SUMMARY Cyclin E is a component of the core cell cycle machinery, and it drives cell proliferation by regulating entry and progression of cells through the DNA synthesis phase. Cyclin E expression is normally restricted to proliferating cells. However, high levels of cyclin E are expressed in the adult brain. The function of cyclin E in quiescent, postmitotic nervous system remains unknown. Here we use a combination of in vivo quantitative proteomics and analyses of cyclin E knockout mice to demonstrate that in terminally differentiated neurons cyclin E forms complexes with Cdk5 and controls the formation of synapses by restraining Cdk5 activation. Ablation of cyclin E led to a decreased number of synapses, reduced number and volume of dendritic spines, and resulted in impaired synaptic plasticity and memory formation in cyclin E-deficient animals. These results reveal a cell cycle-independent role for a core cell cycle protein, cyclin E, in synapse function and memory.

Rationale Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. Objective We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. Results New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Conclusions Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment.

Rationale In rodents, prolonged maternal separation has been used as a model of developmentally early environmental stress to influence adult drug intake. Objectives The aim of the present study was to evaluate the long-term effects of prolonged maternal separation on alcohol consumption using two different self-administration procedures in mice: operant alcohol self-administration vs. three-bottle choice. Materials and methods From postnatal day (PND) 1 to 14, pups were separated from the dam (maternal separation, MS) daily for 180 min or were left undisturbed, only handled during cage cleaning (animal facility rearing, AFR). On PND 60, they were assigned to one of two experimental manipulations: either a three-bottle choice or operant oral alcohol self-administration. In the three-bottle choice procedure, mice were given access to 6% or 10% alcohol or 0.05% saccharin solution for 2 h/day for 10 days. In the second experiment, mice were reinforced for nose poking by delivery of oral alcohol (6% or 10% in saccharin) or 0.05% saccharin solutions during daily 30-min sessions. Following the acquisition phase, “break points” were determined. Later, mice were allowed 1 h access to the reinforcing solution with no dosage limitation. Results In the three-bottle choice procedure, MS mice showed higher alcohol intake than AFR at the 10% alcohol concentration. In the operant alcohol self-administration, MS mice achieved higher alcohol intake than AFR at the concentrations 6% and 10% during the 1-h session. Conclusions The results demonstrate the long-term consequences of MS on alcohol intake in male mice, suggesting early life stress as a risk factor for alcohol consumption and abuse.

Rationale Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons. Objective The study aims to prevent the effects of intermittently scheduled, brief social defeat stress on subsequent intravenous (IV) cocaine self-administration by pretreatment with a CRF receptor subtype 1 (CRF-R1) antagonist. Materials and methods Long–Evans rats were submitted to four intermittent social defeat experiences separated by 72 h over 10 days. Two experiments examined systemic or intra-VTA antagonism of CRF-R1 subtype during stress on the later expression of locomotor sensitization and cocaine self-administration during fixed (0.75 mg/kg/infusion) and progressive ratio schedules of reinforcement (0.3 mg/kg/infusion), including a continuous 24-h “binge” (0.3 mg/kg/infusion). Results Pretreatment with a CRF-R1 antagonist, CP 154,526, (20 mg/kg i.p.) prior to each social defeat episode prevented the development of stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h “binge” In addition, pretreatment with a CRF-R1 antagonist (0.3 μg/0.5 μl/side) into the VTA prior to each social defeat episode prevented stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h “binge”. Conclusions The current results suggest that CRF-R1 subtype in the VTA is critically involved in the development of stress-induced locomotor sensitization which may contribute to escalated cocaine self-administration during continuous access in a 24-h “binge”.

Rationale Escalated, binge-like patterns of cocaine self-administration are engendered by repeated, intermittent exposure to episodes of social defeat stress, as well as by extended drug access. Objectives The present study investigated if prior exposure to brief episodes of social defeat stress would intensify the escalation of cocaine self-administration associated with extended access conditions. The consequences of both stress sensitization and prolonged access were further assessed with progressive ratio (PR) break points and during a 24-h variable dose “binge”. Methods Male Long–Evans rats were exposed to four episodes of defeat stress (days 1–4–7–10), and their locomotor response to cocaine was assessed 10 days later. Rats were subsequently implanted with intravenous catheters. After acquisition, stressed and control rats were allowed daily short (1 h/day) or extended (6 h/day) sessions of cocaine self-administration for 14 days (0.75 mg/kg/infusion). In sequence, we determined break points for cocaine on PR tests and assessed drug intake patterns during a 24-h variable dose binge. Results Defeat stress induced cross-sensitization to a cocaine challenge, increased break points for cocaine, and produced persistent, escalated cocaine taking during a 24-h binge. Rats with extended access to cocaine—both stressed and controls—similarly escalated their drug intake throughout the 14 days. Extended access conditions accelerated the rate of cocaine self-administration in the first half of the binge, indicated by shorter post-infusion intervals, but failed to amplify the accumulated drug intake in non-stressed controls. Conclusions Both social defeat stress and drug access conditions may engender escalated cocaine intake via distinct mechanisms that regulate drug self-administration.