Conditioned inhibition of amphetamine sensitization.

Repeated intermittent exposure to psychostimulants, such as amphetamine, leads to a progressive enhancement of the drug's ability to increase both behavioral and brain neurochemical responses. The expression of these enhancements, known as sensitization, can be regulated by Pavlovian conditioned stimuli. Cues that are associated with drug experience can facilitate sensitization so that it only occurs in the presence of these stimuli (context-specific sensitization). In contrast, cues that are explicitly related to the absence of drugs (conditioned inhibitors) can prevent the expression of sensitization. We hypothesized that disrupting conditioned inhibition would enable amphetamine sensitization in new contexts. Using male Sprague Dawley rats and a two-context amphetamine conditioning procedure, we found that extinguishing amphetamine experience in one environment led to the loss of conditioned inhibition in a separate context. Thus, amphetamine-induced sensitized locomotion, as well as both enhanced dopamine and glutamate neurotransmission in the nucleus accumbens, were observed in a context where the drug was never experienced before. A similar loss of contextual control of sensitization was seen after using baclofen/muscimol microinjections to transiently inhibit the medial prefrontal cortex, basolateral amygdala, or ventral subiculum of the hippocampus. In other words, compared to control infusions, these intracranial injections of GABA-receptor agonists were able to block conditioned inhibitors from preventing the expression of sensitized locomotion. Together, these findings reveal the importance of conditioned inhibitors for regulating addiction-like behavior. The results suggest that dopaminergic and glutamatergic brain circuitry controls the context-specific expression of amphetamine sensitization.

Loss of presenilin function is associated with a selective gain of APP function.

Presenilin 1 (PS1) is an essential γ-secretase component, the enzyme responsible for amyloid precursor protein (APP) intramembraneous cleavage. Mutations in PS1 lead to dominant-inheritance of early-onset familial Alzheimer's disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic Aß production, the importance of other APP metabolites and γ-secretase substrates in the etiology of the disease has not been confirmed. We report that neurons expressing FAD-linked PS1 variants or functionally deficient PS1 exhibit enhanced axodendritic outgrowth due to increased levels of APP intracellular C-terminal fragment (APP-CTF). APP expression is required for exuberant neurite outgrowth and hippocampal axonal sprouting observed in knock-in mice expressing FAD-linked PS1 mutation. APP-CTF accumulation initiates CREB signaling cascade through an association of APP-CTF with Gαs protein. We demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of-function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients.

Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug.

Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) mediate the behavioral and motivational effects of many drugs of abuse, including nicotine. Repeated intermittent administration of these drugs, a pattern often associated with initial drug exposure, sensitises the reactivity of dopamine (DA) neurons in this pathway, enhances the locomotor behaviors the drugs emit, and promotes their pursuit and self-administration. Here we show that activation of nicotinic acetylcholine receptors (nAChRs) in the VTA, but not the NAcc, is essential for the induction of locomotor sensitisation by nicotine. Repeated intermittent nicotine exposure (4 × 0.4 mg/kg, base, i.p., administered over 7 days), a regimen leading to long-lasting locomotor sensitisation, also produced upregulation of nAChRs in the VTA, but not the NAcc, in the hours following the last exposure injection. Functional nAChR upregulation was observed selectively in DA but not GABA neurons in the VTA. These effects were followed by long-term potentiation of excitatory inputs to these cells and increased nicotine-evoked DA overflow in the NAcc. Withdrawal symptoms were not observed following this exposure regimen. Thus, intermittent activation and upregulation by nicotine of nAChRs in DA neurons in the VTA may contribute to the development of behavioral sensitisation and increased liability for nicotine addiction.

Casein kinase 1 enables nucleus accumbens amphetamine-induced locomotion by regulating AMPA receptor phosphorylation.

The closely related δ and ε isoforms of the serine/threonine protein kinase casein kinase 1 (Csnk1) have been implicated in the generation of psychostimulant-induced behaviors. In this study, we show that Csnk1δ/ε produces its effects on behavior by acting on the Darpp-32-PP1 signaling pathway to regulate AMPA receptor phosphorylation in the nucleus accumbens (NAcc). Inhibiting Csnk1δ/ε in the NAcc with the selective inhibitor PF-670462 blocks amphetamine induced locomotion and its ability to increase phosphorylation of Darpp-32 at S137 and T34, decrease PP1 activity and increase phosphorylation of the AMPA receptor subunit at S845. Consistent with these findings, preventing GluR1 phosphorylation with the alanine mutant GluR1(S845A) reduces glutamate-evoked currents in cultured medium spiny neurons and blocks the locomotor activity produced by NAcc amphetamine. Thus, Csnk1 enables the locomotor and likely the incentive motivational effects of amphetamine by regulating Darrp-32-PP1-GlurR1(S845) signaling in the NAcc. As such, Csnk1 may be a critical target for intervention in the treatment of drug use disorders.

The effect of prolonged anesthesia with isoflurane, propofol, dexmedetomidine, or ketamine on neural cell proliferation in the adult rat.

BACKGROUND: Recent evidence indicates that new neurons are produced in the adult hippocampus, and play a functional role in cognitive processes such as learning and memory. In animals, new neuron production is suppressed by increasing age, gamma-aminobutyric acid receptor activity, reductions in basal forebrain activity and brain norepinephrine levels, and decreased environmental stimuli. Similarities between these effects and those of anesthetic administration suggest that anesthetics may modulate new cell production, and raise the possibility that postoperative cognitive dysfunction may result, in part, from anesthetic-induced suppression of adult neurogenesis. To test this hypothesis, we investigated the effects of prolonged anesthesia with four different anesthetics on hippocampal cell proliferation in young and older rats. METHODS: Young (approximately 3 mo) and older, middle-aged (approximately 12 mo) male Sprague-Dawley rats received one of four anesthetics (propofol, isoflurane, dexmedetomidine, and ketamine) for 8 h. Rats breathed spontaneously, and anesthesia was titrated to loss of righting reflex and tolerance of clip-style pulse oximetry. Six hours into the anesthetic, rats received 200 mg/kg bromodeoxyuridine (BrdU) intraperitoneally and were killed hours later. Frozen hippocampal sections were collected and processed for BrdU using an immunoperoxidase technique. BrdU(+) cells in the dentate gyrus were then counted, and compared with unanesthetized controls to determine the degree of new cell production. All four anesthetics were given to young rats. Older rats received isoflurane and ketamine, and also received isoflurane during their dark phase. RESULTS: Forty-two young, and 26 older, middle-aged rats were studied. When compared with controls, prolonged anesthesia in young rats with any drug had no effect on the number of BrdU(+) cells. BrdU labeling was also unaffected in older rats given isoflurane for 8 h during the light phase. Older rats had significantly lower BrdU(+) cell counts than younger rats. In older rats, ketamine anesthesia reduced BrdU(+) cell counts by 26% when compared with unanesthetized controls. Older rats given isoflurane for 8 h during their dark phase demonstrated no difference in BrdU labeling when compared with unanesthetized controls. CONCLUSION: Despite using multiple, mechanistically distinct drugs, we found no effect of prolonged anesthesia on adult hippocampal cell proliferation in young rats, a slight suppressive effect of ketamine in older rats, and no circadian effect with isoflurane. These data indicate that anesthetics are unlikely to alter cell proliferation, and by extension that anesthetic-induced inhibition of cell proliferation is unlikely to play a major role in postoperative cognitive impairment. The contrast between our findings, current concepts of anesthetic action, and known modifiers of cell proliferation suggest an incomplete understanding of the pharmacological and behavioral factors governing new neuron production.

Effect of sleep deprivation on righting reflex in the rat is partially reversed by administration of adenosine A1 and A2 receptor antagonists.

BACKGROUND: Similarities between naturally occurring sleep and general anesthesia suggest that the two states may interact physiologically. The authors have previously demonstrated that sleep deprivation potentiates anesthetic-induced loss of righting reflex (LORR) in rats. One possible mediator for this effect is adenosine, which accumulates in the brains of sleep-deprived animals and reduces anesthetic requirements. The authors tested in rats the hypothesis that potentiating effects of sleep deprivation on LORR can be altered by adenosine A1 and A2a receptor antagonists. METHODS: Five experiments were conducted. In each, rats underwent four trials, consisting of a 24-h period of either sleep deprivation or ad libitum activity followed by administration of a fixed dose of an adenosine antagonist or vehicle. Rats were then given isoflurane, and the time to LORR and recovery were measured. Each experiment tested a specific dose of an A1 receptor antagonist (8-cyclopentyltheophylline given via microinjection into the basal forebrain), an A2a receptor antagonist (ZM241385 via intraperitoneal administration), or both. In each experiment, all rats received all combinations of activity and drug/vehicle, separated by 5-7 days. RESULTS: In rested rats, neither antagonist altered the time to LORR. In sleep-deprived rats, both ZM241385 and 8-cyclopentyltheophylline prolonged the time to LORR and shortened recovery in a dose-dependent manner. Prolongation also occurred when subtherapeutic doses of both agents were coadministered. CONCLUSION: Both antagonists partially reversed the effect of sleep deprivation on anesthetic action. This result implies that deprivation-induced changes in adenosine receptor activity can alter LORR. Neither antagonist completely reversed this effect, suggesting possible non-adenosine-mediated effects of sleep deprivation.

Recovery from sleep deprivation occurs during propofol anesthesia.

BACKGROUND: Some neurophysiologic similarities between sleep and anesthesia suggest that an anesthetized state may reverse effects of sleep deprivation. The effect of anesthesia on sleep homeostasis, however, is unknown. To test the hypothesis that recovery from sleep deprivation occurs during anesthesia, the authors followed 24 h of sleep deprivation in the rat with a 6-h period of either ad libitum sleep or propofol anesthesia, and compared subsequent sleep characteristics. METHODS: With animal care committee approval, electroencephalographic/electromyographic electrodes and intrajugular cannulae were implanted in 32 rats. After a 7-day recovery and 24-h baseline electroencephalographic/electromyographic recording period, rats were sleep deprived for 24 h by the disk-over-water method. Rats then underwent 6 h of either propofol anesthesia (n = 16) or ad libitum sleep with intralipid administration (n = 16), followed by electroencephalographic/electromyographic monitoring for 72 h. RESULTS: In control rats, increases above baseline in non-rapid eye movement sleep, rapid eye movement sleep, and non-rapid eye movement delta power persisted for 12 h after 24 h of sleep deprivation. Recovery from sleep deprivation in anesthetized rats was similar in timing to that of controls. No delayed rebound effects were observed in either group for 72 h after deprivation. CONCLUSION: These data show that a recovery process similar to that occurring during naturally occurring sleep also takes place during anesthesia and suggest that sleep and anesthesia share common regulatory mechanisms. Such interactions between sleep and anesthesia may allow anesthesiologists to better understand a potentially important source of variability in anesthetic action and raise the possibility that anesthetics may facilitate sleep in environments where sleep deprivation is common.