Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats

Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and γ-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction.     

The ups and downs of addiction: role of metabotropic glutamate receptors

Drug addiction is characterized by drug-induced positive affect, followed by withdrawal-associated negative affect. Such drug-induced positive and negative affective states provide crucial sources of motivation that drive compulsive drug consumption. Metabotropic glutamate (mGlu) receptors, which are responsible for slow glutamate-mediated neurotransmission, are located throughout limbic and cortical brain regions that are implicated in drug addiction. Emerging evidence indicates that mGlu receptors regulate many behavioral actions of addictive drugs. In particular, group I mGlu receptors play an important role in regulating the reinforcing effects of drugs of abuse. Furthermore, group II mGlu receptors have been implicated in the synaptic adaptations that occur in response to chronic drug exposure and contribute to the aversive behavioral syndrome observed during withdrawal. These findings increase our understanding of the pathological processes that are associated with the development of drug addiction, and might ultimately lead to new therapies for the treatment of this disorder.     

The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat

Rationale Previous work has indicated a potential role for -aminobutyric acid-B (GABA_B) receptor agonists in treating drug addiction in humans. Specifically, GABA_B receptor agonists decreased cocaine, heroin and nicotine self-administration in rats.Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABA_B receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats.Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABA_B receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules.Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function (r=0.61). Both CGP44532 and (–)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule.Conclusion The present data demonstrate that administration of GABA_B receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABA_B receptor agonists as therapeutics for smoking cessation.     

Adolescent Intermittent Ethanol Exposure Is Associated with Increased Risky Choice and Decreased Dopaminergic and Cholinergic Neuron Markers in Adult Rats

Background:

Binge drinking is prevalent during adolescence and may have effects on the adult brain and behavior. The present study investigated whether adolescent intermittent ethanol exposure alters adult risky choice and prefrontal dopaminergic and forebrain cholinergic neuronal marker levels in male Wistar rats.

Methods:

Adolescent (postnatal day 28–53) rats were administered 5g/kg of 25% (vol/vol) ethanol 3 times/d in a 2-days–on/2-days–off exposure pattern. In adulthood, risky choice was assessed in the probability discounting task with descending and ascending series of large reward probabilities and after acute ethanol challenge. Immunohistochemical analyses assessed tyrosine hydroxylase, a marker of dopamine and norepinephrine in the prelimbic and infralimbic cortices, and choline acetyltransferase, a marker of cholinergic neurons, in the basal forebrain.

Results:

All of the rats preferred the large reward when it was delivered with high probability. When the large reward became unlikely, control rats preferred the smaller, safe reward, whereas adolescent intermittent ethanol-exposed rats continued to prefer the risky alternative. Acute ethanol had no effect on risky choice in either group of rats. Tyrosine hydroxylase (prelimbic cortex only) and choline acetyltransferase immunoreactivity levels were decreased in adolescent intermittent ethanol-exposed rats compared with controls. Risky choice was negatively correlated with choline acetyltransferase, implicating decreased forebrain cholinergic activity in risky choice.

Conclusions:

The decreases in tyrosine hydroxylase and choline acetyltransferase immunoreactivity suggest that adolescent intermittent ethanol exposure has enduring neural effects that may lead to altered adult behaviors, such as increased risky decision making. In humans, increased risky decision making could lead to maladaptive, potentially harmful consequences.     

Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice

The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHbetaE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.     

Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats.

Acute administration of gamma-aminobutyric acid B (GABAB) receptor agonists decreased nicotine, cocaine, ethanol, and heroin self-administration. GABAB receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABAB receptor agonist CGP44532 on nicotine- and food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine- and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.     

Mild anxiogenic effects of nicotine withdrawal in mice

Increased anxiety is one of the symptoms of nicotine withdrawal that may lead to relapse. Previous studies have shown that nicotine withdrawal affects anxiety-like behavior in different tests of anxiety in humans and rats. However, relatively few studies have focused on the anxiogenic effect of nicotine withdrawal in mice. The present study investigated the effect of nicotine withdrawal on anxiety-like behavior in DBA/2J and C57BL/6J mouse strains in the light-dark box, acoustic startle response, and prepulse inhibition tests. An initial experiment showed that nicotine administration of 12 or 24 mg/kg/day (free base) for 14 days did not result in significant effects during withdrawal in startle, prepulse inhibition, or light-dark box, but there was a trend towards an anxiogenic effect in the light-dark box 24 h, but not 1 or 4 h, after cessation of nicotine administration. A subsequent study was therefore performed, with minipumps delivering saline, 24 mg/kg/day nicotine, or 48 mg/kg/day nicotine (free base), for 14 days. The pumps were removed, and the mice were tested 24 h after cessation of nicotine administration. Cessation of administration of 48 mg/kg/day nicotine free base in C57BL/6J mice resulted in increased anxiety-like behavior in the light-dark box, while the behavior of DBA/2J mice was unaffected. The acoustic startle response and prepulse inhibition were also unaffected in both strains. In conclusion, the present data show that nicotine withdrawal is mildly anxiogenic in C57BL/6J mice under the conditions used in the present experiments.