A single injection of a novel kappa opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats.

Behav Pharmacol. 2012 Jan 30;

Authors: Morani AS, Schenk S, Prisinzano TE, Kivell BM

Abstract
Kappa opioid receptor (KOPr) activation antagonizes many cocaine-related behaviors but adverse side-effects such as sedation, dysphoria, and depression limit their therapeutic use. Recently, salvinorin A (Sal A), a naturally occurring KOPr agonist, has been shown to attenuate cocaine-induced drug seeking in a model of relapse in rats. The present study evaluated the effects of acute Sal A exposure on cocaine-induced hyperactivity and cocaine sensitization in rats. Acute treatment with a dose of Sal A that decreased drug seeking in a previous study (0.3 mg/kg) significantly attenuated the expression of cocaine sensitization. This dose of Sal A failed to affect spontaneous locomotion or to produce a conditioned taste aversion to a novel-tasting saccharin solution. However, Sal A decreased climbing and swimming time and increased time spent immobile in the forced swim test. These findings indicate that Sal A, just like traditional KOPr agonists, attenuates cocaine-induced behavioral sensitization but does not produce the adverse effect of conditioned aversion, suggesting improved potential compliance. However, prodepressive effects were also produced and these effects may limit the therapeutic potential.

PMID: 22293826 [PubMed - as supplied by publisher]

Benserazide dosing regimen affects the response to L-3,4-dihydroxyphenylalanine in the 6-hydroxydopamine-lesioned rat.

Behav Pharmacol. 2012 Jan 9;

Authors: Tayarani-Binazir KA, Jackson MJ, Strang I, Jairaj M, Rose S, Jenner P

Abstract
Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We now assess the effect of dose, timing, and supplemental administration of benserazide on the rotational response induced by L-DOPA in unilateral 6-hydroxydopamine-lesioned rats. L-DOPA (12.5 mg/kg, p.o.) concomitant with benserazide (3.125-15 mg/kg, p.o.) produced a dose-dependent increase in contraversive rotation compared with the effects of L-DOPA alone. The optimal L-DOPA response was achieved with 10 mg/kg of benserazide and this dose was used in subsequent experiments. When L-DOPA treatment was delayed for 1, 2, or 3 h after benserazide, the rotational response declined suggesting loss of AADC inhibition. Unexpectedly, there was also a progressive decline in response when benserazide and L-DOPA were given together but at increasingly later time points of 08.00, 09.00, 10.00, and 11.00 h. To assess supplemental administration of benserazide, an additional dose was given 2 h after the initial benserazide/L-DOPA treatment. This produced a further increase in the number of contralateral rotations indicating that the effect of benserazide declines while plasma levels of L-DOPA are maintained. Therefore, optimization of the dose and timing of benserazide administration is essential to achieve a consistent L-DOPA response in 6-hydroxydopamine-lesioned rats. These findings may have implications for the way in which peripheral AADC inhibitors are used in the treatment of PD.

PMID: 22236652 [PubMed - as supplied by publisher]

The potency of fluvoxamine to reduce ethanol self-administration decreases with concurrent availability of food.

Behav Pharmacol. 2011 Dec 27;

Authors: Ginsburg BC, Pinkston JW, Lamb RJ

Abstract
The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigated further the impact that concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions in which food and ethanol were available concurrently and response rates were equal [average variable intervals (VIs) 405 and 14 s for food and ethanol, respectively], as well as when density of food delivery was increased (average VI 60 s for food and VI 14 s for ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14 s for ethanol) and under multiple VIs (VI 30 s for food and ethanol) wherein either food or ethanol was the only programmed reinforcement available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently {ED50 [95% confidence limit (CL): 8.2 (6.5-10.3) and 10.7 (7.9-14.4)]} versus when ethanol was available in isolation [ED50: 4.0 (2.7-5.9) and 5.1 (4.3-6.0)]. Effects on food were similar under each condition in which food was available. The results demonstrate that the potency of fluvoxamine in reducing ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement.

PMID: 22205211 [PubMed - as supplied by publisher]

Vitamin C attenuates the physiological and behavioural changes induced by long-term exposure to noise.

Behav Pharmacol. 2011 Dec 22;

Authors: Angrini MA, Leslie JC

Abstract
Persistent, high-intensity noise is an environmental pollutant that plays a destructive role in daily life, especially in industrialized communities. Its effects may be reduced by Vitamin C supplementation. This study examined the possibility that pretreatment with vitamin C (100 mg or 200 mg/kg) could attenuate behavioural and anxiogenic effects of prolonged exposure to noise (100 dB for 2 months, 5 days/week, 4 h daily) on male laboratory mice, by using open-field and plus maze tests of emotionality, and by measuring the neutrophils-to-lymphocytes ratio, a physiological stress measure. The effects seen on behaviour in the open field and plus maze were consistent with the hypothesis that noise could be considered as a stressor as it significantly affected six measures of behaviour in the predicted directions. The neutrophil-to-lymphocyte ratio was also increased as a result of noise exposure. Furthermore, there was good evidence from all three procedures that vitamin C supplementation can attenuate the effects of noise. We conclude that vitamin C supplementation can attenuate or prevent the psychological and physiological damage induced by prolonged noise exposure in mice.

PMID: 22198322 [PubMed - as supplied by publisher]

Behavioral differences in black Swiss mice from separate colonies: implications for modeling domains of mania.

Behav Pharmacol. 2011 Dec 20;

Authors: Juetten J, Einat H

Abstract
Recent work demonstrated the advantages of using black Swiss (BS) mice to model behavioral domains of mania including reward-seeking, risk-taking, vigor, and sensitivity to psychostimulants. Until recently BS mice were only available from Taconic (TAC) farms, but a colony was recently established by Charles River (CR). The present study compared the behavioral phenotype of mice from the new CR colony to the TAC animals to evaluate if mice from CR also have the advantages as model animals for mania. TAC and CR mice were compared in a battery of tests related to domains of mania, and the effects of lithium were tested in the CR mice. CR mice showed lower activity levels and preference for sweet solution and higher immobility in the forced swim test compared with TAC mice. Furthermore, in contrast with the antimanic-like effects of lithium previously described in TAC mice, in CR mice lithium only had an antidepressant-like effect in the forced swim test. The results indicate that the CR BS mice lack the behavioral properties that make the TAC BS mice advantageous for modeling domains of mania.

PMID: 22193594 [PubMed - as supplied by publisher]

Serotonin antagonists in the five-choice serial reaction time task and their interactions with nicotine.

Behav Pharmacol. 2011 Dec 20;

Authors: Quarta D, Naylor CG, Glennon JC, Stolerman IP

Abstract
Much research has implicated the serotonin (5-HT) system in cognitive functioning and psychomotor stimulant abuse, but its role depends on the subtypes of 5-HT receptors involved and the nature of the behavioural task. Here we aimed to extend previous studies by examining the role of 5-HT1A and 5-HT2C receptors in attentional performance. The effects of the selective 5-HT antagonists WAY-100635 and SB-242084 were assessed alone and for interactions with nicotine in the five-choice serial reaction time task in rats. The effects of several doses of WAY-100635 were tested in combination with a fixed dose of nicotine, and then various doses of nicotine were tested in combination with SB-242084. Systemic administration of WAY-100635 and SB-242084 induced opposing effects on speed-related measures in the five-choice serial reaction time task, with antagonism at 5-HT1A receptors increasing omission errors and response latency, and antagonism at 5-HT2C receptors reducing both omissions and latency, and also increasing anticipatory responses; neither drug affected accuracy. Nicotine itself improved all main indices of attention, and there was preliminary evidence that the detrimental effects of WAY-100635 on response latency were weakened by nicotine. Conversely, treatment with SB-242084 enhanced all speed-related indices of performance to above the levels seen under the influence of nicotine alone, thus suggesting that 5-HT2C antagonists might be useful to decrease reaction times if used as an add-on therapy to treat attentional decline.

PMID: 22193593 [PubMed - as supplied by publisher]

Reversible and persistent decreases in cocaine self-administration after cholinesterase inhibition: different effects of donepezil and rivastigmine.

Behav Pharmacol. 2011 Feb;22(1):58-70

Authors: Grasing K, Yang Y, He S

Abstract
We recently observed that pretreatment with the cholinesterase inhibitor, tacrine can produce long-lasting reductions in cocaine-reinforced behavior, described as persistent attenuation. In addition to inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase, tacrine can potentiate actions of dopamine. This study was carried out to evaluate the effects of donepezil (which selectively inhibits AChE) and rivastigmine (which inhibits both AChE and butyrylcholinesterase) on cocaine self-administration. High self-administration rats self-administered different doses of cocaine under a fixed ratio-5 schedule. Over a 4-day period, vehicle, donepezil, or rivastigmine was infused as animals were maintained in home cages (21 h per day), with signs of cholinergic stimulation (fasciculation, vacuous jaw movements, yawning, and diarrhea) scored by a blinded observer. Both compounds dose-dependently decreased cocaine self-administration, but differed in the potency and temporal pattern of their effects. Self-administration of low-dose cocaine was decreased to a greater degree by rivastigmine than donepezil (50% effective doses of 2.33 and 6.21 mg/kg/day, respectively), but this early effect did not continue beyond sessions immediately after treatment with rivastigmine. Group means for cocaine self-administration were decreased at some time points occurring between 1 and 3 days after the treatment with 10 mg/kg/day of donepezil (late effects), with decreases of more than 80% observed in some individual rats that persisted for 1 week or longer. Early, but not late, effects were correlated with signs of cholinergic stimulation. In summary, pretreatment with donepezil, but not rivastigmine produced persistent reductions in cocaine-reinforced behavior, which were not associated with signs of cholinergic stimulation.

PMID: 22173266 [PubMed - in process]

Comparison of nafadotride, CNQX, and haloperidol on acquisition versus expression of amphetamine-conditioned place preference in rats.

Behav Pharmacol. 2011 Dec 12;

Authors: Banasikowski TJ, Macleod LS, Beninger RJ

PMID: 22157177 [PubMed - as supplied by publisher]

Non-Δ9tetrahydrocannabinol phytocannabinoids stimulate feeding in rats.

Behav Pharmacol. 2011 Dec 12;

Authors: Farrimond JA, Whalley BJ, Williams CM

Abstract
Cannabinoid type 1 receptor-mediated appetite stimulation by Δtetrahydrocannabinol (ΔTHC) is well understood. Recently, it has become apparent that non-ΔTHC phytocannabinoids could also alter feeding patterns. Here, we show definitively that non-ΔTHC phytocannabinoids stimulate feeding. Twelve male, Lister-Hooded rats were prefed to satiety prior to administration of a standardized cannabis extract or to either of two mixtures of pure phytocannabinoids (extract analogues) comprising the phytocannabinoids present in the same proportions as the standardized extract (one with and one without ΔTHC). Hourly intake and meal pattern data were recorded and analysed using two-way analysis of variance followed by one-way analysis of variance and Bonferroni post-hoc tests. Administration of both extract analogues significantly increased feeding behaviours over the period of the test. All three agents increased hour-one intake and meal-one size and decreased the latency to feed, although the zero-ΔTHC extract analogue did so to a lesser degree than the high-ΔTHC analogue. Furthermore, only the analogue containing ΔTHC significantly increased meal duration. The data confirm that at least one non-ΔTHC phytocannabinoid induces feeding pattern changes in rats, although further trials using individual phytocannabinoids are required to fully understand the observed effects.

PMID: 22157176 [PubMed - as supplied by publisher]

Environmental enrichment protects against the acquisition of cocaine self-administration in adult male rats, but does not eliminate avoidance of a drug-associated saccharin cue.

Behav Pharmacol. 2011 Dec 8;

Authors: Puhl MD, Blum JS, Acosta-Torres S, Grigson PS

Abstract
One of the most menacing consequences of drug addiction is the devaluation of natural rewards (e.g. food, sex, work, money, caring for one's offspring). However, evidence also suggests that natural rewards, such as an enriched environment, can devalue drugs of abuse. Thus, this study used a rodent model to test whether exposure to an enriched environment could protect adult rats from acquiring cocaine self-administration and from the resultant drug-induced devaluation of a natural saccharin reward cue. Adult male Sprague-Dawley rats were implanted with intravenous jugular catheters. Rats were then separated into two housing conditions: an enriched condition, including social companions(four/cage) and novel objects (e.g. balls, polyethylene tubes, paper, etc.), and a nonenriched condition where the rats were singly housed with no novel objects. During testing, the rats were given 5-min access to 0.15% saccharin, followed by 1 h to self-administer saline or cocaine (0.167 mg/infusion) on fixed ratio and progressive ratio schedules of reinforcement. The results showed that rats that were singly housed in the nonenriched environment fell into two groups: low drug-takers (n=34) and high drug-takers (n=12). In comparison, only one out of the 22 rats housed in the enriched environment was a high drug-taker. Thus, all rats in the enriched environment, except one, behaved like low drug-takers under the nonenriched condition. As such, these rats self-administered almost no drug on either the fixed ratio or the progressive ratio schedule of reinforcement and were extremely slow to self-administer their first cocaine infusion. Interestingly, despite their very low levels of drug self-administration, low-drug-taking rats housed in the enriched environment continued to avoid intake of the drug-associated saccharin cue. Taken together, these data suggest that the enriched environment itself served as a salient natural reward that reduced cocaine seeking and cocaine taking, but had little impact on avoidance of the cocaine-paired taste cue. The protective effects of the enriched environment were robust and, as such, have important implications for the methods used in the study of drug addiction in animal models and for the prevention, and possibly the treatment, of the disease in adult humans.

PMID: 22157144 [PubMed - as supplied by publisher]

Contextual and behavioral control of antipsychotic sensitization induced by haloperidol and olanzapine.

Behav Pharmacol. 2011 Dec 8;

Authors: Zhang C, Li M

Abstract
Repeated administration of haloperidol (HAL) and olanzapine (OLZ) causes a progressively enhanced disruption of the conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or the PCP (3.2 mg/kg, subcutaneously) hyperlocomotion model under HAL or OLZ for 5 consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated HAL or OLZ treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with HAL or OLZ did not show a stronger inhibition of CAR-induced or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may develop an association with unconditional drug effects through a Pavlovian conditioning process. They may also serve as occasion setters to modulate the expression of sensitized responses. As antipsychotic sensitization mimics the clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic.

PMID: 22157143 [PubMed - as supplied by publisher]

Maternal ethanol consumption by pregnant guinea pigs causes neurobehavioral deficits and increases ethanol preference in offspring.

Behav Pharmacol. 2011 Dec 8;

Authors: Shea KM, Hewitt AJ, Olmstead MC, Brien JF, Reynolds JN

Abstract
The objective of this study was to test the hypothesis that prenatal exposure to ethanol, through maternal consumption of an aqueous ethanol solution, induces neurobehavioral deficits and increases ethanol preference in offspring. Pregnant Dunkin-Hartley-strain guinea pigs were given 24-h access to an aqueous ethanol solution (5%, v/v) sweetened with sucralose (1 g/l), or water sweetened with sucralose (1 g/l), throughout gestation. Spontaneous locomotor activity was measured in the offspring on postnatal day (PD) 10. The offspring underwent either ethanol preference testing using a two-bottle-choice paradigm beginning on PD 40 or Morris water maze testing using a hidden moving platform design beginning on PD 60. Maternal consumption of a 5% (v/v) ethanol solution (average daily dose of 2.3±0.1 g of ethanol/kg maternal body weight; range: 1.8-2.8 g/kg) decreased offspring birth weight, increased spontaneous locomotor activity, and increased preference for an aqueous ethanol solution. In the Morris water maze test, sucralose-exposed offspring decreased escape latency on the second day of testing, whereas the ethanol-exposed offspring showed no improvement. These data demonstrate that moderate maternal consumption of ethanol produces hyperactivity, enhances ethanol preference, and impairs learning and memory in guinea pig offspring.

PMID: 22157142 [PubMed - as supplied by publisher]

Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia.

Behav Pharmacol. 2011 Dec 5;

Authors: Girbovan C, Morin L, Plamondon H

Abstract
Resveratrol, a naturally occurring polyphenol, has been shown to protect the heart and brain against ischemic injury. The current study investigated the effects of administration with either a 1 or 10-mg/kg dose of resveratrol on CA1 neuronal injury and behavioral/cognitive impairments after 10-min global ischemia in rats. The open-field, eight-arm radial maze and object recognition tests served to evaluate effects of resveratrol treatment on ischemia-induced locomotor activity, and spatial and recognition memory impairments, respectively. CA1 and CA3 neuronal injury was assessed upon completion of behavioral testing, 85 days postischemia. A separate series of groups served to assess neuronal injury at 7 days postischemia. Global ischemia (10 min) led to approximately 50% CA1 cell injury, which was prevented at both short (7 days) and long (85 days) postischemic intervals by resveratrol treatment. Importantly, despite comparable neuronal protection, the two resveratrol doses showed distinct behavioral effects. Thus, the 10-mg/kg resveratrol dose led to an enhanced locomotor activity in the open-field 4-days postischemia and an impaired spatial memory in the delayed nonmatching to sample and delayed matching to sample radial-maze tasks initiated on day 13 postischemia. These findings suggest independent actions of resveratrol on distinct physiological systems mediating cellular survival and functional recovery and dose-related actions of the polyphenol on behavioral and memory processes.

PMID: 22146698 [PubMed - as supplied by publisher]

Diphenyl diselenide ameliorates cognitive deficits induced by a model of menopause in rats.

Behav Pharmacol. 2011 Dec 1;

Authors: da Rocha JT, Pinton S, Mazzanti A, Mazzanti CM, Beckemann DV, Nogueira CW, Zeni G

Abstract
Ovarian hormone loss contributes to cognitive decline in postmenopausal women. Studies have demonstrated a positive role of the level of the element selenium in cognitive performance. The present study investigated the effects of the synthetic organoselenium compound diphenyl diselenide (PhSe)2 on cognitive functions in ovariectomized rats. Ninety-day-old female Wistar rats were subjected to ovariectomy (OVX) or Sham operation. One week after surgery, rats were orally treated with (PhSe)2 (5 mg/kg, per oral route) or vehicle once a day for 30 days. Next, the rats were evaluated in behavioral tests [Morris water maze (MWM) and open-field tests] and biochemical [cerebral acetylcholinesterase (AChE)] analyses were carried out. In MWM probe trial, (PhSe)2 decreased the latency to reach the platform location and increased the number of crossings over the platform location, protecting against cognitive impairment induced by OVX. Furthermore, (PhSe)2 prevented the stimulation of AChE activity caused by OVX. In conclusion, the present study showed a cognition-enhancing effect of (PhSe)2 treatment for 30 days in ovariectomized rats in the MWM test, which could be related to its ability to prevent the stimulation of AChE activity caused by OVX in rats. These findings suggest that (PhSe)2 might have a promising role in preventing the cognitive decline related to menopause.

PMID: 22139607 [PubMed - as supplied by publisher]

Intrahippocampal injection of brain-derived neurotrophic factor increases anxiety-related, but not panic-related defensive responses: involvement of serotonin.

Behav Pharmacol. 2011 Dec 1;

Authors: Casarotto PC, de Bortoli VC, Zangrossi H

Abstract
Changes in brain-derived neurotrophic factor (BDNF)-mediated signaling in the hippocampus have been implicated in the etiology of depression and in the mode of action of antidepressant drugs. There is also evidence from animal studies to suggest that BDNF-induced changes in the hippocampus may play a role in another stress-related pathology: anxiety. However, it is still unknown whether this neurotrophin plays a differential role in defensive responses associated with distinguished subtypes of anxiety disorders found in the clinic, such as generalized anxiety and panic disorder. In the present study, we investigated the effect of an acute BDNF injection into the rat dorsal hippocampus (DH) on inhibitory avoidance acquisition and escape expression measured in the elevated T-maze (ETM). We also assessed whether serotonergic neurotransmission may account for such effects. Intra-DH BDNF injection (200 pg) facilitated inhibitory avoidance in ETM. BDNF was equally anxiogenic in the light/dark transition test. Preadministration of the 5-HT1A receptor antagonist WAY-100635 fully counteracted the anxiogenic effect of BDNF in both tests. Intra-DH midazolam administration (10 nmol) impaired avoidance acquisition in ETM, suggesting an anxiolytic effect. Therefore, in the DH, facilitation of BDNF signaling seems to enhance 5-HT1A receptor-mediated neurotransmission to exert an anxiogenic effect associated with generalized anxiety.

PMID: 22139606 [PubMed - as supplied by publisher]

Influence of sigma-1 receptor modulators on ethanol-induced conditioned place preference in the extinction-reinstatement model.

Behav Pharmacol. 2011 Dec 1;

Authors: Bhutada PS, Mundhada YR, Ghodki YR, Chaware P, Dixit PV, Jain KS, Umathe SN

Abstract
Sigma-1 receptor agonists are reported to augment and antagonists block the rewarding effects of drugs of abuse. However, their effect on reinstatement of ethanol-induced conditioned place preference (CPP) has not yet been explored. Therefore, we investigated the ability of 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate (PRE-084), a sigma-1 receptor agonist, and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD-1047), a sigma-1 receptor antagonist, on the acquisition, expression, and reinstatement of ethanol-induced CPP using adult male Swiss mice. BD-1047 (0.1-10 μg/mouse, intracerebroventricularly) dose-dependently blocked the development, expression, and reinstatement of ethanol-induced CPP, and PRE-084 (0.01-10 μg/mouse, intracerebroventricularly) dose-dependently reinstated the extinguished response. These effects of PRE-084 and BD-1047 alone or in combination with ethanol did not influence the motor activity. Therefore, it is concluded that sigma-1 receptor ligands can modulate the acquisition, expression, and reinstatement of conditioned reinforcing effects of ethanol with no reinforcing or aversive influence of their own. The results add to the growing literature on sigma-1 receptor modulation in the pharmacotherapy of ethanol addiction.

PMID: 22139605 [PubMed - as supplied by publisher]

Altered spatial learning and delay discounting in a rat model of human third trimester binge ethanol exposure.

Behav Pharmacol. 2011 Nov 29;

Authors: Bañuelos C, Gilbert RJ, Montgomery KS, Fincher AS, Wang H, Frye GD, Setlow B, Bizon JL

Abstract
Ethanol exposure during perinatal development can cause cognitive abnormalities including difficulties in learning, attention, and memory, as well as heightened impulsivity. The purpose of this study was to assess performance in spatial learning and impulsive choice tasks in rats subjected to an intragastric intubation model of binge ethanol exposure during human third trimester-equivalent brain development. Male and female Sprague-Dawley rat pups were intubated with ethanol (5.25 g/kg/day) on postnatal days 4-9. At adolescence (between postnatal days 35-38), these rats and sham intubated within-litter controls were trained in both spatial and cued versions of the Morris water maze. A subset of the male rats was subsequently tested on a delay-discounting task to assess impulsive choice. Ethanol-exposed rats were spatially impaired relative to controls, but performed comparably to controls on the cued version of the water maze. Ethanol-exposed rats also showed greater preference for large delayed rewards on the delay discounting task, but no evidence for altered reward sensitivity or perseverative behavior. These data demonstrate that early postnatal intermittent binge-like ethanol exposure has prolonged, detrimental, but selective effects on cognition, suggesting that even relatively brief ethanol exposure late in human pregnancy can be deleterious for cognitive function.

PMID: 22129556 [PubMed - as supplied by publisher]

The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K+ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats.

Behav Pharmacol. 2011 Nov 28;

Authors: Gutierrez VP, Zambelli VO, Picolo G, Chacur M, Sampaio SC, Brigatte P, Konno K, Cury Y

Abstract
Crotalphine, a 14 amino acid peptide first isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces a peripheral long-lasting and opioid receptor-mediated antinociceptive effect in a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. In the present study, we further characterized the molecular mechanisms involved in this effect, determining the type of opioid receptor responsible for this effect and the involvement of the nitric oxide-cyclic GMP pathway and of K channels. Crotalphine (0.2 or 5 μg/kg, orally; 0.0006 μg/paw), administered on day 14 after nerve constriction, inhibited mechanical hyperalgesia and low-threshold mechanical allodynia. The effect of the peptide was antagonized by intraplantar administration of naltrindole, an antagonist of δ-opioid receptors, and partially reversed by norbinaltorphimine, an antagonist of κ-opioid receptors. The effect of crotalphine was also blocked by 7-nitroindazole, an inhibitor of the neuronal nitric oxide synthase; by 1H-(1,2,4) oxadiazolo[4,3-a]quinoxaline-1-one, an inhibitor of guanylate cyclase activation; and by glibenclamide, an ATP-sensitive K channel blocker. The results suggest that peripheral δ-opioid and κ-opioid receptors, the nitric oxide-cyclic GMP pathway, and ATP-sensitive K channels are involved in the antinociceptive effect of crotalphine. The present data point to the therapeutic potential of this peptide for the treatment of chronic neuropathic pain.

PMID: 22126967 [PubMed - as supplied by publisher]

Effects of developmental nicotine exposure in rats on decision-making in adulthood.

Behav Pharmacol. 2011 Nov 24;

Authors: Mitchell MR, Mendez IA, Vokes CM, Damborsky JC, Winzer-Serhan UH, Setlow B

Abstract
Exposure to tobacco smoke during pregnancy is associated with a range of adverse outcomes in offspring, including cognitive deficits and increased incidence of attention deficit-hyperactivity disorder, but there is a considerable controversy with regard to the causal role of tobacco smoke in these outcomes. To determine whether developmental exposure to the primary psychoactive ingredient in tobacco smoke, nicotine, may cause long-lasting behavioral alterations analogous to those in attention deficit-hyperactivity disorder, male Sprague-Dawley rats underwent a chronic neonatal nicotine administration regimen, which models third-trimester human exposure. Male rat pups were administered nicotine (6 mg/kg/day) by oral gastric intubation on postnatal days 1-7. In adulthood, rats were tested in two decision-making tasks (risky decision-making and delay discounting) as well as in free-operant responding for food reward and the elevated plus maze. Chronic neonatal nicotine attenuated weight gain during nicotine exposure, but there were no effects on performance in the decision-making task, and only a modest decrease in arm entries in the elevated plus maze in one subgroup of rats. These data are consistent with previous findings that developmental nicotine exposure has no effect on delay discounting, and they extend these findings to risky decision-making as well. They further suggest that at least some neurocognitive alterations associated with prenatal tobacco smoke exposure in humans may be due to genetic or other environmental factors, including non-nicotine components of tobacco smoke.

PMID: 22123182 [PubMed - as supplied by publisher]

Learning impairment by Δ9-tetrahydrocannabinol in adolescence is attributable to deficits in chunking.

Behav Pharmacol. 2011 Dec;22(8):837-46

Authors: Steel RW, Miller JH, Sim DA, Day DJ

Abstract
Cannabis is the most popular illicit drug used by adolescents. Yet, there are only a few studies that have examined the effects of cannabis use on learning and memory during this sensitive and important neurodevelopmental stage. Male adolescent Sprague-Dawley rats were treated with Δ-tetrahydrocannabinol (THC, 6 mg/kg) daily for 27 days and concurrently trained in a spatial learning and memory task. The chronic effects of cannabis use were specifically examined by assessing animal behaviour during the 'postacute' period (17 h after drug exposure), when minimal acute drug burden is expected to be present. The postacute period is a good model for cannabis use patterns in human adolescents. In addition, we investigated whether the hierarchical organization of working memory (chunking) was impaired by THC-treatment. We show that THC exposure impairs adolescent learning when tested in the postacute period, and that THC impairs the ability of animals to use a chunking strategy.

PMID: 22067480 [PubMed - in process]