Region-Specific Effects of Nicotine on Brain Activity: A Pharmacological MRI Study in the Drug-Naïve Rat

Abstract

We have applied pharmacological magnetic resonance imaging (phMRI) methods to map the functional response to nicotine in drug-naïve rats. Nicotine (0.35 mg/kg intravenous (i.v.)) increased relative cerebral blood volume (rCBV) in cortical (including medial prefrontal, cingulate orbitofrontal, insular) and subcortical (including amygdala and dorsomedial hippocampus) structures. The pharmacological specificity of the effect was demonstrated by acute pretreatment with the nicotinic acetylcholine receptor (nAChR) ion-channel-blocking agent mecamylamine, which suppressed the rCBV response to nicotine. Control experiments with norepinephrine, a potent non-brain-penetrant vasopressor, at a dose that mimics the cardiovascular response induced by nicotine were performed to assess the potential confounding effects of peripheral blood pressure changes induced by nicotine. In an attempt to highlight the relative contribution of different nAChR subtypes to the observed activation pattern of nicotine, we also investigated the central phMRI response to an acute challenge with (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (cpdA, at 5, 10, 20, and 30 mg/kg i.v.) and 5-iodo-A-85380 (5IA, 5 mg/kg i.v.). CpdA is a selective agonist at homomeric alpha7 nAChRs, while 5IA features high in vivo affinity for the alpha4beta2* and other less-abundant beta2-containing nicotinic receptors. CpdA did not produce significant rCBV changes at any of the doses tested, whereas 5IA induced a pattern of activation very similar to that induced by nicotine. The lack of phMRI response to cpdA together with the high spatial overlap between the activation profile of nicotine and 5IA, suggest that the acute functional response to nicotine in drug-naïve rats is mediated by beta2-containing nAChR isoforms, presumably belonging to the alpha4beta2* subtype.

Phasic Dopamine Release Evoked by Abused Substances Requires Cannabinoid Receptor Activation

“…1 A, right panel) that subsequently declined in the measurement interval. The timescale of this change is similar to that observed for regional cerebral blood flow in the rat nucleus accumbens with a similar dose (Gozzi et al, 2006). More frequent dopamine transients were superimposed on this response (Fig.…”

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

“…Since the advent of phMRI, a number of mechanisms of action and compounds have been evaluated in the preclinical domain. With use of phMRI, drug action on rodent brain function has been evaluated for a range of compounds that include amphetamine (Chen et al, 2005), nicotine (Gozzi et al, 2006), remifentanil (Liu et al, 2007), and cocaine (Schwarz et al, 2004). Previous studies have also used phMRI as a means to characterize the effects of a pharmacological pretreatment (eg, 5HT-2A receptor antagonist) on a particular challenge (e.g., phencylidine) (Gozzi et al, 2008;Gozzi et al, 2010;Chin et al, 2011;Large et al, 2011;McKie et al, 2011;Baker et al, 2012).…”

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

“…Animal preparation/monitoring and MRI acquisition in each phMRI study were similar to previous studies (Gozzi et al, 2005). Briefly, rats were anesthetized with 3% halothane in a 30% : 70% O 2 : N 2 gas mixture, tracheotomized, and artificially ventilated with a mechanical respirator.…”