Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor

Abstract

There is a greater prevalence of cigarette smoking among cocaine‐dependent individuals and hyperactive children treated with stimulants (e.g., methylphenidate, MP). However, little is known about the neurochemical basis of the interaction between nicotine and cocaine or MP. It is thought that the reinforcing effects of cocaine and MP are due partly to increases in synaptic DA in the nucleus accumbens (NAc). These measurable increases are secondary to the blockade of the DA transporter. In contrast, nicotine stimulates acetylcholine receptors located presynaptically on dopaminergic projections from the ventral tegmental area (VTA) to the NAc and increases DA transmission. Here we investigate the effects of nicotine on NAc DA in animals simultaneously injected with cocaine or MP. Coadministration of nicotine (0.4 mg/kg s.c.) and cocaine (10 mg/kg i.p.) or MP (5 mg/kg i.p.) increased the extracellular NAc DA levels in an additive manner, while coadministration of nicotine (0.4 mg/kg s.c.) and a higher dose of cocaine (20 mg/kg) or MP (10 mg/kg) clearly produced a synergistic elevation in NAc DA. These findings suggest that the degree of DA transporter (DAT) occupancy contributes to the synergistic interaction between nicotine and cocaine or MP. Synapse 38:432–437, 2000. © 2000 Wiley‐Liss, Inc.

Long-Term Effects of Chronic Oral Ritalin Administration on Cognitive and Neural Development in Adolescent Wistar Kyoto Rats

“…From the second week of treatment there was no increase in activity with MPH administration. It might also be expected that chronic treatment with this psychostimulant would produce enhanced or "sensitized" locomotor activity [48], however the lack of sensitized response in the current study is consistent with previous research reporting no increase in locomotor activity following acute therapeutic doses of MPH in "normal" rats [13,44]. Similar findings have also been reported following amphetamine dosing at a therapeutic level [49].…”

“…However, as we have previously shown in this laboratory [68], WKYs were not found to be hypoactive compared to SHRs in operant tasks. Furthermore, the behavioural stimulation following the high oral dose of MPH administration to WKYs in the present study was consistent with increased locomotor activity observed in Sprague-Dawley rats following equivalent dosing [44]. It would be prudent to include additional "normal" rat strains to establish that reported group differences are not the result of deficits in the WKY.…”

Long-Term Effects of Chronic Oral Ritalin Administration on Cognitive and Neural Development in Adolescent Wistar Kyoto Rats

“…From the second week of treatment there was no increase in activity with MPH administration. It might also be expected that chronic treatment with this psychostimulant would produce enhanced or "sensitized" locomotor activity [48], however the lack of sensitized response in the current study is consistent with previous research reporting no increase in locomotor activity following acute therapeutic doses of MPH in "normal" rats [13,44]. Similar findings have also been reported following amphetamine dosing at a therapeutic level [49].…”

“…However, as we have previously shown in this laboratory [68], WKYs were not found to be hypoactive compared to SHRs in operant tasks. Furthermore, the behavioural stimulation following the high oral dose of MPH administration to WKYs in the present study was consistent with increased locomotor activity observed in Sprague-Dawley rats following equivalent dosing [44]. It would be prudent to include additional "normal" rat strains to establish that reported group differences are not the result of deficits in the WKY.…”

A pharmacological analysis of stimulant-induced increases in smoking

“…Nicotine increases extracellular dopamine levels in these areas indirectly via activation of nicotinic acetylcholine receptors located at presynaptic dopaminergic terminals in the ventral tegmental area (Hamada et al 2004). An additive or synergistic increase in mesocorticolimbic dopamine levels might explain the methylphenidate-induced increases in smoking observed in the present as well as the previous experiment (Gerasimov et al 2000;HustonLyons et al 1993;Rush et al 2005). Consistent with this notion, the results of one study demonstrated that methylphenidate augments the reinforcing, discriminative-stimulus, and locomotor-activating effects of nicotine in rats (Wooters et al 2007).…”

Effects of chronic treatment with bupropion on self-administration of nicotine + cocaine mixtures in nonhuman primates.

“…However, decreases in nicotine ϩ cocaine selfadministration during treatment with varenicline was dependent on the dose of cocaine, that is, when the nicotine ϩ cocaine mixtures contained a proportionally high concentration of cocaine, varenicline was ineffective (Mello, Fivel, Kohut, & Carroll, 2014) suggesting that varenicline may not be effective in limiting nicotine ϩ cocaine use. This result was consistent with other studies conducted in rhesus monkeys that demonstrate varenicline increases self-administration of cocaine (Gould, Czoty, Nader, & Nader, 2011; though see Mello, Fivel, Kohut, & Carroll, 2014). Identifying medications that target the mechanisms of both nicotine and cocaine may be a more effective strategy.…”

Long-Term Effects of Chronic Oral Ritalin Administration on Cognitive and Neural Development in Adolescent Wistar Kyoto Rats

“…From the second week of treatment there was no increase in activity with MPH administration. It might also be expected that chronic treatment with this psychostimulant would produce enhanced or "sensitized" locomotor activity [48], however the lack of sensitized response in the current study is consistent with previous research reporting no increase in locomotor activity following acute therapeutic doses of MPH in "normal" rats [13,44]. Similar findings have also been reported following amphetamine dosing at a therapeutic level [49].…”

“…However, as we have previously shown in this laboratory [68], WKYs were not found to be hypoactive compared to SHRs in operant tasks. Furthermore, the behavioural stimulation following the high oral dose of MPH administration to WKYs in the present study was consistent with increased locomotor activity observed in Sprague-Dawley rats following equivalent dosing [44]. It would be prudent to include additional "normal" rat strains to establish that reported group differences are not the result of deficits in the WKY.…”

A pharmacological analysis of stimulant-induced increases in smoking

“…Nicotine increases extracellular dopamine levels in these areas indirectly via activation of nicotinic acetylcholine receptors located at presynaptic dopaminergic terminals in the ventral tegmental area (Hamada et al 2004). An additive or synergistic increase in mesocorticolimbic dopamine levels might explain the methylphenidate-induced increases in smoking observed in the present as well as the previous experiment (Gerasimov et al 2000;HustonLyons et al 1993;Rush et al 2005). Consistent with this notion, the results of one study demonstrated that methylphenidate augments the reinforcing, discriminative-stimulus, and locomotor-activating effects of nicotine in rats (Wooters et al 2007).…”

Effects of chronic treatment with bupropion on self-administration of nicotine + cocaine mixtures in nonhuman primates.

“…However, decreases in nicotine ϩ cocaine selfadministration during treatment with varenicline was dependent on the dose of cocaine, that is, when the nicotine ϩ cocaine mixtures contained a proportionally high concentration of cocaine, varenicline was ineffective (Mello, Fivel, Kohut, & Carroll, 2014) suggesting that varenicline may not be effective in limiting nicotine ϩ cocaine use. This result was consistent with other studies conducted in rhesus monkeys that demonstrate varenicline increases self-administration of cocaine (Gould, Czoty, Nader, & Nader, 2011; though see Mello, Fivel, Kohut, & Carroll, 2014). Identifying medications that target the mechanisms of both nicotine and cocaine may be a more effective strategy.…”

Long-Term Effects of Chronic Oral Ritalin Administration on Cognitive and Neural Development in Adolescent Wistar Kyoto Rats

“…From the second week of treatment there was no increase in activity with MPH administration. It might also be expected that chronic treatment with this psychostimulant would produce enhanced or "sensitized" locomotor activity [48], however the lack of sensitized response in the current study is consistent with previous research reporting no increase in locomotor activity following acute therapeutic doses of MPH in "normal" rats [13,44]. Similar findings have also been reported following amphetamine dosing at a therapeutic level [49].…”

“…However, as we have previously shown in this laboratory [68], WKYs were not found to be hypoactive compared to SHRs in operant tasks. Furthermore, the behavioural stimulation following the high oral dose of MPH administration to WKYs in the present study was consistent with increased locomotor activity observed in Sprague-Dawley rats following equivalent dosing [44]. It would be prudent to include additional "normal" rat strains to establish that reported group differences are not the result of deficits in the WKY.…”

A pharmacological analysis of stimulant-induced increases in smoking

“…Nicotine increases extracellular dopamine levels in these areas indirectly via activation of nicotinic acetylcholine receptors located at presynaptic dopaminergic terminals in the ventral tegmental area (Hamada et al 2004). An additive or synergistic increase in mesocorticolimbic dopamine levels might explain the methylphenidate-induced increases in smoking observed in the present as well as the previous experiment (Gerasimov et al 2000;HustonLyons et al 1993;Rush et al 2005). Consistent with this notion, the results of one study demonstrated that methylphenidate augments the reinforcing, discriminative-stimulus, and locomotor-activating effects of nicotine in rats (Wooters et al 2007).…”

Effects of chronic treatment with bupropion on self-administration of nicotine + cocaine mixtures in nonhuman primates.

“…However, decreases in nicotine ϩ cocaine selfadministration during treatment with varenicline was dependent on the dose of cocaine, that is, when the nicotine ϩ cocaine mixtures contained a proportionally high concentration of cocaine, varenicline was ineffective (Mello, Fivel, Kohut, & Carroll, 2014) suggesting that varenicline may not be effective in limiting nicotine ϩ cocaine use. This result was consistent with other studies conducted in rhesus monkeys that demonstrate varenicline increases self-administration of cocaine (Gould, Czoty, Nader, & Nader, 2011; though see Mello, Fivel, Kohut, & Carroll, 2014). Identifying medications that target the mechanisms of both nicotine and cocaine may be a more effective strategy.…”