Anthony P. Pawlak

Cognitive impairment influences drinking outcome by altering therapeutic mechanisms of change.

Serious neuropsychological impairments are seen in a minority of addiction treatment clients, and, theoretically, these impairments should undermine behavioral changes targeted by treatment; however, little evidence supports a direct influence of impairment on treatment response. To address this paradox, the authors used structural equation modeling and Project MATCH data (N=1,726) to examine direct, mediated, and moderated paths between cognitive impairment, therapeutic processes, and treatment outcome. Mediated relations were found, wherein impairment led to less treatment compliance, lower self-efficacy, and greater Alcoholics Anonymous Involvement, which, in turn, more proximally predicted drinking. Impairment further moderated the effect of self-efficacy, making it a poor predictor of drinking outcomes in impaired clients, thereby suggesting that impaired and unimpaired clients traverse different pathways to addiction recovery.

Changes in activity of the striatum during formation of a motor habit

To examine experience‐dependent plasticity of striatal neurons during habit learning in awake, freely moving animals, single neurons in the dorsolateral striatum (54 neurons related specifically to vertical head movement and 14 unresponsive neurons, i.e. not related to any body movement) were recorded and tracked off‐line to assess changes in firing rate over sessions as performance of instrumental head movement became automatic and habitual. Rats were trained to emit operant vertical head movements that triggered water delivery for 14 sessions (2 h per session, one session per day). Rats significantly increased the number and efficiency of head movements over sessions until reaching asymptotic behaviour. Habit formation was indicated by significantly higher levels of instrumental responding exhibited by rats during a late, relative to an early, session in which the reward was devalued. As head movements became habitual across sessions, most head movement‐related neurons (89%) exhibited decreased firing rate, while a small population (11%) exhibited increased or maintained firing rate. The rate of decrease in firing by the majority correlated with the rate of improvement in movement efficiency over sessions. All unresponsive neurons, though not apparently related to movement, exhibited decreased firing rate over sessions. Our findings suggest that, during habit learning, the striatum may shift from facilitating acquisition of efficient movement with a large population of neurons to modulating or maintaining habitual movement with stronger firing of fewer movement‐related neurons.

Evidence for habitual and goal-directed behavior following devaluation of cocaine: a multifaceted interpretation of relapse.

Background Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drugs consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit. Methodology/Principal Findings We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine. Conclusions/Significance Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus–nearly perfectly correlated with the infusion–likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse.

Brief light as a practical aversive stimulus for the albino rat

Bright light was an effective aversive stimulus for Wistar rats in punishment, escape, and avoidance paradigms. Contingent punishment of lever pressing maintained by concurrent schedules of food delivery shifted presses to an alternate lever, and depressed overall response rates. Periodic non-contingent presentation of the light prompted escape responding (head entry into a hole). Unsignaled avoidance contingencies were not effective, but pre-pulse signaling of light supported avoidance behavior. These results demonstrate a possible alternative to foot-shock, one with greater ecological validity, and one that might avoid some of the physiological effects that accompany electric shock.

Rat ultrasonic vocalizations demonstrate that the motivation to contextually reinstate cocaine-seeking behavior does not necessarily involve a hedonic response

Human self‐reports often indicate that changes in mood are a major contributor to drug relapse. Still, arguments have been made that instances of drug‐seeking following abstinence in animal models (i.e. relapse/reinstatement) may be outside of hedonic control. Therefore, the present study utilized ultrasonic vocalizations in the rat in order to evaluate affect during cocaine self‐administration and contextual reinstatement of cocaine‐seeking in a pre‐clinical model of drug relapse (abstinence‐reinstatement model). Results show that while subjects effectively reinstated drug‐seeking (lever pressing) following 30 days of abstinence, and spontaneously recovered/reinstated drug‐seeking following 60 days of abstinence, ultrasonic vocalizations did not increase over baseline levels during either reinstatement session. These results are consistent with previous results from our laboratory and current theories of addiction suggesting that cues that are weakly associated with drug consumption can motivate drug‐seeking behavior that is outside of hedonic processing.

FLUCTUATIONS IN SOMATOSENSORY RESPONSIVENESS AND BASELINE FIRING RATES OF NEURONS IN THE LATERAL STRIATUM OF FREELY MOVING RATS: EFFECTS OF INTRANIGRAL APOMORPHINE

Somatosensory responsiveness and baseline firing rates of 102 striatal neurons were studied in freely moving rats. For individual neurons, mean levels of responsiveness and baseline firing fluctuated unpredictably in direction and magnitude and independently of each other throughout an experiment. Following microinjections of apomorphine into the substantia nigra, which were used as a means of reducing nigral output activity, the magnitude of fluctuations in striatal somatosensory responsiveness significantly increased, while the magnitude of fluctuations in baseline firing was unaltered. The receptive zones of 54 neurons studied in control experiments remained stable, whereas receptive zones changed in 12 of 25 neurons studied after apomorphine microinjection. Normal nigrostriatal dopamine transmission appears to selectively restrict the magnitude of fluctuations in responsiveness of striatal neurons to corticostriatal synaptic input and may exert additional control over afferent projections from cutaneous receptive zones to these neurons.

Slow phasic and tonic activity of ventral pallidal neurons during cocaine self‐administration

Ventral pallidal (VP) neurons exhibit rapid phasic firing patterns within seconds of cocaine‐reinforced responses. The present investigation examined whether VP neurons exhibited firing rate changes: (1) over minutes during the inter‐infusion interval (slow phasic patterns) and/or (2) over the course of the several‐hour self‐administration session (tonic firing patterns) relative to pre‐session firing. Approximately three‐quarters (43/54) of VP neurons exhibited slow phasic firing patterns. The most common pattern was a post‐infusion decrease in firing followed by a progressive reversal of firing over minutes (51.16%; 22/43). Early reversals were predominantly observed anteriorly whereas progressive and late reversals were observed more posteriorly. Approximately half (51.85%; 28/54) of the neurons exhibited tonic firing patterns consisting of at least a two‐fold change in firing. Most cells decreased firing during drug loading, remained low over self‐administration maintenance, and reversed following lever removal. Over a whole experiment (tonic) timescale, the majority of neurons exhibited an inverse relationship between calculated drug level and firing rates during loading and post‐self‐administration behaviors. Fewer neurons exhibited an inverse relationship of calculated drug level and tonic firing rate during self‐administration maintenance but, among those that did, nearly all were progressive reversal neurons. The present results show that, similar to its main afferent the nucleus accumbens, VP exhibits both slow phasic and tonic firing patterns during cocaine self‐administration. Given that VP neurons are principally GABAergic, the predominant slow phasic decrease and tonic decrease firing patterns within the VP may indicate a disinhibitory influence upon its thalamocortical, mesolimbic, and nigrostriatal targets during cocaine self‐administration. Synapse, 2012.

Dose- and Rate-Dependent Effects of Cocaine on Striatal Firing Related to Licking

To examine the role of striatal mechanisms in cocaine-induced stereotyped licking, we investigated the acute effects of cocaine on striatal neurons in awake, freely moving rats before and after cocaine administration (0, 5, 10, or 20 mg/kg). Stereotyped licking was induced only by the high dose. Relative to control (saline), cocaine reduced lick duration and concurrently increased interlick interval, particularly at the high dose, but it did not affect licking rhythm. Firing rates of striatal neurons phasically related to licking movements were compared between matched licks before and after injection, minimizing any influence of sensorimotor variables on changes in firing. Both increases and decreases in average firing rate of striatal neurons were observed after cocaine injection, and these changes exhibited a dose-dependent pattern that strongly depended on predrug firing rate. At the middle and high doses relative to the saline group, the average firing rates of slow firing neurons were increased by cocaine, resulting from a general elevation of movement-related firing rates. In contrast, fast firing neurons showed decreased average firing rates only in the high-dose group, with reduced firing rates across the entire range for these neurons. Our findings suggest that at the high dose, increased phasic activity of slow firing striatal neurons and simultaneously reduced phasic activity of fast firing striatal neurons may contribute, respectively, to the continual initiation of stereotypic movements and the absence of longer movements.

Absence of cue-evoked firing in rat dorsolateral striatum neurons

The rat dorsolateral striatum (DLS) has been implicated in habit formation. Previous studies in our laboratory found that as animals acquired a motor habit or remained goal-directed, tested by reward devaluation, the vast majority of DLS neurons decreased firing rates during the same responses over training days. However, mixed results have been reported in the literature regarding whether DLS neurons exhibit cue reactivity. In the present study, we reanalyzed a sample of DLS neurons in a task in which habitual behavior was acquired (dataset of Tang et al., 2007 [45]) and found that somatic sensorimotor as well as nonsomatomotor neurons of the DLS exhibited no cue-evoked firing. A second sample of DLS neurons related to licking in a task in which goal-directed behavior occurred (dataset of Tang et al., 2009 [46]) was also reanalyzed for cue-evoked correlates. Although behavior was cue guided, lick neurons did not exhibit cue-evoked firing. Given the complete absence of cue-related firing during habitual or goal-directed behavior, adaptations in DLS firing patterns may be regulated by movement-related learning rather than nonsomatosensory cues, consistent with convergent S1 and M1 afferents to the region. Striatal cue reactivity in the rat, is likely mediated within the dorsomedial and ventromedial striatum, in line with associative and limbic afferents to these regions, respectively.

Representation of the body in the lateral striatum of the freely moving rat: Fast Spiking Interneurons respond to stimulation of individual body parts

Numerous studies have shown that certain types of striatal interneurons play a crucial role in selection and regulation of striatal output. Striatal Fast-Spiking Interneurons (FSIs) are parvalbumin positive, GABAergic interneurons that constitute less than 1% of the total striatal population. It is becoming increasingly evident that these sparsely distributed neurons exert a strong inhibitory effect on Medium Spiny projection Neurons (MSNs). MSNs in lateral striatum receive direct synaptic input from regions of cortex representing discrete body parts, and show phasic increases in activity during touch or movement of specific body parts. In the present study, we sought to determine whether lateral striatal FSIs identified by their electrophysiological properties, i.e., short-duration spike and fast firing rate (FR), display body part sensitivity similar to that exhibited by MSNs. During video recorded somatosensorimotor exams, each individual body part was stimulated and responses of single neurons were observed and quantified. Individual FSIs displayed patterns of activity related selectively to stimulation of a discrete body part. Most patterns of activity were similar to those exhibited by typical MSNs, but some phasic decreases were observed. These results serve as evidence that some striatal FSIs process information related to discrete body parts and participate in sensorimotor processing by striatal networks that contribute to motor output. STATEMENT OF SIGNIFICANCE Parvalbumin positive, striatal FSIs are hypothesized to play an important role in behavior by inhibiting MSNs. We asked a fundamental question regarding information processed during behavior by FSIs: whether FSIs, which preferentially occupy the sensorimotor portion of the striatum, process activity of discrete body parts. Our finding that they do, in a selective manner similar to MSNs, begins to reveal the types of phasic signals that FSI feed forward to projection neurons during striatal processing of cortical input regarding a specific sensorimotor event. These findings suggest new avenues for testing feed-forward inhibition theory as applied to striatum in naturalistic conditions, such as whether FSI decreases facilitate excitation of MSNs related to the current movement while FSI increases silence MSNs unrelated to the current movement.