Comparison of (+)‐methamphetamine, ±‐Methylenedioxymethamphetamine, (+)‐amphetamine and ±‐fenfluramine in rats on egocentric learning in the Cincinnati water maze

Abstract

Abstract(+)-Methamphetamine (MA), (±)-3,4-methylenedioxymethamphetamine (MDMA), (+)-amphetamine (AMPH), and (±)-fenfluramine (FEN) are phenylethylamines with CNS effects. At higher doses, each induces protracted reductions in brain dopamine and/or serotonin. Chronic MA and MDMA users show persistent monoamine reductions and cognitive impairments. In rats, similar neurochemical effects can be induced, yet cognitive impairments have been difficult to demonstrate. We recently showed that rats treated on a single day with MA (10 mg/kg × 4 at 2 h intervals) exhibit impaired egocentric learning (Cincinnati water maze; CWM) without affecting spatial learning (Morris water maze) . Whether this effect is unique to MA or is a general characteristic of these drugs is unknown. Accordingly, this experiment compared these drugs on CWM performance. Drugs were given s.c. in four doses at 2 h intervals. MA doses were 10 or 12.5 mg/kg/dose, AMPH 25 mg/kg/dose (to match MA12.5-induced hyperthermia), MDMA 15 mg/kg/dose (previously established hyperthermia-inducing dose), and FEN 16.5 mg/kg/dose (equimolar to MA12.5). Two weeks later, rats were tested in the CWM (2 trials/day, 21 days). AMPH and MA (both doses) induced significant increases in CWM errors and latency to reach the goal with no differences in swim speed. MDMA and FEN did not significantly alter learning. Given that FEN selectively and MDMA preferentially affect serotonin whereas AMPH selectively and MA preferentially affect dopamine, the data suggest that egocentric learning may be predominantly dopaminergically-mediated.

Dorsal striatal dopamine depletion impairs both allocentric and egocentric navigation in rats

“…This finding is consistent with data that drugs that target DA systems and produce decreases in DA levels affect CWM performance, while drugs that preferentially act on 5-HT do not (Herring et al, 2008;Herring et al, 2010;Vorhees et al, 2010b). However, drugs such as methamphetamine affect DA, 5-HT, and glutamate making it unclear which mechanism contributes most to the effect of the drug on route-based navigation.…”

“…CWM deficits are observed under infrared conditions following exposure to drugs that reduce the levels of neostriatal dopamine (DA) (i.e., (+)-methamphetamine and (+)-amphetamine), but not to drugs that primarily reduce the levels of forebrain serotonin (5-HT) (i.e., (±)-3,4-methylenedioxymethampetamine (MDMA) or (±)-fenfluramine) (Herring et al, 2008;Herring et al, 2010;Vorhees et al, 2010a). These data suggest that route-based navigation may be predominately mediated by dopaminergic neurons in the neostriatum.…”

Prenatal immune challenge in rats: Effects of polyinosinic–polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine

“…Testing was conducted under infrared lighting. Performance was scored by visualizing the animals using infrared LED emitters and a near infrared camera mounted above and connected to a monitor located in an adjacent room (Vorhees et al, 2011). This prevented rats from using distal cues by which to navigate.…”

Cincinnati water maze: A review of the development, methods, and evidence as a test of egocentric learning and memory

“…Drugs that affected or preferentially affected dopamine caused significant increases in CWM errors (MA and amphetamine), whereas substituted amphetamines that primarily affect serotonin did not (MDMA and fenfluramine) (Vorhees et al, 2011). …”

“…Because of our experiment showing that substituted amphetamines that preferentially affect dopamine systems and not serotonin produce long-term deficits in the CWM (Vorhees et al, 2011), we began by exploring the role of dopamine (DA) in CWM learning. In the first experiment, 6-hydroxydopamine (6-OHDA) was infused into the dorsal striatum at doses producing bilateral 80% reductions in DA.…”