CART Peptides Regulate Psychostimulants and May be Endogenous Antidepressants

CART peptides are endogenous neurotransmitters that are involved in a variety of physiologic functions. Injection of CART 55-102 into the nucleus accumbens produces no effect, but when co-administered with cocaine, it reduces the locomotor and rewarding properties of cocaine. In a human study, subjects carrying a missense mutation of the CART gene exhibited increased anxiety and depression. Also, several animal studies support the idea that CART is involved in anxiety and depression, and they also suggest several possible mechanisms by which this may occur. Thus, there is interesting evidence that CART peptides play a role in anxiety and depression, and that CART peptides may be endogenous antidepressants

Understanding the Global Problem of Drug Addiction is a Challenge for IDARS Scientists

IDARS is an acronym for the International Drug Abuse Research Society. Apart from our scientific and educational purposes, we communicate information to the general and scientific community about substance abuse and addiction science and treatment potential. Members of IDARS are research scientists and clinicians from around the world, with scheduled meetings across the globe. IDARS is developing a vibrant and exciting international mechanism not only for scientific interactions in the domain of addiction between countries but also ultimately as a resource for informing public policy across nations. Nonetheless, a lot more research needs to be done to better understand the neurobiological basis of drug addiction – A challenge for IDARS scientists

Regulation of Neurotransmitter Reuptake by Nitric Oxide

PubMed ID: 7832440[No abstract available

Nitric oxide inhibits 3H-glutamate transport in synaptosomes

PubMed ID: 78251203H-glutamate (GLU) uptake was measured in hippocampal synaptosomes from rat brain. Addition of sodium nitroprusside (SNP) (Sodium nitroferricyanide), a generator of nitric oxide (NO), produced a time-, temperature-, and dose-dependent inhibition of 3H-GLU uptake. The inhibition was due to changes in both Kd and Vmax of GLU uptake, and it was at least partially reversible upon washing. Addition of reduced hemoglobin (Hb), a substance that binds NO, prevented the SNP-induced depression of uptake. Potassium ferricyanide, a compound similar to SNP, did not cause a reduction in 3H-GLU uptake. Utilization of another generator of NO, S-nitroso-N-acetylpenicillamine (SNAP), produced similar results as did NO itself. Decreases in uptake were also observed in the striatum and cerebellum. Similar treatments did not consistently affect 3H-norepinephrine (NE) uptake, suggesting some selectivity in the NO effect. Thus, the observed inhibition of 3H-GLU uptake appears to be produced by NO, and it may represent a novel type of transynaptic retrograde regulation of transport. If found in vivo, inhibition of uptake activity could also be involved in the toxic effects of NO, the neurotoxicity of glutamate, and other potential neuronal changes associated with NO such as hippocampal long-term potentiation. © 1994 Wiley-Liss, Inc. Copyright © 1994 Wiley-Liss, Inc

Recovery of dopamine transporter binding and function after intrastriatal administration of the irreversible inhibitor RTI-76 {3ß-(3p-chlorophenyl)tropan-2ß-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride}

PubMed ID: 8858994Effects of in vivo, intrastriatal administration of RTI-76 {3ß-(3-p-chlorophenyl)tropan-2ß-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride}, an irreversible inhibitor of dopamine transporter (DAT) binding in vitro, on [125I]RTI-55 {3ß-[4-iodophenyl]tropan-2ß-carboxylic acid methyl ester tartrate} binding to striatal DAT in vitro were examined in male rats. Effects on [3H]DAT and D1 dopamine receptor binding in vitro after intrastriatal RTI-76 injection were also determined. One hour after direct intrastriatal injection, RTI-76 caused a dose-related increase in KD for [125I]RTI-55 binding in vitro in striatal tissue, without affecting transporter maximum binding (Bmax). In contrast, 24 hr after administration, RTI-76 caused a dose-related decrease in striatal DAT Bmax without affecting KD, a decrease that reversed over the next several days. Transport of [3H]dopamine into synaptosomes was decreased similarly. Intrastriatal injection of reversible inhibitors of DAT, such as cocaine or WIN-35428 {3ß-[4-fluorophenyl]tropan-2ß-carboxylic acid methyl ester tartrate}, was without effect on transporter binding 1 and 6 days after administration. RTI-76 had little effect on [3H]SCH-23390 {R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine} binding 1 or 24 hr after intrastriatal injection, indicating at least some selectivity of RTI-76 for DAT. The RTI-76-induced decrease in Bmax, as well as the concurrent decrease in [3H]DAT, were reversible, with the T1/2 of transporter recovery estimated to be 6 days

Parkinsonian patients report blunted subjective effects of methylphenidate

Mesolimbic-mesocortical dopamine brain circuits important for psychostimulant reward in animals are developed to greater extents in humans. Brains of patients with Parkinson's disease show depletion of ventral tegmental area mesolimbic-mesocortical neurons. The authors assessed psychostimulant responses in parkinsonian patients to test whether intact dopaminergic systems are required for subjective psychostimulant effects. Responses to placebo and 15, 20, 25, and 30 mg of methylphenidate were studied in 12 parkinsonian patients and 12 neurologically intact matched controls. Physiological and subjective mood responses were recorded using the Profile of Mood Slates, Addiction Research Center Inventory, and Visual Analog Scale. Drug-induced changes in "good" feelings and overall drug responses were attenuated in the parkinsonian patients. These results, in conjunction with animal data, provide support for dopamine hypotheses of psychostimulant reward in humans and suggest possible bases for some of the mood disturbances found in many parkinsonian patients