to 12.0 ± 1.2 nM which was significantly lower than all other groups, whereas L-METH promoted an increase to 64.8 ± 4.9 nM, which was significantly higher than all other groups.
There have been no studies directly comparing the pharmacodynamics and pharmacokinetics of the methamphetamine enantiomers in mice. It is often suggested that dmethamphetamine exerts more potent physiological and pharmacological effects than l-methamphetamine does, and that the stimulating effects exerted by l-methamphetamine on the central nervous system are 2–10 times less potent than those of d-methamphetamine (Mendelson et al. 2006). The results of the present study indicated that psychostimulant effects induced by l-methamphetamine are lower than those elicited by one-tenth the dose of d-methamphetamine. In addition, plasma pharmacokinetic parameters and striatal concentrations of methamphetamine following administration of l-methamphetamine at 10 mg/ kg (which did not induce psychomotor activity) were approximately 11 and 16 times as high, respectively, as those following administration of 1 mg/kg d-methamphetamine. Despite the fact that there are differentiable psycho-stimulating effects between two enantiomers, no significant difference in plasma pharmacokinetic parameters was detected at 1 mg/kg.
{{cite book}}: |journal= ignored (help)There is also evidence to support our finding that administration of SB 242084 alone induces stimulant-like effects, because administration of a high dose of SB 242084 (1.0 mg/kg) significantly increased basal locomotor activity in rats (Zaniewska et al., 2009). [...] This discrepancy may be accounted for by highlighting the tested dose range within each experiment. For example, the dose of SB 242084 used for reinstatement experiments in the previous rodent study (0.5 mg/kg) also failed to induce significant locomotor effects (Fletcher et al., 2002). However, increasing the dose of SB 242084 to 1.0 mg/kg did produce a modest, but significant, effect on locomotor activity in a separate study (Zaniewska et al., 2009).
In addition to enhanced dopamine release, TAAR1-KO mice show enhanced hyperlocomotion in response to psychostimulant drugs including amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) [19,20,41,55], as well as to drugs that increase monoamine levels, such as MAO inhibitors [56]. By contrast, TAAR1-OE animals are hyposensitive to the stimulatory effects of amphetamine [54] in comparison to wild-type animals. [...] Three TAAR1 full agonists, RO5166017, RO5256390, and SEP-363856, were all able to prevent psychostimulant-induced hyperlocomotion in wild-type but not TAAR1-KO mice [47,78,79].
Most notably, Caron & Gainetdinov (personal communication) have recently observed that group-housed TA1 KO mice show enhanced sensitivity to the locomotor stimulating effects of both amphetamine and b-PEA relative to group-housed WT littermates, as well as normal habituation to an open field.
Psychostimulants like cocaine and d-amphetamine interact with the DA transporter (DAT) to elevate extracellular DA concentration. In rodents, this translates into excessive [locomotor activity (LMA)] (Figures 2A, B; Figure S3A, B in Supplement 1), the reversal of which can be used to predict the potential antipsychotic activity of drugs (22). RO5203648 given orally reduced hyperlocomotion in both rats and mice treated with cocaine (Figure 2A, B), although not at the highest dose in mice (10 mg/kg). RO5203648 reduced d-amphetamine-induced hyperlocomotion by one half at a high dose (30 mg/kg) in rats, whereas in mice it had no effect at the doses tested (Figure S3A, B in Supplement 1).
[...] EPPTB's effect on the spontaneous locomotor activity in a familiar environment displayed by WT and taar1-deficient mice chronically exposed to 3 mg/kg METH (i.p.) over a range of doses was examined. The results of this study (Grandy, 2014; SfN abstracts) support the interpretation that EPPTB prevents to a significant degree METH-stimulated locomotor activity but only in WT mice with a history of chronic METH exposure.
It was found that visual stimulation of rats with white-light of 82 lux intensity induced locomotor activity and increased extracellular 5-HT and dopamine (DA) levels in the visual cortex (Müller et al., 2007a; Müller and Huston, 2007) and 5-HT in the medial prefrontal cortex (Pum et al., 2008). The 5-HT and DA increase were also seen in anesthetized animals (Pum et al., 2008). Cocaine, which induces serotonergic and dopaminergic activation (Izenwasser et al., 1990; Müller and Homberg, 2015), potentiates [light-induced locomotor activity (LIA)] (Pum et al., 2011).
In the present experiments, two monoamine releasers, l-MA and PAL-329, were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous. For example, the subjective effects of l-MA in human studies are similar in some respects to those of d-MA. However, the subjective effects of the two isomers also differ in potentially important ways. While both l-MA and d-MA produce subjective ratings of "drug liking" and "good effects" in experienced stimulant users, only l-MA produces concomitant ratings of bad or aversive drug effects (Mendelson et al 2006), a factor which may limit its abuse liability.
When considered with neurochemical data that l-MA is similarly potent in releasing norepinephrine (NE) but 15- to 20-fold less potent in releasing dopamine (DA), as compared to d-MA (Kuczenski et al., 1995; Melega et al., 1999), l-MA may appear to carry lower abuse liability than d-MA.
Consistent with our past results, in response to 2 mg/kg D-AMPH, mean caudate extracellular DA increased approximately 15-fold to a peak concentration of 688 ± 121 nM during the initial 20 min interval, then returned to baseline over the next 3 hr. Similarly, in response to 2 mg/kg D-METH, DA increased to a peak concentration of 648 ± 71 nM during the initial 20 min interval and then declined toward baseline. In contrast, in response to both 6 mg/kg L-AMPH and 12 mg/kg L-METH, peak DA concentrations (508 ± 51 and 287 ± 49 nM, respectively) were delayed to the second 20 min interval, before returning toward baseline. [...] Similar to our previous results, 2 mg/kg D-AMPH increased NE to a maximum of 29.3 ± 3.1 nM, about 20-fold over baseline, during the second 20 min interval. L-AMPH (6 mg/kg) produced a comparable effect, increasing NE concentrations to 32.0 ± 8.9 nM. In contrast, D-METH promoted an increase in NE to 12.0 ± 1.2 nM which was significantly lower than all other groups, whereas L-METH promoted an increase to 64.8 ± 4.9 nM, which was significantly higher than all other groups.
There have been no studies directly comparing the pharmacodynamics and pharmacokinetics of the methamphetamine enantiomers in mice. It is often suggested that dmethamphetamine exerts more potent physiological and pharmacological effects than l-methamphetamine does, and that the stimulating effects exerted by l-methamphetamine on the central nervous system are 2–10 times less potent than those of d-methamphetamine (Mendelson et al. 2006). The results of the present study indicated that psychostimulant effects induced by l-methamphetamine are lower than those elicited by one-tenth the dose of d-methamphetamine. In addition, plasma pharmacokinetic parameters and striatal concentrations of methamphetamine following administration of l-methamphetamine at 10 mg/ kg (which did not induce psychomotor activity) were approximately 11 and 16 times as high, respectively, as those following administration of 1 mg/kg d-methamphetamine. Despite the fact that there are differentiable psycho-stimulating effects between two enantiomers, no significant difference in plasma pharmacokinetic parameters was detected at 1 mg/kg.
There is also evidence to support our finding that administration of SB 242084 alone induces stimulant-like effects, because administration of a high dose of SB 242084 (1.0 mg/kg) significantly increased basal locomotor activity in rats (Zaniewska et al., 2009). [...] This discrepancy may be accounted for by highlighting the tested dose range within each experiment. For example, the dose of SB 242084 used for reinstatement experiments in the previous rodent study (0.5 mg/kg) also failed to induce significant locomotor effects (Fletcher et al., 2002). However, increasing the dose of SB 242084 to 1.0 mg/kg did produce a modest, but significant, effect on locomotor activity in a separate study (Zaniewska et al., 2009).
[...] EPPTB's effect on the spontaneous locomotor activity in a familiar environment displayed by WT and taar1-deficient mice chronically exposed to 3 mg/kg METH (i.p.) over a range of doses was examined. The results of this study (Grandy, 2014; SfN abstracts) support the interpretation that EPPTB prevents to a significant degree METH-stimulated locomotor activity but only in WT mice with a history of chronic METH exposure.
Another potential determinant for increased abuse potential of MARs is selectivity for DA versus NE. Although DA is well-established to be a key neurotransmitter in mediating abuse-related effects of monoamine releasers and other drugs (for review, Leshner and Koob, 1999), amphetamine and other abused monoamine releasers have slightly (2 to 3x) higher potency to release NE than DA (Rothman et al., 2001). Moreover, methamphetamine self-administration in rats was relatively resistant to pretreatment with DA-antagonists (Brennan et al., 2009), and ephedrine (a 19-fold NE-selective releaser) has been shown to maintain self-administration in monkeys (Anderson et al., 2001) and substitute for amphetamine (Young et al., 1998) and methamphetamine (Bondareva et al., 2002) in drug discrimination studies in rats. Perhaps the most compelling data on the importance of NE comes from human subjects where amphetamine-like discriminative stimuli produced by monoamine releasers correlate with potency to release NE, not DA (Rothman et al., 2001). [...] There is also evidence of noradrenergic innervation of the dopaminergic system (Geisler and Zahm, 2005; Jones and Moore, 1977). Electrical stimulation of the locus coeruleus (LC) neurons increased levels of NE in the VTA and increased activity of DA neurons (Grenhoff et al., 1993). However, when exogenous NE was applied to the VTA, a decrease in firing rates of DA neurons was seen (Aghajanian and Bunney, 1977; White and Wang, 1984). Similar to the results of the latter study, lesions of the NE system by injection of 6-OHDA into the locus coeruleus increased firing of DA neurons in the VTA by 70% (Guiard et al., 2008). These data suggest that there may be both excitatory and inhibitory roles of NE on the activity of VTA dopaminergic neurons. [...] The receptors by which NE modulates DA at the level of the VTA are fairly well characterized. In particular, it appears that the α-1 receptor is responsible for increases in DA neuron firing following NE administration while the α-2 receptor mediates the inhibitory effects of NE (Grenhoff and Svensson, 1988; Grenhoff and Svensson 1989; Grenhoff and Svensson, 1993; Grenhoff et al., 1995). In addition to the α-2 receptor, it appears that NE can act directly on D2 dopaminergic autoreceptors to produce inhibitory effects (Grenhoff et al., 1995; Lacey et al., 1987; Arencibia-Albite et al., 2007; Guiard et al., 2008). ß-adrenoreceptors are not known to exist in the VTA (Grenhoff et al., 1995; Jones et al., 1990) and ß-adrenergic compounds do not mediate the effects of NE in the VTA (Grenhoff et al., 1995).
The role of DA in the abuse-related effects of psychostimulants is well established in animal models. Still, deletions of DA D1, D2, and D3 receptor genes in mice had minimal impact on MDMA-induced locomotor activity,97 and DAT inhibition did not affect neurocognitive effects of MDMA in cynomolgus monkeys.98 In humans, D2 receptor antagonists reduced amphetamine-induced and MDMA-induced euphoria only at doses that produced dysphoria on their own.99 Therefore, it seems likely that systems unrelated to DA may be principally responsible for the acute effects of MDMA.40