Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRδ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring.

Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment.

Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidilic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5′-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation, and a negative correlation between OLZ sensitization magnitude and hippocampal short term cell survival. The implications of the relationship between behavioral and neurobiological results are discussed.

Summary As a highly motivated social behavior, maternal behavior in rats has been routinely used to study psychoactive drugs for clinical, neuroscience and pharmacological purposes. Recent evidence indicates that acute activation of serotonin 2C (5-HT2C) receptors causes a disruption of rat maternal behavior. The present study was designed to elucidate the behavioral, pharmacological mechanisms and neuroanatomical basis of this 5-HT2C effect. First, we replicated the finding that acute MK212 injection (2.0 mg/kg, a highly selective 5-HT2C agonist) disrupts maternal behavior, especially on pup retrieval. Interestingly, this disruption was significantly attenuated by 4-h pup separation (a procedure putatively increased maternal motivation). MK212 also suppressed food retrieval, indicating that it has a general effect on motivated behaviors. Second, we showed that MK212 disrupts maternal behavior by specifically activating 5-HT2C receptor, as pretreatment with a 5-HT2C receptor antagonist SB242084 (0.6 and 1.0 mg/kg) alleviated MK212-induced disruption on pup retrieval. Third, we microinjected MK212 into various brain regions implicated in the regulation of maternal behavior: nucleus accumbens shell (25, 75, 250 ng/0.5μl/side), medial prefrontal cortex (25 and 250 ng, 1, 2 and 5 μg/0.5μl/side), and medial preoptic area (MPOA, 75 ng, 1 and 5 μg/0.5μl/side). Pup retrieval and other maternal responses were not affected by any of these manipulations. Finally, we used c-Fos immunohistochemistry to identify the central mechanisms of the acute and repeated MK212 effects on maternal behavior. Acute MK212 (2.0 mg/kg) disrupted pup retrieval and concurrently decreased c-Fos expression in the ventral part of lateral septal nucleus (LSv), MPOA, dentate gyrus (DG) and dorsal raphe (DR), but increased it in the central amygdala (CeA). Five days of repeated MK212 (2.0 mg/kg) treatment produced a persistent disruption of pup retrieval and only decreased c-Fos expression in the DR. These findings not only confirm a role of 5-HT2C receptor in rat maternal behavior, but also suggest that the coordinated 5-HT2C activity in various limbic (e.g., LSv, DG, CeA), hypothalamic regions (e.g., MPOA) and brainstem areas (e.g. DR), is likely involved in the mediation of important psychological processes (e.g. motor function, motivation) necessary for the normal expression of maternal behavior.

While research has revealed heightened vulnerability to meth addiction in women, preclinical models rarely use female subjects when investigating meth seeking and relapse. The goal of the present study was to examine the effects of varenicline (Chantix®), a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in female rats. Sprague-Dawley rats were surgically implanted with an indwelling jugular catheter. Half of the rats were then trained to self-administer meth (0.056 mg/kg/infusion) on a variable ratio 3 schedule of reinforcement; the other half earned intravenous saline during daily, 2 hour sessions. When responding stabilized, varenicline (0.0, 0.3, 1.0, 3.0 mg/kg) was tested to determine how it altered meth taking. Varenicline was probed on 4 test days; each test separated by 2 standard self-administration sessions to assure responding remained stable. Following this testing was 15 extinction sessions. Twenty-four hours after the last extinction session were four consecutive days of meth-primed reinstatement. The same 4 doses of varenicline were examined to determine how it altered reinstatement triggered by 0.3 mg/kg meth (IP). Rats readily self-administered meth. The higher doses of varenicline did not affect meth-taking in a specific fashion as active lever pressing wasalso slightly reduced in rats that has access to saline in the self-administration phase. Female rats displayed robust meth-primed reinstatement. Notably, the lower doses of varenicline increased meth-primed reinstatement. This amplified susceptibility to reinstatement (i.e., relapse) may be an impediment for the use of varenicline as a therapeutic to treat meth use disorder.

Investigator-administered nicotine alters neurotensin and substance P levels in Sprague-Dawley rats. This finding suggests a role of the dopamine-related endogenous neuropeptides in nicotine addiction. We sought to extend this observation by determining the responses of neurotensin and substance P systems (assessed using radioimmunoassay) in male and female rats following nicotine self-administration (SA). Male and female Sprague-Dawley were trained to self-administer nicotine, or receive saline infusions yoked to a nicotine-administering rat during daily sessions (1-h; 21 days). Brains were extracted 3 h after the last SA session. Nicotine SA increased tissue levels of neurotensin in the males in the anterior and posterior caudate, globus pallidus, frontal cortex, nucleus accumbens core and shell, and ventral tegmental area. Nicotine SA also increased tissue levels of neurotensin in the females in the anterior caudate, globus pallidus, nucleus accumbens core and shell, but not in the posterior caudate, frontal cortex, or ventral tegmental area. There were fewer sex differences observed in the substance P systems. Nicotine SA increased tissue levels of substance P in both the males and females in the posterior caudate, globus pallidus, frontal cortex, nucleus accumbens shell, and ventral tegmental area. A sex difference was observed in the nucleus accumbens core, where nicotine SA increased tissue levels of substance P in the males, yet decreased levels in the females. The regulation of neuropeptides following nicotine SA may play a role in the susceptibility to nicotine dependence in females and males.

Methamphetamine (meth) addiction is a costly burden to both the individual user and society as a whole. Establishing effective pharmacotherapies to treat meth dependence is needed to help solve this health problem. The study reported herein examined the effects of varenicline, a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in male Sprague-Dawley rats. Following indwelling jugular catheter surgery, rats were either trained to self-administer meth or saline on a variable ratio (VR) 3 schedule of reinforcement. Self-administration sessions (2 hour duration; 19 total sessions) were conducted daily. The effect of varenicline pretreatment on meth and saline self-administration was then determined using a within-study design. All rats received varenicline (0.0, 0.3, 1.0, and 3.0 mg/kg) prior to 4 different test sessions. Dose order was randomly assigned and each test was separated by 2 standard self-administration sessions to assess stability of responding. Fifteen extinction sessions (no meth available) followed the last test. Extinction was followed by meth-primed (0.3 mg/kg IP) reinstatement tests to examine the effect of varenicline on meth-seeking behavior. All rats again received all doses of varenicline over 4 separate reinstatement tests performed on 4 consecutive days. Varenicline did not alter self-administration of meth or saline. Additionally, the 0.3 and 1.0 doses of varenicline non-specifically increased active lever responding during the reinstatement test sessions. This latter finding suggests that varenicline may increase relapse liability and should not be utilized as pharmacotherapy to treat meth dependence.

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