Differential roles of the dorsolateral and midlateral striatum in punished cocaine seeking.

Continued instrumental drug seeking despite contingent punishment is a core phenotype of drug addiction. Although the neuroanatomical basis of punished drug seeking is unclear, we hypothesize that the sensorimotor striatum, a structure that mediates habitual drug seeking, also mediates punished cocaine seeking. Forelimb sensorimotor projections into the striatum of the rat extend from the dorsolateral to midlateral striatum. Here, we selectively inactivated the dorsolateral and midlateral striatum in rats responding for cocaine in a seeking-taking task. We inactivated both regions after the acquisition of cocaine seeking, after extended cocaine self-administration and finally after the introduction of intermittent, seeking-contingent foot shock. The results show that inactivation of the dorsolateral striatum selectively disrupted punished drug seeking but did not affect unpunished drug seeking, even after extended training. Inactivation of the midlateral striatum, on the other hand, disrupted drug seeking at all stages of training. The effect of inactivating the dorsolateral striatum under punishment conditions was present before delivery of the first shock in the session, and responding reverted to baseline the next day. Thus, inactivation of the dorsolateral striatum seems to enhance the influence of recalled threat of negative consequences of cocaine seeking. The proportional reduction in responding after inactivation of the dorsolateral striatum did not vary with the individual level of compulsivity. Together, these results suggest a novel differentiation of function in the sensorimotor striatum, where the dorsolateral striatum selectively mediates the rigidity of responding after overtraining, while the midlateral striatum mediates responding itself at all stages of training.

Dorsal and ventral striatal protein synthesis inhibition affect reinforcer valuation but not the consolidation of instrumental learning.

The evidence for a role of the striatum in the acquisition of uncued instrumental responding is ambiguous. It has been shown that post-session infusions of anisomycin into the core of the nucleus accumbens (NAcc) impaired instrumental acquisition, but pre-training lesions of the NAcc suggest that it is not necessary. Recently, we demonstrated that the infusion of anisomycin into the anterior cingulate cortex impaired instrumental acquisition indirectly through a taste aversion. Thus, we hypothesized that post-session anisomycin infusions into the NAcc affected instrumental acquisition through an effect on reinforcer valuation. For the dorsal striatum, both post-session infusions of anisomycin and pre-training lesion studies suggest that neither the dorsolateral nor the dorsomedial striatum is necessary for the acquisition of instrumental responding. However, it has not been attempted to block plasticity in both regions concurrently, and we hypothesized that both regions independently contribute to acquisition through goal-directed and habitual learning. In the current experiments, we first replicated the effect of unprotected post-session anisomycin infusions into the NAcc on instrumental acquisition. Subsequently, we investigated the effect of protein synthesis inhibition in the NAcc and dorsomedial and dorsolateral striatum concurrently on instrumental acquisition, critically controlling for effects on reinforcer valuation. The anisomycin infusions induced an aversive state, but did not affect instrumental acquisition.

Opposing roles for striatonigral and striatopallidal neurons in dorsolateral striatum in consolidating new instrumental actions.

Comparatively little is known about how new instrumental actions are encoded in the brain. Using whole-brain c-Fos mapping, we show that neural activity is increased in the anterior dorsolateral striatum (aDLS) of mice that successfully learn a new lever-press response to earn food rewards. Post-learning chemogenetic inhibition of aDLS disrupts consolidation of the new instrumental response. Similarly, post-learning infusion of the protein synthesis inhibitor anisomycin into the aDLS disrupts consolidation of the new response. Activity of D1 receptor-expressing medium spiny neurons (D1-MSNs) increases and D2-MSNs activity decreases in the aDLS during consolidation. Chemogenetic inhibition of D1-MSNs in aDLS disrupts the consolidation process whereas D2-MSN inhibition strengthens consolidation but blocks the expression of previously learned habit-like responses. These findings suggest that D1-MSNs in the aDLS encode new instrumental actions whereas D2-MSNs oppose this new learning and instead promote expression of habitual actions.

Post-learning infusion of anisomycin into the anterior cingulate cortex impairs instrumental acquisition through an effect on reinforcer valuation.

The integrity of the rodent anterior cingulate cortex (ACC) is essential for various aspects of instrumental behavior, but it is not clear if the ACC is important for the acquisition of a simple instrumental response. Here, it was demonstrated that post-session infusions of anisomycin into the rat ACC completely prevented the acquisition of instrumental responding. The experimental use of post-session intracranial infusions of plasticity inhibitors is assumed to affect local consolidation of plasticity, but not behavioral task performance. However, in associative appetitive conditioning, post-session intracranial infusion of pharmaco-active compounds could actually interfere with subsequent task performance indirectly through retrospective effects on the valuation of ingested rewards. Thus, it was subsequently demonstrated that the intracranial infusion of anisomycin into the ACC after sucrose pellet consumption significantly reduced subsequent pellet consumption, suggesting that the infusion of anisomycin into the ACC produced conditioned taste avoidance. In the third experiment, an innovative procedure was introduced that dissociated the effects of intracranial infusions after conditioning sessions on task-learning and unconditioned stimulus valuation. With this procedure, the infusion of anisomycin into the ACC after instrumental sessions did not affect instrumental reinforcer valuation or the acquisition of instrumental responding, suggesting that plasticity in the ACC is not necessary for the acquisition of instrumental behavior.

Delayed rewards facilitate habit formation.

The transition from goal-directed to habitual forms of instrumental behavior is determined by variables such as the amount of training, schedules of reinforcement, the availability of choices, and exposure to drugs of abuse. Less is known about the control of goal-directed behavior when reinforcement is delayed rather than immediate. In these experiments, we investigated in rats the role of response-outcome contiguity on the control of goal-directed action, assessed through satiety-specific outcome devaluation tests. In Experiment 1 using a within-subjects design we observed goal-directed behavior after 6 days of FR1 training when the outcome was presented immediately following the lever press, but not when it was delayed for 20 s, revealing habit formation with delayed outcomes. Experiment 2 revealed that the habitual control observed with 20-s delays of reinforcement can be prevented if, immediately before each instrumental training session, the rats were exposed to the experimental context in the absence of both the lever and reinforcement. In summary, these experiments suggest that response-outcome contiguity plays an important role in the control of goal-directed actions and habits. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Spontaneous nicotine withdrawal potentiates the effects of stress in rats.

Anxiety is a common symptom of nicotine withdrawal in humans, and may predict an inability to abstain from cigarette smoking. It is not clear if self-reports of anxiety during abstinence reflect increased baseline anxiety and/or increased responses to exogenous stressors. We hypothesized that nicotine withdrawal selectively exacerbates reactivity to aversive stimuli in rodents. Here, we investigated the effect of withdrawal from chronic nicotine administration (3.16 mg/kg per day base, delivered via subcutaneous osmotic minipumps) in the light-enhanced startle (LES) test in Wistar rats. In this procedure, baseline startle responding in the dark is compared to startle responding when the chamber is brightly lit. Bright illumination is aversive for rats and potentiates the startle response. Hence, this procedure allows comparisons of withdrawal effects on startle reactivity between relatively neutral and stressful contexts. We found that spontaneous nicotine withdrawal (24 h post-pump removal) did not influence baseline startle responding, but produced a selective increase in LES. Precipitated nicotine withdrawal through injections of one of two nicotinic acetylcholine receptor (nAChR) antagonists, dihydro-beta-erythroidine hydrobromide (DHbetaE: 0, 1.5, 3, or 6 mg/kg) or mecamylamine (0, 1, 2, or 4 mg/kg), did not influence baseline startle responding or LES. These results suggest that spontaneous nicotine withdrawal selectively potentiates responses to anxiogenic stimuli, but does not by itself produce a strong anxiogenic effect. These findings support the hypothesis that nicotine withdrawal exacerbates stress responding, and indicate LES may be a useful model to examine withdrawal effects on anxiety.

Rats assess costs and benefits according to an internal standard.

Variation in effort to obtain rewards is a fact of mammalian everyday life. In this study, we assess how rats scale variable costs and benefits. Different groups of rats were trained in a T-maze to discriminate a high (three or five sugar pellets) from a low reward (one sugar pellet) arm. Subsequently barriers were introduced at the high and low reward side such that the overall long-term pay-off of the high reward arm finally became lower than that of the low reward arm. The data show that under different regimes of costs (climbing barriers) and benefits (number of rewards) of the two arms rats appear to shift their behaviour towards the better side according to a constant relative cost-benefit ratio between the arms. Such a ratio allows them to deal with variation in the (physical appearance of) costs and benefits and choose the best long-term option.

Blockade of nicotinic acetylcholine or dopamine D1-like receptors in the central nucleus of the amygdala or the bed nucleus of the stria terminalis does not precipitate nicotine withdrawal in nicotine-dependent rats.

Approximately 70% of tobacco smokers wish to quit, but attempts are often unsuccessful partly due to the aversive nicotine withdrawal syndrome. We investigated the possible involvement of nicotinic and dopaminergic signalling in the central nucleus of the amygdala (CeA) and dorsolateral bed nucleus of the stria terminalis (dlBNST) in the anhedonic depression-like effect of precipitated nicotine withdrawal in rats. Nicotine-dependent rats exhibit elevations in intracranial self-stimulation (ICSS) thresholds compared to control rats after cessation of chronic nicotine administration (spontaneous withdrawal) or systemic or intra-ventral tegmental area (VTA), but not intra-nucleus accumbens (NAcc), administration of nicotinic acetylcholine receptor (nAchR) antagonists while exposed to nicotine (precipitated withdrawal). We examined whether intracerebral administration of the nAChR antagonist dihydro-beta-erythroidine (DHbetaE; 0.6-20 microg total bilateral dose) or the dopamine D1-like receptor antagonist SCH 23390 (2-16 microg total bilateral dose) into the CeA and dlBNST results in withdrawal-like threshold elevations in nicotine-treated rats. Nicotinic acetylcholine and D1-like receptor blockade in the CeA or the dlBNST did not induce differential threshold elevations in nicotine- and saline-treated rats. Further, the highest SCH 23390 dose (16 microg bilateral dose) injected into the dlBNST, but not the CeA, elevated thresholds similarly in both saline- and nicotine-treated rats, suggesting that dopaminergic signalling in the dlBNST may regulate brain reward function under baseline conditions. These results suggest that nACh and D1-like signalling in the CeA and the dlBNST does not develop neuroadaptations with the development of nicotine dependence that may be involved in the depression-like aspects of nicotine withdrawal.

Mild anxiogenic effects of nicotine withdrawal in mice.

Increased anxiety is one of the symptoms of nicotine withdrawal that may lead to relapse. Previous studies have shown that nicotine withdrawal affects anxiety-like behavior in different tests of anxiety in humans and rats. However, relatively few studies have focused on the anxiogenic effect of nicotine withdrawal in mice. The present study investigated the effect of nicotine withdrawal on anxiety-like behavior in DBA/2J and C57BL/6J mouse strains in the light-dark box, acoustic startle response, and prepulse inhibition tests. An initial experiment showed that nicotine administration of 12 or 24 mg/kg/day (free base) for 14 days did not result in significant effects during withdrawal in startle, prepulse inhibition, or light-dark box, but there was a trend towards an anxiogenic effect in the light-dark box 24 h, but not 1 or 4 h, after cessation of nicotine administration. A subsequent study was therefore performed, with minipumps delivering saline, 24 mg/kg/day nicotine, or 48 mg/kg/day nicotine (free base), for 14 days. The pumps were removed, and the mice were tested 24 h after cessation of nicotine administration. Cessation of administration of 48 mg/kg/day nicotine free base in C57BL/6J mice resulted in increased anxiety-like behavior in the light-dark box, while the behavior of DBA/2J mice was unaffected. The acoustic startle response and prepulse inhibition were also unaffected in both strains. In conclusion, the present data show that nicotine withdrawal is mildly anxiogenic in C57BL/6J mice under the conditions used in the present experiments.

Molecular, cellular, and structural mechanisms of cocaine addiction: a key role for microRNAs.

The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their highly pleiotropic nature, each miRNA has the potential to regulate hundreds or even thousands of protein-coding RNA transcripts. This property of miRNAs has generated considerable interest in their potential involvement in complex psychiatric disorders such as addiction, as each miRNA could potentially influence the many different molecular and cellular adaptations that arise in response to drug use that are hypothesized to drive the emergence of addiction. Here, we review recent evidence supporting a key role for miRNAs in the ventral striatum in regulating the rewarding and reinforcing properties of cocaine in animals with limited exposure to the drug. Moreover, we discuss evidence suggesting that miRNAs in the dorsal striatum control the escalation of drug intake in rats with extended cocaine access. These findings highlight the central role for miRNAs in drug-induced neuroplasticity in brain reward systems that drive the emergence of compulsive-like drug use in animals, and suggest that a better understanding of how miRNAs control drug intake will provide new insights into the neurobiology of drug addiction.

Drug intake is sufficient, but conditioning is not necessary for the emergence of compulsive cocaine seeking after extended self-administration.

Compulsive drug seeking, which is characterized by continued instrumental effort despite contingent punishment, has been shown to emerge after extended drug self-administration. Exactly what aspect of drug self-administration drives the appearance of addictive behavior is unclear, but the mechanistic explanations that have been offered differ in one key respect. On one hand, it has been suggested that dysfunctional conditioning during self-administration drives unrealistic reward expectations, ultimately producing resistance to punishment. If this is indeed the pathological process that drives compulsive behavior, then compulsivity should be apparent only in the presence of the pavlovian and instrumental stimuli that underwent frequent pairing with the drug reward. On the other hand, it has also been suggested that extended drug intake produces general changes to reward and decision-making circuits that manifest as compulsive drug seeking. Unfortunately, conditioning history and drug intake are generally intrinsically intertwined. However, here we used an animal model of compulsive cocaine seeking to selectively manipulate drug intake and the degree of conditioning in the test context, to investigate which of the two is more important for the emergence of compulsive cocaine seeking. The results show that extended drug intake alone is sufficient, but extended conditioning in the test context is not necessary for the emergence of compulsive cocaine seeking, resolving a fundamental question in addiction research.

The role of contextual conditioning in the effect of reinforcer devaluation on instrumental performance by rats.

Different groups of rats received different amounts of training to lever press for a food reinforcer before an aversion was conditioned to the food. This devaluation of the reinforcer reduced responding in both subsequent extinction and reinforced tests of responding to a degree that was independent of the amount of instrumental training. Moreover, interpolating context extinction between aversion conditioning and the extinction test reduced the magnitude of the devaluation effect, thereby indicating that Pavlovian contextual conditioning may play a role in the instrumental devaluation effect.

Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction.

In this review we discuss the evidence that drug addiction, defined as a maladaptive compulsive habit, results from the progressive subversion by addictive drugs of striatum-dependent operant and Pavlovian learning mechanisms that are usually involved in the control over behaviour by stimuli associated with natural reinforcement. Although mainly organized through segregated parallel cortico-striato-pallido-thalamo-cortical loops involved in motor or emotional functions, the basal ganglia, and especially the striatum, are key mediators of the modulation of behavioural responses, under the control of both action-outcome and stimulus-response mechanisms, by incentive motivational processes and Pavlovian associations. Here we suggest that protracted exposure to addictive drugs recruits serial and dopamine-dependent, striato-nigro-striatal ascending spirals from the nucleus accumbens to more dorsal regions of the striatum that underlie a shift from action-outcome to stimulus-response mechanisms in the control over drug seeking. When this progressive ventral to dorsal striatum shift is combined with drug-associated Pavlovian influences from limbic structures such as the amygdala and the orbitofrontal cortex, drug seeking behaviour becomes established as an incentive habit. This instantiation of implicit sub-cortical processing of drug-associated stimuli and instrumental responding might be a key mechanism underlying the development of compulsive drug seeking and the high vulnerability to relapse which are hallmarks of drug addiction.

The rat prelimbic cortex mediates inhibitory response control but not the consolidation of instrumental learning.

The potential role of the prelimbic cortex of the rat in the acquisition of instrumental responding is currently uncertain. In addition, modeling the acquisition of Pavlovian and spatial conditioning tasks has suggested that the process of acquisition can, for certain forms of learning, be step like and consequently misrepresented in averaged group curves. Here, the authors report an experiment investigating the potential involvement of the prelimbic cortex in instrumental acquisition, in which the authors used the control data to model individual acquisition curves mathematically. The authors show that instrumental acquisition under fixed interval schedules was a gradual process extending over 4 instrumental sessions that is well represented in averaged group curves. Postsession infusion of a protein synthesis inhibitor into the prelimbic cortex did not affect any measure of acquisition, showing that during acquisition the prelimbic cortex does not mediate postsession consolidation of instrumental learning. However, inactivation of the prelimbic cortex increased responding, suggesting that the prelimbic cortex mediates a form of inhibitory response control.