Neuropharmacology
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More than 200 novel psychoactive drugs have been reported in Europe, with 73 added in 2012 and additional compounds encountered every week in 2013. Many of these are "designer psychostimulants" which aim to mimic the subjective effects of amphetamines, cocaine or 3,4-methylenedioxymethylamphetamine (MDMA; "Ecstasy"). Several drugs are based on the beta-ketoamphetamine cathinone chemical structure, others include aminoindanes, aminotetralins, piperazines, amphetamine analogues and pipradrol derivatives. ⋯ Those activating principally DA systems are amphetamine-like stimulants, such as naphyrone, desoxypipradrol, 3,4-methylenedioxypyrovalerone (MDPV), and benzylpiperazine while those preferentially activating 5-HT mechanisms are MDMA-like or cocaine-like stimulants, such as mephedrone, methylone and other substituted cathinones, aminoindanes, aminotetralins and piperazines. The ability of mephedrone and other novel psychostimulants to substitute for methylamphetamine or cocaine in drug discrimination tests in rats, and the ability of mephedrone to induce conditioned place preference and to sustain self-administration behaviour suggests that this and other cocaine/methylamphetamine-like drugs have dependence liability. This article is part of the Special Issue entitled 'CNS Stimulants'.
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There has been a dramatic rise in the abuse of synthetic cathinones known as "bath salts," including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of "second generation" pyrrolidinophenones has appeared on the market, with α-pyrrolidinovalerophenone (α-PVP) being most popular. ⋯ Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users. This article is part of the Special Issue entitled 'CNS Stimulants'.
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There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral ('rACC': Cg1 and Cg3 (prelimbic area)) and caudal ('cACC': Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. ⋯ Glutamate efflux in the rACC was increased by local infusion of dopamine (5-50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine increased glutamate efflux and only in the cACC. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC. This article is part of the Special Issue entitled 'CNS Stimulants'.
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Comparative Study
Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease.
Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. ⋯ The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured.
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Despite many advances, our understanding of the involvement of prodynorphin systems in the development of neuropathic pain is not fully understood. Recent studies suggest an important role of neuro-glial interactions in the dynorphin effects associated with neuropathic pain conditions. Our studies show that minocycline reduced prodynorphin mRNA levels that were previously elevated in the spinal and/or dorsal root ganglia (DRG) following sciatic nerve injury. ⋯ These results suggest an important role of these proinflammatory cytokines in the development of the neurotoxic effects of dynorphin. Similar to minocycline, a selective inhibitor of MMP-9 (MMP-9 levels are reduced by minocycline) exerts an analgesic effect in behavioral studies, and its administration prevents the occurrence of flaccid paralysis caused by high-dose dynorphin administration (15 nmol). In conclusion, our results underline the importance of neuro-glial interactions as evidenced by the involvement of IL-1β and IL-6 and the minocycline effect in dynorphin-induced toxicity, which suggests that drugs that alter the prodynorphin system could be used to better control neuropathic pain.