• Neuronal nicotinic receptors are ligand-gated ion channels of the central and peripheral central nervous system that regulate  synaptic activity from both pre- and postsynaptic sites.
• Bupropion was found to block nicotine's antinociception (in two tests), motor effects, hypothermia,  and convulsive effects with different potencies in the present investigation, suggesting that bupropion possesses some selectivity  for neuronal nicotinic receptors underlying these various nicotinic effects.
• In addition, bupropion blocks nicotine activation  of α₃β₂, α₄β₂, and α₇ neuronal acetylcholine nicotinic receptors (nAChRs) with some degree of selectivity.
• This functional blockade was noncompetitive, because it was insurmountable by increasing concentration of ACh in the nAChRs  subtypes tested
• Additionally, bupropion (Zyban), an atypical antidepressant, has been approved  for smoking cessation
• In addition, bupropion has been found to lack binding affinity for almost all of the major classes of neuronal receptors,  including serotonergic, dopaminergic, β-adrenergic, α₁- and α₂-adrenergic receptors, and muscarinic cholinergic receptors
• This functional blockade is noncompetitive, because it was insurmountable by increasing concentration of ACh in the nAChRs  subtypes tested
• The relatively high sensitivity of bupropion on α₃β₂ subtype is very important, because α₃ subunits are located in catecholamine-rich brain regions implicated in pleasure and reward

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• We found that desipramine (DMI), nisoxetine, cocaine, citalopram, and nomifensine inhibit the nicotine-evoked release of [³H]NA with an IC₅₀ of 0.36, 0.59, 0.81, 0.93, and 1.84 μM, respectively.
• In whole-cell patch clamp experiments neither drug blocked Na⁺ currents at 1 μM in sympathetic neurons from rat superior cervical ganglia, and only DMI produced a pronounced inhibition (52% decrease)
• DMI, in contrast to TTX, inhibits only the nicotine-induced response, indicating that the target of DMI is not the Na⁺ channel.
• These results indicated that the effect of nAChR agonists is mediated through nAChRs and that the release is a consequence of vesicular exocytosis.
• [desipramine (DMI), nisoxetine, and nomifensine] could effectively block not only the carrier-mediated but also the nAChR-mediated release of NA in the low micromolar concentration range (1-10 μM) ; in other words, they showed a functional nAChR antagonist property.
• DMI and nisoxetine inhibit primarily the NA uptake
• Su and Bevan (1970) reported that DMI and cocaine inhibited the nicotine-evoked release of [³H]NA from spiral strips of the rabbit pulmonary artery.
• It has been shown that antidepressant drugs like DMI and imipramine are able to suppress the fast inward Na⁺ current in various neuronal preparations
• Our data showed that only DMI had a pronounced inhibitory effect on the Na⁺ current in the rat sympathetic neuron preparation
• our data showed that DMI blocked only the nicotine-evoked NA release but had no inhibitory effect on the electrical stimulation-evoked release.
• These receptor binding studies suggest that DMI and cocaine may behave like channel blocker-type nAChR antagonists.
• Su C. & Bevan J.A. (1970) Blockade of the nicotine-induced norepinephrine release by cocaine, phenoxybenzamine and desipramine. J. Pharmacol. Exp. Ther. 175,533–540.

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• Pharmacol Biochem Behav. 2008 October; 90(4): 598–607.

  doi: 10.1016/j.pbb.2008.05.002.
• Bupropion Differentially Alters the Aversive, Locomotor and Rewarding Properties of Nicotine in CD-1 Mice

  Anthony S. Rauhut,^1,2 Michael Hawrylak,¹ and Stacey K. Mardekian
• Preliminary experiments determined effective nicotine doses (0.1 – 2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference
• The two highest nicotine doses produced CTAs and a moderate nicotine dose (0.4 mg/kg) produced a CPP.
• Bupropion dose-dependently blocked nicotine CTA.
• Thus, bupropion selectively altered the aversive properties of nicotine in CD-1 mice.
• Several studies have found that acute or chronic bupropion pretreatment increases nicotine self-administration in rats (Rauhut et al., 2003; Shoaib et al., 2002).
• First, nicotine dose-dependently produced a CTA, CPP or induced changes in locomotor activity in CD-1 mice
• Rauhut AS, Neugebauer N, Dwoskin LP, Bardo MT. Effect of bupropion on nicotine self-administration in rats. Psychopharmacology. 2003;169:1–9
• Shoaib M, Gommans J, Morley A, Stolerman IP, Grailhe R, Changeux JP. The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology. 2002;42:530–539

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• Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area.

  Authors:

  Laviolette SR; van der Kooy D

  Author Address:

  Neurobiology Research Group, Department of Anatomy & Cell Biology, University of Toronto, Canada. SRLaviolette@netscape.net

  Source:

  Molecular Psychiatry [Mol Psychiatry] 2003 Jan; Vol. 8 (1), pp. 50-9, 9.
• Our results suggest that blockade of mesolimbic DA signalling induced by neuroleptic medications may block selectively the aversive properties of nicotine, thus increasing the vulnerability to nicotine's rewarding and addictive properties by inducing a unique, drug-vulnerable phenotype.

• Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory

  1. M. I. Miranda^1,2,
  2. R. T. LaLumiere¹,
  3. T. V. Buen¹,
  4. F. Bermudez-Rattoni²,
  5. J. L. McGaugh¹

  Article first published online: 10 NOV 2003

  DOI: 10.1046/j.1460-9568.2003.03008.x

  Issue

  

  European Journal of Neuroscience

  Volume 18, Issue 9, pages 2605–2610, November 2003
• Conditioned taste aversion (CTA) is a learning paradigm in which the novel taste of food or drink (conditioned stimulus, CS) is paired with visceral signals of malaise (unconditioned stimulus, US). After a single CS-US pairing, animals avoid consuming the food or drink previously associated with the US.

• The effects of chronic versus acute desipramine on nicotine withdrawal and nicotine self-administration in the rat

  Neil E. Paterson,^*+ Svetlana Semenova,^* and Athina Markou
• Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding.
• The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal, and may alter the rewarding effects of nicotine and food.
• Desipramine (DMI) is a preferential inhibitor of norepinephrine reuptake inhibition, a weak inhibitor of serotonin reuptake (Richelson and Pfenning 1984) and a nicotinic acetylcholine receptor antagonist (Rana et al. 1993; Izaguirre et al. 1997).
• the present study assessed the effects of DMI on the anhedonic and somatic components of nicotine withdrawal. DMI was selected because this compound shares the norepinephrine reuptake inhibition properties of bupropion and nortriptyline, but not their dopaminergic (bupropion) or serotonergic (nortriptyline) effects
• We predicted that norepinephrine reuptake inhibition via chronic DMI administration would decrease nicotine self-administration in rats
• The results of the present study indicated that chronic, but not acute, DMI treatment attenuated the anhedonic and somatic components of nicotine withdrawal, and that chronic DMI treatment significantly decreased nicotine- and food-maintained responding.
• In contrast, chronic DMI selectively attenuated the anhedonic and somatic component of nicotine withdrawal at a dose that had no effects in control rats.
• Although acute DMI had no direct effect on dopamine reuptake in the rat substantia nigra (Hoffman and Gerhardt 1998), prolonged administration of DMI increased dopamine transporter mRNA expression and protein levels in subregions of the mesolimbic pathway
• DMI has only been tested at the α3β4 nicotinic subtype (Hennings et al. 1997), at which reboxetine was 100-fold more potent than at the α4β2 nicotinic receptor (Miller et al. 2002). It is unknown whether DMI blocks β2-containing nicotinic acetylcholine receptor subtypes that are critical to the reinforcing effects of nicotine
• Finally, DMI is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (Sernagor et al. 1989; Mjellem et al. 1993), which could contribute to DMI-induced attenuation of nicotine self-administration (Blokhina et al. 2005; Kenny and Markou, unpublished observations). Blockade of either NMDA receptors or α3β4 nAChRs (Glick et al. 2002) would selectively attenuate responding for nicotine- not food-maintained responding.

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