Sensory gating in tobacco-naïve cannabis users is unaffected by acute nicotine administration.

OBJECTIVES: Long-term cannabis use has been associated with the appearance of psychotic symptoms and schizophrenia-like cognitive impairments; however these studies may be confounded by concomitant use of tobacco by cannabis users. We aimed to determine if previously observed cannabis-associated deficits in sensory gating would be seen in cannabis users with no history of tobacco use, as evidenced by changes in the P50, N100, and P200 event-related potentials. A secondary objective of this study was to examine the effects of acute nicotine administration on cannabis users with no tobacco use history. METHODS: Three components (P50, N100, P200) of the mid-latency auditory-evoked response (MLAER) were elicited by a paired-stimulus paradigm in 43 healthy, non-tobacco smoking male volunteers between the ages of 18-30. Cannabis users (CU, n = 20) were administered nicotine (6 mg) and placebo gum within a randomized, double-blind design. Non-cannabis users (NU, n = 23) did not receive nicotine. RESULTS: Between-group sensory gating effects were only observed for the N100, with CUs exhibiting a smaller N100 to S1 of the paired stimulus paradigm, in addition to reduced dN100 (indicating poorer gating). Results revealed no significant sensory gating differences with acute administration of nicotine compared to placebo cannabis conditions. CONCLUSIONS: These findings suggest a relationship between gating impairment and cannabis use; however, acute nicotine administration nicotine does not appear to impact sensory gating function.

Acute separate and combined effects of cannabinoid and nicotinic receptor agonists on MMN-indexed auditory deviance detection in healthy humans.

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.

Combining CDP-choline and galantamine: Effects of a selective α7 nicotinic acetylcholine receptor agonist strategy on P50 sensory gating of speech sounds in healthy volunteers.

BACKGROUND: Schizophrenia (SCZ) patients and relatives have deficits in early cortical sensory gating (SG) typically measured by suppression of electroencephalography-derived P50 event-related potentials (ERPs) in a conditioning-testing (S1-S2) paradigm. Associated with alpha 7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction and shown to be improved with nicotine and α7 nAChR agonists, SG has recently been shown to be improved in low P50 suppressing SCZ patients following acute CDP-choline treatment. AIMS: This pilot study in healthy humans assessed the SG effects of an α7 nAChR strategy combining CDP-choline with galantamine, a positive allosteric modulator (PAM) of nAChRs, aimed at increasing and prolonging nicotinic receptor activity. METHODS: The combined effect of CDP-choline (500 mg) and galantamine (16 mg) on speech P50 gating indices rP50 (S2/S1) and dP50 (S1-S2) was examined in 30 healthy participants stratified into low and high baseline P50 suppressors in a randomized, double-blind, placebo-controlled and counterbalanced design. RESULTS: In low suppressors, CDP-choline/galantamine (vs. placebo) improved rP50 and dP50 gating, and reduced S2P50 amplitudes. No P50 gating effects were observed in high suppressors; however, CDP-choline/galantamine (vs. placebo) increased their S2P50 amplitudes. CONCLUSION: Findings from this pilot study with CDP-choline/galantamine in a healthy, SCZ-like surrogate deficient gating sample are consistent with the association of α7 nAChR mechanisms in SG impairment in SCZ and support further research trials with CDP-choline and galantamine targeting sensory processes.

Effect of GAD1 genotype status on auditory attention and acute nicotine administration in healthy volunteers.

OBJECTIVE: The effects of GABA modulating drugs and nicotine, the prototypical nicotinic cholinergic agonist, on attention have been investigated using subcomponents of the P300 event-related potentials (ERP), which index involuntary (P3a) and voluntary attention (P3b). However, investigations into how such pharmacologic effects interact with genetic features in the GABA system remain unclear. This study examined the moderating effects of a single nucleotide polymorphism (rs7557793) in the glutamic acid decarboxylase 67 (GAD1) gene, which is implicated in the conversion of glutamate to GABA, on P300-indices of auditory attentional processing; the influence of nicotine administration was also assessed. METHODS: The effects of GAD1 genotype (TT/CC/CT) were examined on the P3a/b in response to an auditory selective attention task in healthy, nonsmoking male volunteers (N = 126; 18-40 years). Participants responded to rare target stimuli (P3b-eliciting) and ignored frequent nontarget stimuli as well as rare distractor stimuli (P3a-eliciting). In a subsample (N = 59), P3a/b profiles to acute nicotine (vs. placebo) administration were examined as a function of GAD1 genotype. As a secondary aim, earlier sensory processes were assessed with N200 ERP subcomponents elicited by novel (N2a) and target (N2b) auditory stimuli. RESULTS: GAD1 allelic variation moderated early sensory processes, enhancing N2a amplitudes in CT versus TT carriers. Further, TT homozygotes exhibited larger P3b amplitudes than CC homozygotes in the placebo versus nicotine condition. Regardless of genotype, nicotine versus placebo moderated the N200 ERP. CONCLUSION: These findings expand our knowledge regarding the attentional effects of GAD1 genetic variants in relation to nicotine.

Mismatch negativity in tobacco-naïve cannabis users and its alteration with acute nicotine administration.

Chronic cannabis use may interact with factors, such as age of onset of cannabis use, family history, and genetic factors, to elicit schizophrenia (SZ)-like symptoms, including sensory and cognitive deficits. However, evidence of a relationship between cannabis use and cognitive impairment is confounded by concomitant use of tobacco. The objective of this study was to compare tobacco-naïve cannabis users with individuals without a history of tobacco/cannabis use on the auditory mismatch negativity (MMN) event-related potential (ERP), a neural measure of auditory deviance detection which is diminished in SZ. An exploratory arm of the study, conducted within a randomized, double-blind, placebo controlled design, examined the acute effects of nicotine gum (6mg) on MMN in cannabis users. MMN was recorded in response to 5 deviant stimuli within an optimal MMN paradigm in 44 healthy, non-tobacco smoking volunteers aged 18-26. Cannabis users (n=21) started smoking cannabis prior to age 17, at least 1 joint per month. To examine the effects of chronicity, users were grouped into relatively heavy long-term (HLT; n=11) users and light short-term (LST; n=10) users. Impaired deviance detection was shown in cannabis users vs. nonusers as reflected by a smaller MMN to duration deviants. Chronicity of use was also associated with MMN alterations, as HLTs displayed a reduced duration and gap MMN vs. LSTs. Compared with placebo, nicotine treatment enhanced select MMN deviants in cannabis user subgroups. As deficits associated with early and persistent cannabis use are similar to those seen in SZ, these dose-dependant disturbances in early sensory processing with cannabis use may be one cognitive pathway which mediates an increased risk for SZ in vulnerable youth, and be influenced by concurrent cigarette smoking behavior.

Modulation of auditory deviance detection by acute nicotine is baseline and deviant dependent in healthy nonsmokers: a mismatch negativity study.

OBJECTIVE: Cognitive enhancement resulting from nicotinic acetylcholine receptor stimulation may be evidenced by increased efficiency of the auditory-frontal cortex network of auditory discrimination, which is impaired in schizophrenia, a cognitive disorder associated with excessive tobacco use. Investigating automatic (preattentive) detection of acoustic change with the mismatch negativity (MMN) brain event-related potential in response to nicotine in individuals with varying baseline levels of auditory discrimination may provide useful insight into the cholinergic regulation of this neural network and its potential amelioration with novel nicotinic agents. METHODS: Sixty healthy, non-smoking male volunteers were presented with an 'optimal' multi-feature MMN paradigm in a randomized, placebo controlled double-blind design with 6 mg of nicotine gum. RESULTS: Participants with low, medium, and high baseline amplitudes responded differently to nicotine (vs. placebo), and nicotine response was feature specific. Whereas MMN in individuals with high amplitudes was diminished by nicotine, MMN increased in those with low amplitudes. Nicotine effects were not shown in medium amplitude participants. CONCLUSIONS: These findings provide preliminary support for the role of nicotinic neurotransmission in sensory memory processing of auditory change and suggest that nicotinic receptor modulation can both enhance and diminish change detection, depending on baseline MMN and its eliciting stimulus feature.

Baseline-dependent modulating effects of nicotine on voluntary and involuntary attention measured with brain event-related P3 potentials.

Cholinergic stimulation produces cognitive effects that vary across individuals, and stimulus/task conditions. As of yet, the role of individual differences in moderating the effects of the nicotinic acetylcholine receptor agonist nicotine on specific attentional functions and their neural and behavioral correlates is not fully understood. In this randomized, double-blind, placebo-controlled study of 64 healthy non-smokers, we address the contribution of baseline-dependence to inter-individual variability in response to nicotine gum (6 mg) assessed with event-related brain potential (ERP) indices of involuntary (the anteriorly distributed P3a) and voluntary (the posteriorly distributed P3b) attention derived from an active 3-stimulus auditory oddball paradigm involving listening to standard and novel stimuli and detection and response to target stimuli. Nicotine enhanced the amplitude of P3a elicited during the processing of novel stimuli but only in individuals with relatively low baseline P3a amplitudes. Exhibiting an inverted-U nicotine response profile, target P3b and standard N1 amplitudes were increased and decreased in participants with low and high baseline amplitudes, respectively. In all, the findings corroborate the involvement of nicotinic mechanisms in attention, generally acting to increase attentional capacity in relatively low attentional functioning (reduced baseline ERPs) individuals, while having negative or detrimental effects in those with medium/high attentional levels (increased baseline ERPs), and in a manner that is differentially expressed during bottom-up (involuntary) attentional capture and top-down (voluntary) attentional allocation.

Baseline dependency of nicotine's sensory gating actions: similarities and differences in low, medium and high P50 suppressors.

Reduced suppression of the P50 auditory event-related potential in schizophrenia patients relative to normal controls is indicative of a sensory gating deficit and is one of the most robust findings reported for functional brain abnormalities in this disorder. However, there is considerable gating variability in patients and controls and there is little understanding as to how inter-individual differences moderate gating responses to drugs and nicotinic agonists in particular, which have shown potential to reverse gating deficits. In this study the effects of acutely administered nicotine (gum, 6 mg) on sensory gating in a paired (S1-S2) auditory stimulus paradigm were investigated in 57 healthy, non-smoking volunteers stratified as low (n = 19), medium (n = 19) and high (n = 19) P50 suppressors on the basis of three separate baseline derived gating indices, P50 ratios, P50 difference scores, and gating difference waveforms. Relative to placebo, nicotine consistently improved gating in low suppressors as stratified with all three gating indices, exerted no effects in medium suppressors and reduced gating in high suppressors. Analysis of individual stimulus (S2, S2) amplitudes showed distinctly different mechanisms of action underlying nicotine effects in individuals with low and high baseline suppression. The results parallel similar findings of baseline-dependency in the gating effects of several antipsychotic drugs in healthy volunteers and support the use of group segmentation as a translational model in novel cognitive drug development for schizophrenia.