Dose-dependent Relationships of Same-day and Typical Substance Use to Sleep Duration in College Cannabis and Alcohol Users: A Multilevel Modeling Approach Using Daily Diary Data.

This study characterized how quantities of cannabis and alcohol use affect sleep. Single-day and typical cannabis and alcohol use patterns were considered to assess acute-chronic use interactions. Linear and non-linear associations assessed dose-dependence. College students (n=337; 52% female) provided 11,417 days of data, with up to five time points per day. Daily self-reported sleep duration, cannabis use quantity, and alcohol use quantity were subjected to linear mixed modeling to capture linear and curvilinear associations between single-day and typical use on same-night and typical sleep. Sleep duration (difference between bedtime and waketime) was the outcome. Quantity of cannabis used each day andtypical quantity used across all days were predictors in the cannabis models. Parallel single-day and typical alcohol variables were predictors in the alcohol models. Follow-up analyses excluded days with alcohol-cannabis co-use. Main effects of single-day and typical cannabis quantity on sleep duration were observed when all cannabis-use days were modeled. Higher than typical doses of single-day and typical cannabis were associated with longer sleep durations, but only to a point; at the highest doses, cannabis shortened sleep. A main effect of single-day alcohol quantity and two interactions (single-day use with both linear and curvilinear typical use) on sleep duration were observed when all alcohol-use days were modeled. Greater alcohol consumption on a given day led to shorter same-night sleep, but typically heavier drinkers required higher doses than typically lighter drinkers to experience these adverse effects. Follow-up models suggested alcohol co-use may contribute to the purported sleep-promoting effects of cannabis.

Acquired Alterations in Nucleus Accumbens Responsiveness to a Cocaine-Paired Discriminative Stimulus Preceding Rats' Daily Cocaine Consumption.

Resumption of drug taking is a primary focus for substance use disorder research and can be triggered by drug-associated environmental stimuli. The Nucleus Accumbens (NAc) is a key brain region which guides motivated behavior and is implicated in resumption. There remains a pressing need to characterize NAc neurons' responsiveness to drug associated stimuli during withdrawal and abstinence. We recorded discriminative stimulus (DS) induced NAc activity via in vivo single-unit electrophysiology in rats that self-administered cocaine. Male and female rats implanted with a jugular catheter and a microwire array in NAc Core and Shell self-administered cocaine under control of a 30s auditory DS for 6 hours per session across 14 consecutive days. Rats acquired tone discrimination within 4 sessions. To exclude pharmacological effects of circulating cocaine from all neural analyses, we studied changes in DS-induced firing only for trials preceding the first infusion of cocaine in each of the 14 sessions, which were defined as "pre-drug trials." NAc neuron responses were assessed prior to tone-evoked movement onset. Responsiveness to the DS tone was exhibited throughout all sessions by the NAc Core population, but only during Early sessions by the NAc Shell population. Both Core and Shell responded selectively to the DS, i.e., more strongly on drug taking trials, or Hits, than on Missed opportunities. These findings suggest that NAc Core and Shell play distinct roles in initiating cocaine seeking prior to daily cocaine consumption, and align with reports suggesting that as drug use becomes chronic, cue-evoked activity shifts from NAc Shell to NAc Core.

Use and perceived usefulness of a just-in-time resonance breathing intervention adjunct for substance use disorder: Contextual and physiological predictors.

Craving for alcohol and other drugs is often described as a momentary hyperarousal state that interferes with one's ability to use top-down strategies. As such, it may be best interrupted 'in the moment' through bottom-up modulation. We recently reported that episodic resonance paced breathing (eRPB) delivered via mobile phone app as an add-on to outpatient treatment for substance use disorder (SUD) was effective at dampening craving over the course of an 8-week intervention (NCT#02579317). However, not all participants engaged with the eRPB app and there was high intra- and inter-individual variability in weekly ratings of usefulness. Here we examined baseline demographic, physiological, and psychiatric measures as well as time-varying exposure to positive, negative, and temptation craving triggers as predictors of frequency of eRPB app use and ratings of usefulness. Seventy-seven outpatient women were randomized to an eRPB (0.1 Hz) or a faster paced breathing sham (0.23 Hz) condition. Baseline measures were assessed within the first 3 weeks of treatment entry prior to randomization. App use frequency, ratings of usefulness, and trigger exposure were measured weekly throughout the intervention. Variables were entered into marginal means models with forward stepwise model selection and examined as predictors of use and usefulness. Frequent app use was associated with a lifetime alcohol use disorder (AUD) diagnosis (p = 0.026), higher ratings of usefulness (p < 0.001), and fewer exposures to positive triggers (e.g., celebration, socialization; p < 0.001). There was a trend-level association between frequency of app use and greater cardiovascular capacity at baseline (p = 0.088). Higher ratings of usefulness were associated with greater exposure to negative triggers (e.g,. loneliness, frustration; p < 0.001) and parasympathetic dysregulation at baseline (p = 0.05). A positive relationship between app use frequency and ratings of usefulness was present only in the eRPB group (p = 0.045). Matching ideal candidates and moments to an arousal modulation anti-craving intervention can help streamline screening and implementation of eRPB in the treatment of SUD. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02579317, identifier NCT02579317.

Reward versus motoric activations in nucleus accumbens core of rats during Pavlovian conditioning.

The nucleus accumbens (NAc) core plays an important role in processing of events related to food reward, such as conditioned cues, approach or consumption. Nonetheless, there is lack of clarity regarding whether NAc core processes these separable events differently. We used the high temporal and spatial resolution of single unit recording with trial-by-trial video analysis to examine firing during three distinct categories termed cue, approach and consumption in a Pavlovian task. We had three goals. First, we sought to precisely define task-related behaviour in terms of distinct phases, in order to compare neural activity between motorically matched behaviours. We found that cue-evoked firing did not distinguish between trials on which animals initiated an approach versus ones on which they did not. Firing associated with consumption was greater than firing associated with motorically similar uncued head entry, indicating that previously reported decreases in NAc core firing during consumption relative to approach or baseline may reflect differences in motor behaviour. Secondly, we assessed changes in firing over the course of training. We found that NAc core neurons acquired a response to the tone cue within three sessions but did not change further across 10 total sessions. Thirdly, we correlated individual neuron firing during a given event with its firing during the same event on subsequent sessions. We found substantial variation in processing of cue and approach but not consumption, indicating that a given neuron may process certain events differently from session to session, while maintaining more stable processing of appetitive reward.

Functional connectivity in the central executive network predicts changes in binge drinking behavior during emerging adulthood: an observational prospective study.

BACKGROUND AND AIMS: Binge drinking contributes to the immense public health burden associated with alcohol use, especially among younger drinkers. Little is known about the underlying neurobiology of changes in this behavior over time. This preliminary study aimed to identify neurobiological markers of binge drinking behavior change during emerging adulthood. DESIGN: Observational prospective investigation of neurobiological predictors of binge drinking behavior. SETTING: Communities surrounding a large, public university in the northeastern United States. PARTICIPANTS: A total of 42 emerging adults (48% female), approximately half meeting criteria for an alcohol use disorder. MEASUREMENTS: Past month binge drinking, the dependent variable, was assessed at two time-points (T1, T2) via self-report. Ten indices of resting-state functional connectivity within the central executive network (CEN), a brain network involved in executive function, were collected at T1 and specified as independent variables in cross-sectional and prospective Poisson models. All models controlled for age, sex, and alcohol use disorder status. FINDINGS: The cross-sectional model yielded five significant associations between CEN connectivity and binge drinking incidence. Connections anchored primarily in the anterior CEN exhibited negative associations with binge drinking incidence (P = 0.001, 0.004, 0.011), and connections stemming from the right posterior parietal cortex exhibited positive associations with binge drinking incidence (P = 0.041, 0.045). In prospective models, stronger frontoparietal connectivity between the right dorsolateral prefrontal cortex and left posterior parietal cortex predicted greater increases in binge drinking incidence over time (P = 0.003). CONCLUSIONS: There is an association between central executive network connectivity and heavy drinking, as well as evidence that functional pathways within the central executive network may contribute to changes in problematic drinking behaviors.

Long-lasting Behavioral and Neuroanatomical Effects of Postnatal Valproic Acid Treatment.

Valproic acid (VPA) administered to mice during the early postnatal period causes social, cognitive, and motor deficits similar to those observed in humans with autism spectrum disorder (ASD). However, previous studies on the effects of early exposure to VPA have largely focused on behavioral deficits occurring before or during the juvenile period of life. Given that ASD is a life-long condition, the present study ought to extend our understanding of the behavioral profile following early postnatal VPA into adulthood. Male mice treated with VPA on postnatal day 14 (P14) displayed increased aggression, decreased avoidance of the open arms in the elevated plus maze, and impaired reversal learning in the Y maze. This may indicate a disinhibited or impulsive phenotype in male, but not female, mice treated with VPA during the second week of postnatal life. Decreased dendritic spine density and dendritic spine morphological abnormalities in the mPFC of VPA-treated mice may be indicative of PFC hypofunction, consistent with the observed behavioral differences. Since these types of long-lasting deficits are not exclusively found in ASD, early life exposure to VPA may reflect dysfunction of a neurobiological domain common to several developmental disorders, including ASD, ADHD, and conduct disorder.

Emergence of negative affect as motivation for drug taking in rats chronically self-administering cocaine.

RATIONALE: The role of negative affect as a motivational factor in animal models of drug addiction has been underexplored in the context of cocaine self-administration. OBJECTIVES: The present investigation studied the relationship between magnitude of affective response and quantity of cocaine consumed in order to clarify the affective components that drive drug use in a preclinical model. METHODS: Rats self-administered (SA) cocaine 6 h/day for 14 consecutive days while their ultrasonic vocalizations (USVs) were recorded. RESULTS: Animals displayed an increase in 50-kHz call rates (indicating positive affect) when their drug levels were rapidly rising and an increase in 22-kHz call rates (indicating negative affect) when forced to abstain. The rate of 50-kHz calls predicted drug consumption during the 1st week of SA, but not week two. Contrarily, there was a strongly predictive positive association between rate of 22-kHz calls and amount of drug consumed during the 2nd week of SA. CONCLUSIONS: Experimental results indicate that after chronic cocaine self-administration, negative affect emerges when animals are deprived of expected drug during withdrawal. Moreover, the increase in USVs indicating negative affect when deprived of drug was directly related to drug intake, concurrent with a decay in the direct relationship between USVs indicating positive affect and drug intake. The present preclinical support for the widely hypothesized shift from positive to negative affect as a salient motivational factor in human drug abuse adds to growing evidence of the unique value of rat USVs for understanding the role of emotion in drug addiction.

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.

Electrophysiological evidence of alterations to the nucleus accumbens and dorsolateral striatum during chronic cocaine self-administration.

As drug use becomes chronic, aberrant striatal processing contributes to the development of perseverative drug-taking behaviors. Two particular portions of the striatum, the nucleus accumbens (NAc) and the dorsolateral striatum (DLS), are known to undergo neurobiological changes from acute to chronic drug use. However, little is known about the exact progression of changes in functional striatal processing as drug intake persists. We sampled single-unit activity in the NAc and DLS throughout 24 daily sessions of chronic long-access cocaine self-administration, and longitudinally tracked firing rates (FR) specifically during the operant response, an upward vertical head movement. A total of 103 neurons were held longitudinally and immunohistochemically localised to either NAc Medial Shell (n = 29), NAc Core (n = 30), or DLS (n = 54). We modeled changes representative of each category as a whole. Results demonstrated that FRs of DLS Head Movement neurons were significantly increased relative to baseline during all sessions, while FRs of DLS Uncategorised neurons were significantly reduced relative to baseline during all sessions. NAc Shell neurons' FRs were also significantly decreased relative to baseline during all sessions while FRs of NAc Core neurons were reduced relative to baseline only during training days 1-18 but were not significantly reduced on the remaining sessions (19-24). The data suggest that all striatal subregions show changes in FR during the operant response relative to baseline, but longitudinal changes in response firing patterns were observed only in the NAc Core, suggesting that this region is particularly susceptible to plastic changes induced by abused drugs.

Sensitivity to self-administered cocaine within the lateral preoptic-rostral lateral hypothalamic continuum.

The lateral preoptic-rostral lateral hypothalamic continuum (LPH) receives projections from the nucleus accumbens and is believed to be one route by which nucleus accumbens signaling affects motivated behaviors. While accumbens firing patterns are known to be modulated by fluctuating levels of cocaine, studies of the LPH's drug-related firing are absent from the literature. The present study sought to electrophysiologically test whether drug-related tonic and slow-phasic patterns exist in the firing of LPH neurons during a free-access cocaine self-administration task. Results demonstrated that a majority of neurons in the LPH exhibited changes in both tonic and slow-phasic firing rates during fluctuating drug levels. During the maintenance phase of self-administration, 69.6% of neurons exhibited at least a twofold change in tonic firing rate when compared to their pre-drug firing rates. Moreover, 54.4% of LPH neurons demonstrated slow-phasic patterns, specifically "progressive reversal" patterns, which have been shown to be related to pharmacological changes across the inter-infusion interval. Firing rate was correlated with calculated drug level in 58.7% of recorded cells. Typically, a negative correlation between drug level and firing rate was observed, with a majority of neurons showing decreases in firing during cocaine self-administration. A small percentage of LPH neurons also exhibited correlations between locomotor behavior and firing rate; however, correlations with drug level in these same neurons were always stronger. Thus, the weak relationships between LPH firing and locomotor behaviors during cocaine self-administration do not account for the observed changes in firing. Overall, these findings suggest that a proportion of LPH neurons are sensitive to fluctuations in cocaine concentration and may contribute to neural activity that controls drug taking.

Ultrasonic vocalizations: evidence for an affective opponent process during cocaine self-administration.

RATIONALE: Preclinical models of cocaine addiction in the rodent have shown that cocaine induces both positive and negative affective states. These observations have led to the notion that the initial positive/euphoric state induced by cocaine administration may be followed by an opposing, negative process. In the rodent, one method for inferring positive and negative affective states involves measuring their ultrasonic vocalizations (USVs). Previous USV recordings from our laboratory suggested that the transition between positive and negative affect might involve decaying or sub-satiety levels of self-administered cocaine. OBJECTIVES: In order to explicitly test the role of cocaine levels on these affective states, the present study examined USVs when calculated body levels of cocaine were clamped (i.e., held at a constant level via experimenter-controlled infusions) at, below, or above subjects' self-determined drug satiety thresholds. RESULTS: USVs indicated that (1) positive affect was predominantly observed during the drug loading period, but declined quickly to near zero during maintenance and exhibited little relation to calculated drug level, and (2) in contrast, negative affect was observed at sub-satiety cocaine levels, but was relatively absent when body levels of cocaine were clamped at or above subjects' satiety thresholds. CONCLUSIONS: The results reinforce the opponent-process hypothesis of addiction and suggest that an understanding of the mechanisms underlying negative affect might serve to inform behavioral and pharmacological therapies.

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.

Amphetamine's dose-dependent effects on dorsolateral striatum sensorimotor neuron firing.

Amphetamine elicits motoric changes by increasing the activity of central neurotransmitters such as dopamine and serotonin, but how these neurochemical signals are transduced into motor commands is unclear. The dorsolateral striatum (DLS), a component of the cortico-subcortical reentrant motor loop, contains abundant neurotransmitter transporters that amphetamine could affect. It has been hypothesized that DLS medium spiny neurons contribute to amphetamine's motor effects. To study striatal activity contributing to amphetamine-induced movements, activity of DLS neurons related to vertical head movement was recorded while tracking head movements before and after acute amphetamine injection. Relative to saline, all amphetamine doses induced head movements above pre-injection levels, revealing an inverted U-shaped dose-response function. Lower doses (1 mg/kg and 2 mg/kg, intraperitoneal) induced a greater number of long (distance and duration) movements than the high dose (4 mg/kg), which induced stereotypy. Firing rates (FR) of individual head movement neurons were compared before and after injection during similar head movements, defined by direction, distance, duration, and apex. Changes in FR induced by amphetamine were co-determined by dose and pre-injection FR of the neuron. Specifically, all doses increased the FRs of slower firing neurons but decreased the FRs of faster firing neurons. The magnitudes of elevation or reduction were greater at lower doses, but less pronounced at the high dose, forming an inverted U function. Modulation of DLS firing may interfere with sensorimotor processing. Furthermore, pervasive elevation of slow firing neurons' FRs may feed-forward and increase excitability in thalamocortical premotor areas, contributing to the increased movement initiation rate.

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.

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.

Dose-dependent differences in short ultrasonic vocalizations emitted by rats during cocaine self-administration.

RATIONALE: The motivational impetuses underlying self-administration of cocaine and other drugs of abuse are not fully understood. One emerging factor is affect. Both positive and negative affective states have been hypothesized to influence drug seeking and drug taking. In parallel, it has been posited that the ultrasonic vocalizations (USVs) of Rattus norvegicus provide insight into the animals' affective reactions. Furthermore, it has been shown that mesolimbic dopamine (DA) plays a key role in cocaine self-administration and in USV production. Thus, affective processing as measured by rodent USVs likely coincides with cocaine self-administration, but to date has not been studied. OBJECTIVE: The present study examined USVs in both the negative affective (18-32.99 kHz) and positive affective (38-80 kHz) ranges of rats during self-administration of a low (0.355 mg/kg/infusion) or high (0.71 mg/kg/infusion) dose of cocaine. RESULTS: USVs in both ranges were observed in both dose groups. Vocalizations of the low-dose animals occurred primarily in the 22-kHz range (18-32.99 kHz), but exhibited shorter durations (10-500 ms) than those traditionally observed for 22-kHz calls in aversive situations. In contrast, USVs of the high-dose group were primarily observed in the 50-kHz frequency range (38-80 kHz), typically associated with appetitive outcomes. CONCLUSIONS: These results provide evidence for the presence of USVs during cocaine self-administration. The observed dose-dependent difference in USVs provides novel support for the view that affect is one potential motivational factor influencing human drug use and relapse behaviors. Rodent USVs may provide a powerful tool for understanding the role of affect in addiction.

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.

Acute effects of cocaine on movement-related firing of dorsolateral striatal neurons depend on predrug firing rate and dose.

To investigate striatal mechanisms underlying the acute effects of stimulants on motor behavior, firing rates (FRs) of striatal neurons related specifically to vertical head movement were studied exclusively during vertical head movements. Precocaine FRs were recorded after intraperitoneal saline injection (time 1; T1), and rats performed conditioned vertical head movements (>10,000) similar to those induced by stimulants. After cocaine injection (0, 5, 10, or 20 mg/kg; T2), animals continued in the task. The proportion of long head movements was increased by low doses but decreased by the high dose, which induced stereotypic head movements. Comparing each neuron's FR during movements that were matched between T1 and T2 (e.g., regarding direction, distance), cocaine's effects depended on predrug FR and dose. Plots regressing T2FR on T1FR showed dose-dependent, "clockwise" rotations of regression lines in plots of all the neurons' average FRs and of individual neurons' FRs during different movements. All three doses elevated normally low FRs; the high dose also suppressed many higher FRs. Enhancement of a neuron's FR associated with weak and suppression of FR associated with strong corticostriatal inputs contradict several current theories of dopamine (DA) function. Induction of stereotypy by a single, high-dose injection suggests that this cocaine level exceeded that in other studies using cocaine self-administration, in which stereotypy develops only after several sessions. Suppressive effects observed only at the high dose and in numerous electrophysiological studies of DA agonist effects may be unrepresentative of uniform elevations in lateral striatal firing related to movement observed at lower cocaine levels.

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 drug's 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.