Abstract:Drugs that inhibit the dopamine (DA) transporter (DAT) include both therapeutic agents and abused drugs. Recent studies identified a novel series of putative allosteric DAT inhibitors, but the in vivo effects of these compounds are unknown. This study examined the abuse-related behavioral and neurochemical effects produced in rats by SRI-31142 [2-(7-methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine], one compound from this series. In behavioral studies, intracranial self-st… Show more
“…These findings suggest that cocaine, DAT inhibitors, or D 1 R agonists each potentiate the rewarding effects of eICSS and imply that these drugs have rewarding effects of their own. In contrast, withdrawal from chronic cocaine or amphetamine administration is associated with depression‐like effects and deficits in brain reward function, as assessed by BSR threshold elevation or a rightward/downward shift of eICSS 56–59 . Based on these findings, if a test drug produces a cocaine‐like leftward or upward shift in ICSS curve, we interpret the drug to be rewarding or reward enhancing.…”
Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self‐stimulation (ICSS) (oICSS) to re‐examine the abuse potential of cannabinoids in mice. A specific adeno‐associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light‐sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)‐Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical “sigmoidal”‐shaped stimulation–response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose‐dependently enhanced oICSS and shifted stimulation–response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ9‐tetrahydrocannabinol (Δ9‐THC), but not cannabidiol, dose‐dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212‐2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose‐dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR‐11 produced a cocaine‐like increase, AM‐2201 produced a Δ9‐THC‐like reduction, while 5F‐AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB1Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB1R and/or CB2R in different populations of neurons in the brain may underlie the observed actions.
“…These findings suggest that cocaine, DAT inhibitors, or D 1 R agonists each potentiate the rewarding effects of eICSS and imply that these drugs have rewarding effects of their own. In contrast, withdrawal from chronic cocaine or amphetamine administration is associated with depression‐like effects and deficits in brain reward function, as assessed by BSR threshold elevation or a rightward/downward shift of eICSS 56–59 . Based on these findings, if a test drug produces a cocaine‐like leftward or upward shift in ICSS curve, we interpret the drug to be rewarding or reward enhancing.…”
Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self‐stimulation (ICSS) (oICSS) to re‐examine the abuse potential of cannabinoids in mice. A specific adeno‐associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light‐sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)‐Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical “sigmoidal”‐shaped stimulation–response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose‐dependently enhanced oICSS and shifted stimulation–response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ9‐tetrahydrocannabinol (Δ9‐THC), but not cannabidiol, dose‐dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212‐2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose‐dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR‐11 produced a cocaine‐like increase, AM‐2201 produced a Δ9‐THC‐like reduction, while 5F‐AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB1Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB1R and/or CB2R in different populations of neurons in the brain may underlie the observed actions.
“…4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP + ) acts as a substrate at the monoamine transporters and therefore was used to examine the effects of the compounds on APP + -induced signals (3 μM) at hDAT as previously described . APP + does not fluoresce on its own but only when it is taken up by cells and undergoes interactions with intracellular components . The fluorescence intensity was measured in FlpIn-TRex HEK293 cells stably expressing hDAT and plated in 96-well imaging plates.…”
Section: Methodsmentioning
confidence: 99%
“…An epifluorescence microscope (Olympus IX70) equipped with a monochromator (Polychrome V), digital EMCCD camera (Andor), and a pressurized perfusion system (Automate Scientific) was used to monitor the activity of DAT in live cells which were exposed to APP + as described previously . The DsRed fluorescent signal was used to find the focal plane of the cell monolayer, and then the APP + signal was measured using wavelengths of 460 nm for excitation and 540 nm for emission at a 10 Hz acquisition rate. , The imaging solution (IS) used for the experiment consisted of 130 NaCl, 4 KCl, 1 MgCl 2 , 2 CaCl 2 , 5 glucose, 10 Hepes, in mM, and the pH was adjusted to 7.3 using NaOH. Cells were exposed to IS for 10 s, then exposed to the test compound for 30 s, and then exposed to the test compound plus APP + for 30 s. Each well was exposed to a single concentration of the test compound, and control wells without a test compound were run every experimental day to define the 100% APP + uptake.…”
Section: Methodsmentioning
confidence: 99%
“…In addition, we prepared and examined the des -keto analogue of 4 (i.e., 5 ) to determine if the keto group of 4 (or if the ester function of 1 ) is important for DAT transporter activity. The compounds were examined as DAT reuptake inhibitors competing for the uptake of the fluorescent nonselective DAT substrate APP + as previously reported . Additional testing confirmed that none behaved as releasing agents; all behaved as DAT reuptake inhibitors.…”
Synthetic cathinones are, primarily, stimulant drugs of abuse that act at monoamine transporters (e.g., the dopamine transporter or DAT) as releasing agents or as reuptake inhibitors. In the past few years, the emergence of >150 new synthetic cathinones has attracted considerable attention from medical and law enforcement communities. threo-Methylphenidate (tMP), used clinically for the treatment of ADHD and narcolepsy, is also a DAT reuptake inhibitor. tMP is somewhat structurally similar to abused cathinone stimulants, and the structure− activity relationships (SAR) of tMP have been well-defined. Hence, available tMP literature might assist in understanding the SAR of synthetic cathinones, about which less is known. In the present study, we synthesized and examined eight 2-benzoylpiperidine analogues (4, 6− 12) to determine if tMP SAR might be applicable to cathinone SAR. The benzoylpiperidine analogues were evaluated in a competition assay using live-cell imaging against APP + in HEK293 cells stably expressing hDAT and in cells coexpressing DAT and voltage-gated Ca 2+ channels. All compounds were found to be DAT reuptake inhibitors, and a significant correlation was obtained between the potency of the benzoylpiperidines and tMP binding data (r = 0.91), suggesting that the SAR of tMP analogues might be directly applicable to certain synthetic cathinones as DAT reuptake inhibitors.
“…An appropriate number of dopamine molecules are needed at any given time to activate these receptors appropriately, and this dopamine balance is systematically regulated by the brain. Cocaine actively interferes with the brain’s efforts to achieve and maintain optimal dopamine levels by occupying the dopamine transporters, the proteins by which the brain’s dopamine-producing cells use to retrieve excess dopamine molecules [ 23 ]. By allowing these dopamine molecules to accumulate, the dopamine receptors become excessively stimulated [ 22 ].…”
Cocaine is taken frequently together with ethanol and this combination produces a psychoactive metabolite called cocaethylene which has similar properties to the parent drug and may be more cardiotoxic. Cocaethylene has a longer half-life than cocaine, so that people who combine cocaine and ethanol may experience a longer-lasting, as well as more intense, psychoactive effect. Cocaethylene is the only known instance where a new psychoactive substance is formed entirely within the body. Although known to science for decades, cocaethylene has not been extensively studied and even its metabolic pathways are not entirely elucidated. Like its parent drug, cocaethylene blocks the reuptake of dopamine and increases post-synaptic neuronal activity; the parent drug may also block reuptake of serotonin as well. Cocaethylene has been studied in animal models in terms of its pharmacology and its potential neurological effects. Since the combination of cocaine and alcohol is commonly used, it is important for clinicians to be aware of cocaethylene, its role in prolonging or intensifying cocaine intoxication, and how it may exacerbate cocaineinduced cardiovascular disorders. Most cardiac-related risk assessment tools do not ask about cocaine use, which can prevent clinicians from making optimal therapeutic choices. Greater awareness of cocaethylene is needed for clinicians, and those who use cocaine should also be aware of the potential for polysubstance use of cocaine and ethanol to produce a potentially potent and long-lasting psychoactive metabolite.
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