Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson's disease via mechanisms associated with increased protein kinase activity in the striatum.

Parkinson's disease (PD) is a devastating neurodegenerative disease that leads to motor deficits and selective destruction of nigrostriatal dopaminergic neurons. PD is typically treated by dopamine replacement agents; however, dopamine replacement loses effectiveness in the later stages of the disease. Here, we describe the neuroprotective effects of the omega-3 fatty acid docosahexaenoic acid (DHA) in the medial forebrain bundle 6-hydroxydopamine (6-OHDA) model of advanced-stage PD in rats. We show that daily administration of DHA protects against core symptoms of PD, including deficits in postural stability, gait integrity, and dopamine neurochemistry in motor areas of the striatum. Our results also demonstrate that DHA increases striatal dopamine synthesis via phosphorylation of the rate-limiting catecholamine synthesizing enzyme tyrosine hydroxylase, in a manner dependent on the second messenger-linked protein kinases PKA and PKC. We also show that DHA specifically reverses dopamine loss in the nigrostriatal pathway, with no effect in the mesolimbic or mesocortical pathways. This suggests that DHA is unlikely to produce pharmacotherapeutic or adverse effects that depend on dopamine pathways other than the nigrostriatal pathway. To our knowledge, previous reports have not examined the effects of DHA in such an advanced-stage model, documented that the dopamine synthesizing effects of DHA in vivo are mediated through the activation of protein kinases and regulation of TH activity, or demonstrated specificity to the nigrostriatal pathway. These novel findings corroborate the beneficial effects of omega-3 fatty acids seen in PD patients and suggest that DHA provides a novel means of protecting patients for dopamine neurodegeneration.

The acute toxic and neurotoxic effects of 3,4-methylenedioxymethamphetamine are more pronounced in adolescent than adult mice.

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of MDMA can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse. In the current study, adolescent (6-7 weeks of age) and mature adult (16-18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 h). Acute lethality, acute hyperthermia, and acute decreases in body weight following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.

Effects of the second-generation "bath salt" cathinone alpha-pyrrolidinopropiophenone (α-PPP) on behavior and monoamine neurochemistry in male mice.

RATIONALE: Synthetic cathinones ("bath salts") are ß-ketone analogs of amphetamines, yet few studies have examined their potential neurotoxic effects. OBJECTIVE: In the current study, we assessed the persistent behavioral and neurochemical effects of exposure to the second-generation synthetic cathinone α-pyrrolidinopropiophenone (α-PPP). METHODS: Male, Swiss-Webster mice were exposed to α-PPP (80 mg/kg) using a binge-like dosing regimen (QID, q2h). Behavior was assessed 4-5 days after the dosing regimen, and neurochemistry was assessed the following day. Behavior was studied using the elevated plus maze, Y-maze, and novel object recognition tests. Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography. Additional experiments assessed the time courses of the effects of α-PPP on locomotor activity and core temperature using telemetry. RESULTS: Exposure to α-PPP significantly impaired performance in the Y-maze, decreased overall exploratory activity in the novel object recognition test, and resulted in regionally specific depletions in monoamine neurochemistry. In contrast, it had no significant effect on elevated plus maze performance or object discrimination in the novel object recognition test. The locomotor-stimulant effects of α-PPP were comparable to cocaine (30 mg/kg), and α-PPP (80 mg/kg) did not induce hyperthermia. CONCLUSIONS: α-PPP exposure results in persistent changes in exploratory behavior, spatial working memory, and monoamine neurochemistry. This research highlights potential dangers of α-PPP, including potential neurotoxicity, and suggests that the mechanisms underlying the persistent untoward effects of the cathinones may be distinct from those of the amphetamines.