In Vivo Effects of Amphetamine Analogs Reveal Evidence for Serotonergic Inhibition of Mesolimbic Dopamine Transmission in the Rat

Abstract

Evidence suggests that elevations in extracellular serotonin (5-HT) in the brain can diminish stimulant effects of dopamine (DA). To assess this proposal, we evaluated the pharmacology of amphetamine analogs (m-fluoroamphetamine, p-fluoroamphetamine, m-methylamphetamine, p-methylamphetamine), which display similar in vitro potency as DA releasers (EC 50 ϭ 24 -52 nM) but differ in potency as 5-HT releasers (EC 50 ϭ 53-1937 nM). In vivo microdialysis was used to assess the effects of drugs on extracellular DA and 5-HT in rat nucleus accumbens, while simultaneously measuring ambulation (i.e., forward locomotion) and stereotypy (i.e., repetitive movements). Rats received two intravenous injections of drug, 1 mg/kg at time 0 followed by 3 mg/kg 60 min later. All analogs produced dose-related increases in dialysate DA and 5-HT, but the effects on DA did not agree with in vitro predictions. Maximal elevation of dialysate DA ranged from 5-to 14-fold above baseline and varied inversely with 5-HT response, which ranged from 6-to 24-fold above baseline. All analogs increased ambulation and stereotypy, but drugs causing greater 5-HT release (e.g., p-methylamphetamine) were associated with significantly less forward locomotion. The magnitude of ambulation was positively correlated with extracellular DA (p Ͻ 0.001) and less so with the ratio of DA release to 5-HT release (i.e., percentage DA increase divided by percentage 5-HT increase) (p Ͻ 0.029). Collectively, our findings are consistent with the hypothesis that 5-HT release dampens stimulant effects of amphetamine-type drugs, but further studies are required to address the precise mechanisms underlying this phenomenon.

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

“…Collectively, the potent and efficacious actions of MDPV on extracellular dopamine and motor activity suggest a high potential for abuse. The fact that MDPV has weak effects on SERT may further enhance its reinforcing properties, as substantial evidence indicates that elevations in synaptic 5-HT can dampen stimulant effects mediated by DA (Wee et al, 2005;Baumann et al, 2011). A recent study by Watterson et al (2012) demonstrates that MDPV is readily self-administered by rats, and the range of self-injected doses (0.05-0.20 mg/ kg, i.v.)…”

“…It is well established that drug-induced elevations in extracellular dopamine in the nucleus accumbens are involved with locomotor-activating properties of stimulant drugs (Ikemoto, 2002;Pennartz et al, 1994). Our previous 3,4-Methylenedioxypyrovalerone and monoamine transportersexperiments examining stimulant drug effects in rats have shown strong positive correlations between dialysate dopamine responses and the extent of hyperactivity (Baumann et al, 2011;Zolkowska et al, 2009). The present data show that MDPV produces robust dose-related forward locomotion and stereotypy.…”

“…On the next morning, dialysate samples were collected at 20-min intervals. Samples were immediately assayed for dopamine by HPLC-ECD as described elsewhere (Baumann et al, 2011). Rats were randomly assigned to groups receiving either drug or saline injections.…”

Serotonin is involved in the psychostimulant and hypothermic effect of 4-methylamphetamine in rats

“…The reported human toxicity is most likely the result of the combined dopaminergic activity of amphetamine and the serotonergic activity of 4-MA [2]. In this regard, it was described a massive adrenergic overstimulation just after inhaling material, which had been purchased in the belief that it was amphetamine but also contained 4-MA and dimethyl-amphetamine [3].…”

“…It has been speculated that, compared to amphetamine, the most pronounced serotonergic action of 4-MA could diminish the psychoactive effects of amphetamine leading to the consumption of repeated and higher doses of contaminated amphetamine [2]. Serotonin (5-HT) in the hypothalamus is involved in the regulation of body temperature [6].…”