Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS ϩ and a DS Ϫ , respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40 -50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS ϩ to reinstate cocaine seeking behavior. The DS ϩ was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS ϩ . We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.

Cognitive-motivational styles describe predominant patterns of processing or biases that broadly influence human cognition and performance. Here we focus on the impact of cognitive-motivational styles on the response to cues predicting the availability of food or addictive drugs. An individual may preferably conduct an analysis of the motivational significance of reward cues, with the result that such cues per se are perceived as rewarding and worth approaching and working for. Alternatively, a propensity for a “cold” analysis of the behavioral utility of a reward cue may yield search behavior for food or drugs but not involve cue approach. Animal models for studying the neuronal mechanisms mediating such styles have originated from research concerning behavioral indices that predict differential vulnerability to addiction-like behaviors. Rats classified as sign- or goal-trackers (STs, GTs) were found to have opposed attentional biases (bottom-up or cue-driven attention vs. top-down or goal-driven attentional control) that are mediated primarily via relatively unresponsive versus elevated levels of cholinergic neuromodulation in the cortex. The capacity for cholinergic neuromodulation in STs is limited by a neuronal choline transporter (CHT) that fails to support increases in cholinergic activity. Moreover, in contrast to STs, the frontal dopamine system in GTs does not respond to the presence of drug cues and, thus, biases against cue-oriented behavior. The opponent cognitive-motivational styles that are indexed by sign- and goal-tracking bestow different cognitive–behavioral vulnerabilities that may contribute to the manifestation of a wide range of neuropsychiatric disorders.

Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and to impairments in gait and balance, and the resulting risks for falls, in patients with Parkinson's disease (PD). Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. Here we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that an M1 PAM amplifies such transient signaling, thereby enhancing and rescuing attentional performance. Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period assessing their capacity for recovering performance. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance recovery. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose).Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, and also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d') in lesioned rats and facilitated the adoption of a more liberal response bias (B" D) in all female rats. Collectively, these findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.

The identification of broadly defined psychological traits that bestow vulnerability for the manifestation of addiction-like behaviors can guide the discovery of the neuronal mechanisms underlying the propensity for drug taking. Sign-tracking behavior in rats (STs) signifies the presence of a trait that predicts a relatively greater behavioral control of Pavlovian drug and reward cues than in rats that exhibit goal-tracking behavior (GTs). We previously demonstrated that relatively poor cholinergic-attentional control in STs is an essential component of the trait indexed by sign-tracking and that this trait aspect contributes to the relatively greater power of drug cues to control the behavior of STs. Here we addressed the possibility that STs and GTs employ fundamentally different psychological mechanisms for the detection of cues in attention-demanding contexts. Rats were trained to perform an operant Sustained Attention Task. As task training advanced to the stage that taxed attentional control, the relative brightness of visual target signals significantly influenced detection performance in STs but not GTs. This finding suggests that STs, but not GTs, rely on bottom-up, cue salience-driven mechanisms to detect cues. GTs may be able to resist behavioral control by Pavlovian drug cues by utilizing goal-directed decisional processes that minimize the influence of the salience of drug cues.

Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and to impairments in gait and balance, and the resulting risks for falls, in patients with Parkinson's disease (PD). Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. Here we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that an M1 PAM amplifies such transient signaling, thereby enhancing and rescuing attentional performance. Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period assessing their capacity for recovering performance. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance recovery. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose).Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, and also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d') in lesioned rats and facilitated the adoption of a more liberal response bias (B" D) in all female rats. Collectively, these findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.