Meet Dr. Vorhees
Charles V. Vorhees, PhD
Division of Neurology
Cincinnati Children's Research Foundation
Effects of Meth and MDMA
The effects of club drugs such as methamphetamine (meth), 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'), or the new drug, 5-methoxy-diisoproplytryptamine ('foxy'), on health are a concern because their long-term effects are poorly understood despite their widespread use among adolescents and younger adults. The lab's main area of research is to understand how these drugs affect the developing and mature brain, and how these changes are translated into alterations in brain function (behavior).
It has been known for years that high doses of meth cause severe reductions in brain dopamine, especially in the caudate nucleus, and serotonin (5-HT) in multiple regions (caudate, prefrontal cortex, and hippocampus). These effects occur in the presence of drug-induced hyperthermia and results in the appearance of markers of neurotoxicity, including astrogliosis and increased silver staining of degenerating neurons. Despite this knowledge the mechanism of the effects is not fully understood nor are the consequences of these effects on behavior understood. We and others have shown that meth induces the generation of reactive oxygen species (ROS) and these molecules play a key role in the damage seen in dopaminergic nerve terminals after meth exposure.
MDMA, by contrast, has fewer effects on dopamine, although we have recently shown that some of the dopamine changes last longer than previously thought. MDMA primarily affect 5-HT neurons, causing reductions in most forebrain regions. MDMA also induces hyperthermia and this is crucial to inducing the long-term 5-HT reductions. Any intervention that prevents hyperthermia also prevents 5-HT depletion.
Both drugs depend on entry into neurons by transporter proteins. In addition, both drugs have recently been shown to affect learning and memory. Meth primarily affects the dopamine transporter, and blocking the transporter with an antagonist, prevents dopamine nerve terminal injury and astrogliosis. MDMA, on the other hand, requires the serotonin transporter to enter neurons to cause 5-HT reduction, and blocking this transporter prevents 5-HT nerve terminal reduction, but MDMA does not cause astrogliosis, so this effect is never seen with MDMA. The lab is currently investigating what makes these two structurally similar drugs so different in their effects on brain neurotransmitters and how these changes result in changes in learning and memory. Interestingly, MDMA causes path integration, but not spatial learning impairments, whereas meth causes impairments in novel object recognition but not in path integration.
Much less is known about the effects of prenatal exposure to meth or MDMA. We have found that rats exposed to these drugs neonatally, which is a period in brain development similar to a human brain during third trimester of pregnancy, causes permanent spatial learning and memory impairments. We are now investigating the mechanisms by which these effects occur.
Research in the lab
The lab has recently begun research on the new designer drug 'foxy.' There is almost no scientific information known about this drug, but the U.S. Drug Enforcement Agency increased it to a Schedule I drug recently so that its possession is unlawful. We have obtained approval from the DEA and FDA to have this compound synthesized so that we can investigate its short and long-term effects on the adult and developing brain.
Research in Foxy is just one research project. Others are:
- Developmental and adult effects of substituted amphetamines (methamphetamine and methylenedioxymethamphetamine, MDMA, and Foxy);Effects of lead, manganese and stress on neurobehavioral development;
- Creatine transporter deficiency;
- Role of Na-K-ATPases in the brain including the function of the ouabain binding site on these proteins;
- Role of phosphodiesterases (especially the PDE1 family) in the brain;
- A model of developmental dopamine hyperfunction/supersensitivity using the D2 agonist quinpirole;
- The roles of prosaposin and the saposins in progressive CNS deterioration as animal models of lipid storage diseases;
- The prenatal effects of PCBs on the Ah receptor and its interaction with CYP1A2 on brain development and behavior;
- The role of antioxidants in brain development using GCLM and GULO knockout mice (mice impaired in glutathione and ascorbate synthesis, respectively);
- Developmental hypoxia-ischemia (HI) injury and its long-term effects;
- The longitudinal behavioral phenotype of MPSI mice (a model of mucopolysaccharidosis type-I;
- The function of the PET-1 gene in brain development and later behavior (Pet-1 deficient mice develop with only 20% of normal brain serotonin);
- Testing the effects of embryonic exposure to Poly IC and its effects on brain development and behavior (Poly-IC induces inflammatory responses); and
- Testing the effects of SSRI's (selective serotonin reuptake inhibitors) given during stages of adolescent brain development to determine they induce abnormal anxiety or responses to stressors either during drug treatment or long after treatment.
The projects on ATPases, saposins, PCBs, GCLM, GULO, MPSI and HI are in collaboration with other investigators.
We have recently shown that adult exposure to methamphetamine leads to cognitive deficits in path integration learning. Methamphetamine is known to activate the HPA axis and reduce brain monoamine neurotransmitters. Accordingly, tested the hypothesis that these effects and the effects on core body temperature are related to the drug's ability to release corticosterone from the adrenals. We showed that each effect is independent of adrenal output. We also characterized the neurochemical and behavioral effects of 5-methoxy-diisopropyltryptamine, the first experiment of its kind, and showed that the effects of developmental exposure to methamphetamine and MDMA have different patterns of effects on the developing brain than they do in adults and are also different from one another. We showed that the isoforms of Na-K-ATPases (α1, α2, and α3) each have unique functional/regulatory roles in brain function, with striking effects caused by haploinsufficiency of the α3 isoform. We also found that the PDE1B knockout mouse shows a striking phenotype when subjected to the Porsolt test of swimming 'despair,' a model of depression, raising the possibility that this protein may be a therapeutic target for drug development. Given this, we have begun a project to target PDE1C for disruption and are following up with the PDE1B finding with Dr. Ron Duman's lab at Yale. We also characterized the phenotype of the prosaposin and MPSI knockout mice. The lead studies are in early stages and involve comparing the effects of different stressful conditions and blood lead concentrations during development on corticosterone release and monoaminergic brain development. Preliminary PCB findings suggest that PCB interacts with maternal genotype such that if the gravid female has a high affinity AHR and is deficient in CYP1A2, her offspring exhibit deficits in the acoustic startle response compared to other genotype/PCB combinations, which is what we hypothesized would occur. If this prediction holds up to further analyses it will represent an advance in understanding why some individuals show long-term effects and others do not after prenatal exposure to this environmental toxin. Progress on creation of a conditional creatine transporter deficient mouse directly on a C57BL background is progressing. Projects on the antioxidant deficient and PET-1 deficient mice are in progress, and the project on SSRI's has just begun. The first experiment on developmental induction of dopaminergic hyperfunction is not yet completed but preliminary analyses suggest that the treatment was not fully effective at induces dopaminergic supersensitivity. In recent discussions with Neil Richtand, MD, PhD (Department of Psychiatry) we are opening a new collaboration using a different model of developmentally-induced dopaminergic hyperfunction by treating gravid rats with Poly IC. We are also in discussion with Steven Danzer, PhD to collaborate on mouse models of autism and temporal lobe epilepsy.
The Vorhees lab works in close collaboration with the lab of Dr. Michael Williams. The labs share research interests and work together seamlessly.
