Oxytocin: The great facilitator of life

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review.     

Involvement of the brain histaminergic system in addiction and addiction-related behaviors: A comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is involved in many physiological and behavioral functions such as arousal, feeding behavior and learning. Although conflicting data have been published, several studies have also demonstrated a role of histamine in the psychomotor and rewarding effects of addictive drugs. Pharmacological and brain lesion experiments initially led to the proposition that the histaminergic system exerts an inhibitory influence on drug reward processes, opposed to that of the dopaminergic system. The purpose of this review is to summarize the relevant literature on this topic and to discuss whether the inhibitory function of histamine on drug reward is supported by current evidence from published results. Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors. Finally, the hypothesis that the histaminergic system plays an inhibitory role on drug reward appears to be essentially supported by place conditioning studies that focused on morphine reward. The present review suggests that the development of drugs capable of activating the histaminergic system may offer promising therapeutic tools for the treatment of opioid dependence.     

The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: Dual role in nicotine addiction and lung cancer

More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine to nicotinic acetylcholine receptors, ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine. These receptors serve as prototypes for all ligand-gated ion channels and have been extensively studied in an attempt to elucidate their role in nicotine addiction. Many of these studies have focused on heteromeric nicotinic acetylcholine receptors containing α4 and β2 subunits and homomeric nicotinic acetylcholine receptors containing the α7 subunit, two of the most abundant subtypes expressed in the brain. Recently however, a series of linkage analyses, candidate-gene analyses and genome-wide association studies have brought attention to three other members of the nicotinic acetylcholine receptor family: the α5, α3 and β4 subunits. The genes encoding these subunits lie in a genomic cluster that contains variants associated with increased risk for several diseases including nicotine dependence and lung cancer. The underlying mechanisms for these associations have not yet been elucidated but decades of research on the nicotinic receptor gene family as well as emerging data provide insight on how these receptors may function in pathological states. Here, we review this body of work, focusing on the clustered nicotinic acetylcholine receptor genes and evaluating their role in nicotine addiction and lung cancer.     

Tryptophan-deficient diet increases the neurochemical and behavioral response to amphetamine

The present study examined the effects of a tryptophan-deficient diet on behavioral and neurochemical response to amphetamine. A tryptophan-deficient diet (14 days) decreased striatal serotonin and 5-hydroxyindolacetic acid content in rats. Under the latter conditions, amphetamine increased dopamine efflux in striatum and nucleus accumbens and produced a greater increase in motor activity when compared to controls. These results indicate how response to psychostimulants might be altered in the presence of a tryptophan-deficient diet.     

Reward-related activity in the human motor cortex

The human primary motor cortex (M1) participates in motor learning and response selection, functions that rely on feedback on the success of behavior (i.e. reward). To investigate the possibility that behavioral contingencies alter M1 activity in humans, we tested intracortical inhibition with single and paired (subthreshold/suprathreshold) transcranial magnetic stimulation during a slot machine simulation that delivered variable money rewards for three-way matches and required no movement. A two-way match before the third barrel had stopped (increased reward expectation) was associated with more paired-pulse inhibition than no match. Receiving a large reward on the preceding trial augmented this effect. A control task that manipulated attention to the same stimuli produced no changes in excitability. The origin of this reward-related activity is not clear, although dopaminergic ventral tegmental area neurons project to M1, where they are thought to inhibit output neurons and could be the source of the finding. Transcranial magnetic stimulation of M1 may be useful as a quantitative measure of reward-related activity.     

Effect of memantine and CNQX in the acquisition, expression and reinstatement of cocaine-induced conditioned place preference

The present study evaluates the effect of memantine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist and CNQX, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist on the rewarding effects of cocaine in mice, using the conditioned place preference (CPP) paradigm. Cocaine-induced CPP was studied pairing this drug with different memantine or CNQX doses during either the acquisition or the expression phase of the procedure. Once CPP was established, and the preference extinguished, reinstatement was induced by a priming dose of cocaine. Both antagonists, which in themselves do not present motivational actions on the preference shown by the animals, abolished the acquisition and expression of the cocaine-induced CPP. Neither of the antagonists precipitated reinstatement of the preference induced by cocaine but memantine blocked the cocaine-primed reinstatement. Our results suggest that cocaine-induced CPP and reinstatement is largely dependent on glutamate neurotransmission, and confer a putative role for memantine among the tools useful for cocaine management and treatment.     

Dose response effect of methylphenidate on ventral tegmental area neurons and animal behavior

Methylphenidate (MPD) is the drug of choice prescribed to treat ADHD patients. More recently, MPD is also used as a cognitive enhancement and recreationally by young adults and its therapeutic effects are not fully understood. One of the neuroanatomical sites is reported to be the ventral tegmental area (VTA). The ventral tegmental area neuronal activity was recorded from freely behaving non-anesthetized rats implanted bilaterally with semi-permanent electrodes which were recorded from a wireless telemetric system. Thirty-three animals, divided randomly into four groups, were used: saline (n = 10), 0.6 mg/kg (n = 6), 2.5 mg/kg (n = 7) and 10.0 mg/kg MPD (n = 10). MPD caused an increase in locomotor activity with a dose response characteristic; 0.6 mg/kg MPD elicited some increase in locomotion, but not significantly, while 2.5 and 10.0 mg/kg MPD elicited significant increases in behavior of 191% and 870% respectively. A total of 209 ventral tegmental area units were recorded; 100% (36/36) units showed no response to saline; 89% (154/173) of the neurons responded to MPD, with the majority 66% (101/154) showing an increase in activity. In response to 0.6 mg/kg (n = 52), the majority of units 54% (28/52) showed a decrease in activity. For both 2.5 (n = 60) and 10.0 mg/kg (n = 61), the majority of ventral tegmental area units responded with an increase in activity with 63% (38/60) and 70% (43/61) respectively. This study demonstrated that the majority of ventral tegmental area neurons respond to acute MPD in a dose response characteristic and are not related to the animal's locomotor activity.