Changes in feeding and locomotion induced by amphetamine analogs in rats

Abstract

Studies of the biobehavioral actions of psychostimulants commonly focus on locomotion and less commonly on feeding, and only rarely are these measures considered in conjunction within the same animal. The present study compared the impact of (+)-amphetamine and three amphetamine analogs, PAL-287, PAL-313, and PAL-353, on eating and locomotion assessed concurrently using an automated activity/feeding chamber during a daily 45 min session. Each analog is a potent releaser of norepinephrine and of dopamine, but exerts differential serotonin releasing activity (PAL-287 > PAL-313 > amphetamine > PAL-353). Rats were tested with each of five doses of drug (0, 2, 4, 8, or 16 umol/kg, i.p.), given in equimolar concentrations and in random dose order. PAL-353, an analog with minimal serotonin-relasing capacity, markedly stimulated forward locomotion at 2, 4, 8 and 16 umol/kg, as did amphetamine, whereas PAL-287 and PAL-313 did not. In contrast to the locomotor findings, all four amphetamine-like drugs exerted similar effects on the suppression of food intake. These results suggest that the capacity of an amphetamine analog (i.e. amphetamine and PAL-353) to stimulate serotonin release can diminish its psychostimulant action on locomotion, but does not reliably augment drug-induced hypophagia.

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

“…The present behavioral data are reminiscent of those reported by Wellman et al (2009), who compared locomotor and hypophagic effects of (ϩ)-amphetamine, PAL-353, PAL-313, and the preferential 5-HT releaser 1-naphthyl-2-amino- propane (PAL-287) in male rats. Those investigators found that PAL-353 produced robust hyperactivity similar to (ϩ)-amphetamine, whereas PAL-313 was much less potent and had effects similar to PAL-287 (Rothman et al, 2005).…”

“…The selectivity for DA release versus 5-HT release for these drugs ranges from 80-fold DA-selective for m-fluoroamphetamine (PAL-353) to nonselective for p-methylamphetamine (PAL-313) (see Table 1). Various behavioral effects of these analogs in rats and nonhuman primates have been reported (Wee et al, 2005;Negus et al, 2007;Kimmel et al, 2009;Wellman et al, 2009), andKimmel et al (2009) used in vivo microdialysis in squirrel monkey nucleus accumbens to demonstrate that PAL-313 evokes significantly less DA release than PAL-353. It is noteworthy that PAL-313 supports less self-administration behavior in rhesus monkeys compared with other PAL analogs, but the precise role of DA and 5-HT in mediating differences in behavioral responsiveness to these drugs remains unclear.…”

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

“…Wellman et al compared the psychostimulant effect of three amphetamine analogues, including 4-MA [5]. They concluded that 4-MA had a very low effect on locomotion that is attributed to a high activity at 5-HT transporter.…”

“…There are very few published studies on the pharmacology of 4-MA in laboratory animals [4,5]. 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].…”

New Synthetic Drugs in Addictovigilance

“…[15,16] Regarding behaviour, in rats and monkeys it has anorectic effects comparable to those of Damphetamine, it increases locomotor activity very little or not at all, and has low positive reinforcement potential. [14,16,17] In humans, in a clinical study implemented in 1950, at doses of 1.5 and 2 mg/kg, anorexia, sweating, nausea and vomiting, elevated blood pressure, hypersialosis, abdominal pain, cough and bronchorrhea were all observed. [18] In its report on the evaluation of risks linked to 4-MA in 2014, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) reported 20 cases on non-fatal acute toxicity in 5 European countries, and 21 cases of death backed up by toxicology analyses, having occurred in Belgium, Denmark, Netherlands and UK since 2010.…”