Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine‐Type Drugs

Abstract

The abuse of illicit stimulants is a worldwide crisis, yet few medicines are available for treating stimulant addiction. We have advocated the idea of "agonist therapy" for cocaine dependence. This strategy involves administration of stimulant-like medications (e.g., monoamine releasers) to alleviate cocaine withdrawal symptoms and prevent relapse. A chief limitation of this strategy is that many candidate medicines possess high abuse liability due to activation of mesolimbic dopamine (DA) neurons in reward pathways. Evidence suggests that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is a critical variable when developing medications with reduced stimulant side effects. In this article, we review recent studies from our laboratory that examined neurochemical and behavioral effects of a series of monoamine releasers which displayed different potencies at DA and 5-HT transporters. The data show that increasing 5-HT release can attenuate stimulant effects mediated by DA release, such as motor stimulation and drug self-administration. Our findings support the work of others and indicate that elevated synaptic 5-HT can dampen certain behavioral effects of DA-releasing agents. Moreover, the relationship between DA and 5-HT releasing potency is an important determinant in developing new agonist medications with reduced stimulant properties.

Prenatal Stress Enhances Responsiveness to Cocaine

“…In particular, enhanced dopamine (basal and stimulated) and low basal with greater stimulated glutamate have been implicated in the sensitized locomotor response observed following repeated psychostimulant drug treatments (Heidbreder et al, 1996;Hooks et al, 1994;Kalivas and Duffy, 1993;Pierce et al, 1996;Reid and Berger, 1996;Szumlinski et al, 2006) and probably contribute to the presensitized behavioral responding of PNS rats. Further, serotonin inhibits dopamine (eg Rothman and Baumann, 2006) and glutamate (Szumlinski et al, 2004) transmission in the NAC. Thus, our observed reduction in overall serotonin levels in cocaine-naïve PNS rats could facilitate dopamine and glutamate in this region.…”

Comparative potencies of 3,4‐methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5‐HT transport in mammalian cell lines

“…In light of the central role of monoamine transporters in mediating the pharmacological actions of MDMA, it was decided to investigate the effects of the MDMA analogues on NET and SERT transport in vitro, using two separate mammalian cell lines. Although the significance of DAT in mediating both the physiological and potentially toxicological effects of MDMA should not be underestimated (Colado et al, 2004;Breier et al, 2006;Rothman and Baumann, 2006), MDMA has typically demonstrated a greater inhibitory potency at NET and SERT compared to DAT in vitro (Rothman and Baumann, 2003;Pifl et al, 2005;Verrico et al, 2005). Consequently, it was decided to perform this investigation using NET and SERT.…”

Seven fatalities associated with ethylphenidate

“…The increase in locomotor activity is commonly used, among other in vivo tests (such as self-stimulation) as an indicator of abuse potential [28]. The increase in motor activity suggesting that ethylphenidate has abuse potential, further evidence can be found from the ratio of DAT/SERT inhibition with higher ratios thought to indicate a higher abuse potential [29]. From in vitro data [26] both (-/+) and (+) ethylphenidate have a DAT/SERT ratio of >105 indicating a high abuse potential, this is backed up by case studies where users of ethylphenidate feel the need to redose [8,9].…”