Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D 2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D 2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.

The central nucleus of the amygdala (CeA) serves as a major output of this structure and plays a critical role in the expression of conditioned fear. By combining cell- and tissue-specific pharmacogenetic inhibition with functional magnetic resonance imaging (fMRI), we identified circuits downstream of CeA that control fear expression in mice. Selective inhibition of a subset of neurons in CeA led to decreased conditioned freezing behavior and increased cortical arousal as visualized by fMRI. Correlation analysis of fMRI signals identified functional connectivity between CeA, cholinergic forebrain nuclei, and activated cortical structures, and cortical arousal was blocked by cholinergic antagonists. Importantly, inhibition of these neurons switched behavioral responses to the fear stimulus from passive to active responses. Our findings identify a neural circuit in CeA that biases fear responses toward either passive or active coping strategies.

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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.

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