Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice.

Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long-term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self-stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently.

Depressive phenotypes evoked by experimental diabetes are reversed by insulin.

Clinical studies suggest a bidirectional relationship between diabetes and depression, where diabetes may increase risk for depressive symptoms and depression may increase risk for diabetes. Preclinical models examining the effects of diabetes on brain and behavior can provide insights to the pathophysiology underlying this relationship. The current study comprehensively examined, in C57BL/6 mice, the development of depressive phenotypes evoked by diabetes induced by streptozotocin (STZ) and determined if insulin treatment was able to reverse the diabetes-related changes on brain and affective behavior. Since anxiety is often comorbid with mood disturbances, behavioral tests for both anxiety and depression were administered. Possible physiological correlates of behavioral changes, including hippocampal cell proliferation, brain derived neurotrophic factor, and plasma corticosterone, were also measured. STZ-induced diabetes resulted in increased immobility in the tail suspension test, increased intracranial self-stimulation thresholds, decreased hippocampal cell proliferation, and increased corticosterone levels. Insulin treatment, on the other hand, reduced hyperglycemia, reversed the behavioral effects, and returned hippocampal cell proliferation and corticosterone to levels comparable to the control group. Anxiety-related behaviors were unaffected. This study showed that experimental diabetes in the mouse produced depressive phenotypes that were reversed by insulin therapy. Changes in reward-related behaviors and hippocampal cell proliferation may be useful markers to identify therapeutic interventions for comorbid diabetes and depression.

Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill.

The learning of new skills is characterized by an initial phase of rapid improvement in performance and a phase of more gradual improvements as skills are automatized and performance asymptotes. Using in vivo striatal recordings, we observed region-specific changes in neural activity during the different phases of skill learning, with the associative or dorsomedial striatum being preferentially engaged early in training and the sensorimotor or dorsolateral striatum being engaged later in training. Ex vivo recordings from medium spiny striatal neurons in brain slices of trained mice revealed that the changes observed in vivo corresponded to regional- and training-specific changes in excitatory synaptic transmission in the striatum. Furthermore, the potentiation of glutamatergic transmission observed in dorsolateral striatum after extensive training was preferentially expressed in striatopallidal neurons, rather than striatonigral neurons. These findings demonstrate that region- and pathway-specific plasticity sculpts the circuits involved in the performance of the skill as it becomes automatized.

High on habits.

The neural circuits involved in learning and executing goal-directed actions, which are governed by action-outcome contingencies and sensitive to changes in the expected value of the outcome, have been shown to be different from those mediating habits, which are less dependent on action-outcome relations and changes in outcome value. Extended training, different reinforcement schedules, and substances of abuse have been shown to induce a shift from goal-directed performance to habitual performance. This shift can be beneficial in everyday life, but can also lead to loss of voluntary control and compulsive behavior, namely during drug seeking in addiction. Although the brain circuits underlying habit formation are becoming clearer, the molecular mechanisms underlying habit formation are still not understood. Here, we review a recent study where Hilario et al. (2007) established behavioral procedures to investigate habit formation in mice in order to investigate the molecular mechanisms underlying habit formation. Using those procedures, and a combination of genetic and pharmacological tools, the authors showed that endocannabinoid signaling is critical for habit formation.

Endocannabinoid signaling is critical for habit formation.

Extended training can induce a shift in behavioral control from goal-directed actions, which are governed by action-outcome contingencies and sensitive to changes in the expected value of the outcome, to habits which are less dependent on action-outcome relations and insensitive to changes in outcome value. Previous studies in rats have shown that interval schedules of reinforcement favor habit formation while ratio schedules favor goal-directed behavior. However, the molecular mechanisms underlying habit formation are not well understood. Endocannabinoids, which can function as retrograde messengers acting through presynaptic CB1 receptors, are highly expressed in the dorsolateral striatum, a key region involved in habit formation. Using a reversible devaluation paradigm, we confirmed that in mice random interval schedules also favor habit formation compared with random ratio schedules. We also found that training with interval schedules resulted in a preference for exploration of a novel lever, whereas training with ratio schedules resulted in less generalization and more exploitation of the reinforced lever. Furthermore, mice carrying either a heterozygous or a homozygous null mutation of the cannabinoid receptor type I (CB1) showed reduced habit formation and enhanced exploitation. The impaired habit formation in CB1 mutant mice cannot be attributed to chronic developmental or behavioral abnormalities because pharmacological blockade of CB1 receptors specifically during training also impairs habit formation. Taken together our data suggest that endocannabinoid signaling is critical for habit formation.