Rimonabant (SR141716), a CB1 receptor antagonist, Blocks the Expression, but not the Development of Locomotor Sensitization to Nicotine Administration

Siena Calabro (Psychology)

Advisor: John Kelsey

Cannabinoid receptors have been indicated in the mesolimbic pathway of reward that extends from the ventral tegmental area to the nucleus accumbens. Rimonabant (SR141716), a CB1 receptor antagonist, is a drug marketed for weight loss that has also shown promising results in reducing a variety of rewarding behaviors produced by addictive drugs. Research has shown that rimonabant reduces self-administration, conditioned place preference, and reinstatement of drugs of abuse, such as opiates, alcohol, and nicotine, in animal models of addiction. The purposed of the current study was to determine whether rimonabant would block the development or expression of locomotor sensitization due to nicotine administration. Rats were injected with either vehicle-saline, vehicle-nicotine (0.4 mg/kg), rimonabant (2 mg/kg)-saline, or rimonabant- nicotine before placement in an activity box for six 1-hr sessions on alternating days. Although rimonabant appeared to block the development of sensitization during the six sessions, a subsequent challenge of just 0.4 mg/kg nicotine indicated that the rimonabant-nicotine group had developed as much sensitization as the vehicle-nicotine group. Furthermore a subsequent rimonabant-nicotine challenge blocked the expression of sensitization in both the nicotine-pretreated groups. Thus, it appears as though 2 mg/kg rimonabant does not block the development of locomotor sensitization to nicotine, but it does block or mask its expression. If rimonabant continues to block the rewarding effects of addictive substances, it may someday prove to be an effective treatment for drug addiction.

Molecular Characterization and Pharmacological Analysis of Helisoma trivolvis Glutamate Receptors Hel-GluR1 and Hel- GluR7

Shelly Davgun (Biology)

Advisor: Nancy Kleckner

Glutamate is a neurotransmitter involved in Helisoma trivolvus feeding and is known to excite certain neurons while inhibiting others. This activity maintains a rhythmic feeding pattern, and further illustrates that glutamate activates two different receptor-types. The excitatory receptors are known to be similar to vertebrate KA and AMPA receptor types based upon previous research with glutamate agonists and antagonists. In this research partial excitatory glutamate receptor clones, Hel -GluR1 has been fully sequenced and using RACE PCR to obtain a desired 90 bp sequence fragment on 5’ Hel-GluR1. This fragment will be verified with multiple contigs and assembled into the overall 3,000 bp Hel-GluR1 sequence in order to successfully amplify the sequence for further studies. It is anticipated that further studies on Hel-GluR1 in will allow for pharmacological dose-response analysis.

Inhibition of Extracellular-signal Regulated Kinase (ERK) in the Ventral Tegmental Area (VTA), but not the Nucleus Accumbens, Slows the Development of Nicotine-Induced Locomotor Sensitization in Rats

Sam Golden (Neuroscience-Honors)

Advisor: John Kelsey

Many of the persistent and habitual drug seeking behaviors associated with drug addiction are presumed to be modulated by the reward and reinforcement circuitry of the nucleus accumbens (NAc), via direct or indirect activation of the mesolimbic dopaminergic pathway originating in the ventral tegmental area (VTA). Nicotine, arguably one of the most socially ubiquitous and accessible drugs in American society, is believed to exert its addictive effects by binding to nicotinic acetylcholine receptors on the cell bodies of mesolimbic neurons, where it enhances dopamine (DA) transmission and mimics the effects of naturally reinforcing stimuli. Unfortunately, the molecular basis of this process is poorly understood. Recent evidence has implicated the extracellular-signaling regulated kinase (ERK) signaling cascade in the development of neuroadaptations that lead to addictive behaviors. One such behavior is known as locomotor sensitization, in which repeated administration of nicotine results in progressive increases in locomotor activity. To further elucidate the possible role of ERK in the development neuroadaptations that lead to locomotor sensitization, bilateral infusions of the selective MEK/ERK inhibitor U0126 (2.0 mg/hemisphere) into the NAc or VTA were given in conjunction with five once daily injections of nicotine (0.4 mg/kg, s.c.). It was found that intra-VTA, but not intra-NAc, inhibition of the ERK cascade slowed the development of locomotor sensitization. Thus, it appears that activation of the ERK signaling cascade in the ventral tegmental area may be critical to the development of nicotine-induced addictive behaviors.

The Effects of Chronic Nicotine on the Cognitive Symptoms of Schizophrenia in the Phencyclidine Animal Model

Shannon E. Tully (Psychology)

Advisor: John Kelsey

Schizophrenia is a psychotic disorder characterized by positive and negative symptoms, and most notably, cognitive deficits. Phencyclidine (PCP) has been shown to produce many of these symptoms in humans and in animal models. Given that upwards of 90% of schizophrenics smoke, it has been hypothesized that smoking is an attempt to self-medicate their symptoms. The intent of this study was to determine if chronic nicotine exposure could ameliorate the cognitive deficits produced by PCP in an animal model. Eight male Long Evans rats were trained on a delayed non-match to sample (DNMTS) working memory task that required them to remember which of two levers they initially pressed. Subjects were injected with 4.0 mg/kg and 5.0 mg/kg of PCP and nicotine was administered chronically at 0.8 mg/kg. PCP dose- dependently impaired performance on the DNMTS task, nicotine slightly worsened performance, and chronic nicotine exacerbated the cognitive impairments of PCP. Explanations for the failure of nicotine to ameliorate the cognitive deficits produced by PCP are discussed.

Melatonin in Clinical Treatment of Depression: Putative Application as a Diagnostic Marker and Novel Drug Therapy

Jose Gabriel Villareal Tungol (Neuroscience)

Advisor: Roxanne Prichard

Due to the prevalence of sleep abnormalities and circadian pathophysiologies that occur concomitantly with depression, we compared the efficacies of photoperiodic therapy, classical antidepressant medication, and the circadian modulating hormone melatonin in a depressed animal model. 23 Fawn-Hooded (depressed-strain) and 24 Long Evans (normal control) rats were entrained to either an extended (16:8 h) or abbreviated (8:16 h) light:dark schedule, and their behaviors were observed in a rewarding food preference test of anhedonia and the Porsolt forced swim test of despair. Synchronization to the extended photoperiod led to a marginal increase in latency to immobility (p = .417) for both rat strains; in addition, the Fawn-Hooded strain overall demonstrated slightly shorter latencies to immobility than Long Evans rats (p = .636). Fawn-Hooded animals consumed more high-fat (p << .01) and less high-carbohydrate (p = .065) chow than Long Evans rats, though no effect of photoperiod on food preference was observed. A pilot ELISA of pooled serum samples show a marked reduction in levels of endogenous melatonin during daylight hours compared to the peak concentrations that occur scotopically, and that animals entrained to the extended photoperiod tended to have lower serum melatonin levels than those in the short light cycle. Furthermore, Fawn-Hooded rats displayed greater daytime suppression of melatonin than Long Evans controls. After re- entrainment to a normal (12:12 h) photoperiod, animals were injected with 10 mg/kg desipramine, melatonin, or vehicle every day for a seven day period. On the eighth day, Fawn-Hooded and Long Evans behaviors were observed in the Porsolt forced swim test, a sucrose test of hedonic reward, and an open field apparatus. Relative to administrations of vehicle, melatonin (p = .057) demonstrated near-equivalent efficacy as desipramine (p = .01) in increasing Fawn-Hooded latency to immobility in the forced swim test, though its effects on decreasing total immobility were less significant (p = .301). Melatonin also increased Fawn-Hooded preference for sucrose over water (p =.147), and enhanced the amount of time Fawn-Hooded animals spent in the center of the open field compared to both desipramine (p < .089) and vehicle (p < .197); furthermore, Fawn-Hooded rats engaged in significantly less horizontal (p < .001) and vertical (p < .05) exploratory behavior than Long Evans rats. These data support other findings which indicate that melatonin plays an important role in circadian rhythm, and furthermore, that melatonin holds great potential in developing new antidepressant therapies. In addition, we conclude that the Fawn-Hooded rat provides an appropriate animal model for investigations of depressive affect.