Dopamine-associated cached values are not sufficient as the basis for action selection.

Phasic dopamine transmission is posited to act as a critical teaching signal that updates the stored (or "cached") values assigned to reward-predictive stimuli and actions. It is widely hypothesized that these cached values determine the selection among multiple courses of action, a premise that has provided a foundation for contemporary theories of decision making. In the current work we used fast-scan cyclic voltammetry to probe dopamine-associated cached values from cue-evoked dopamine release in the nucleus accumbens of rats performing cost-benefit decision-making paradigms to evaluate critically the relationship between dopamine-associated cached values and preferences. By manipulating the amount of effort required to obtain rewards of different sizes, we were able to bias rats toward preferring an option yielding a high-value reward in some sessions and toward instead preferring an option yielding a low-value reward in others. Therefore, this approach permitted the investigation of dopamine-associated cached values in a context in which reward magnitude and subjective preference were dissociated. We observed greater cue-evoked mesolimbic dopamine release to options yielding the high-value reward even when rats preferred the option yielding the low-value reward. This result identifies a clear mismatch between the ordinal utility of the available options and the rank ordering of their cached values, thereby providing robust evidence that dopamine-associated cached values cannot be the sole determinant of choices in simple economic decision making.

Reinforcing and neural activating effects of norharmane, a non-nicotine tobacco constituent, alone and in combination with nicotine.

Tobacco use is the leading cause of preventable death. Although the health risks are well known, cessation rates remain low. Whereas behavioral and neuroanatomical studies on tobacco addiction conventionally use nicotine, there is evidence that other constituents, such as monoamine oxidase inhibitors, may be important factors for modeling smoking. The aims of the present study were therefore to determine whether norharmane, a tobacco constituent and monoamine oxidase inhibitor, is self-administered alone and/or in combination with nicotine, and to evaluate the neural mechanisms underlying acquisition of self-administration of the two drugs. Sprague-Dawley rats were catheterized and allowed to intravenously self-administer either saline, nicotine (7.5 µg/kg/inj), norharmane (0.25 or 2.5 µg/kg/inj), alone or combined together (7.5+2.5 µg/kg/inj) for five days at fixed ratio (FR)1, two days each at FR2 and FR5, and one day at progressive ratio. Animals acquired self-administration of norharmane alone (2.5 µg/kg/inj), and the reinforcing effects of nicotine and norharmane were additive. For neuroanatomical analyses, rats self-administered the same treatments for six days at FR1, then brains were collected and processed by in situ hybridization for cfos mRNA expression. Treatment-specific profiles of regional cfos expression and correlations between cfos mRNA levels and behavioral responding were observed. Thus, not only was norharmane behaviorally reinforcing but, when combined with nicotine, resulted in patterns of neural activation distinct from that of norharmane or nicotine alone. This suggests that non-nicotine constituents can have central activating effects independent of nicotine, further substantiating the need for their inclusion in preclinical investigations of tobacco dependence.

Synaptoneurosome micromethod for fractionation of mouse and human brain, and primary neuronal cultures.

Brain and primary neuron fractions enriched in synaptic terminals are important tools for neuroscientists in biochemical, neuroanatomical and physiological studies. We describe an annotated updated micro-method for preparing synaptoneurosomes (SNs) enriched in presynaptic and postsynaptic elements. An easy to follow, step-by-step, protocol is provided for making SNs from small amounts of mammalian brain tissue. This includes novel applications for material obtained from human neurosurgical procedures and primary rat neuronal cultures. Our updated method for preparing SNs using smaller amounts of tissue provides a valuable new tool and expands the capabilities of neuroscientists.

The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition.

Our current study aims to evaluate the mechanisms of tranylcypromine (TCP)-mediated enhancement of nicotine self-administration. We replicated our previous findings which demonstrate that 1 h pretreatment with TCP (3 mg/kg, i.p.) enhances nicotine self-administration (7.5 µg/kg/inj, i.v.) when compared with vehicle-treated rodents. We tested whether TCP-mediated enhancement of nicotine self-administration was due to MAO inhibition or off-target effects by (i) extending the TCP pretreatment time from 1 to 20 h, and (ii) evaluating the role of the individual TCP stereoisomers in nicotine self-administration studies. While 20 h and (-)TCP pretreatment induced significant inhibition of MAO (60-90%), animals found nicotine only weakly reinforcing. Furthermore, while both (+) and (±)TCP treatment induced nearly 100% MAO inhibition, (+)TCP pretreated animals took longer to acquire nicotine self-administration compared to (±)TCP pretreated animals. Stable nicotine self-administration in (+)TCP pretreated animals was influenced by nicotinic receptor activation but not nicotine-paired cues. The opposite was found in (±)TCP pretreated animals. Treatment with (-) or (±)TCP increased dopamine and serotonin overflow, while the (+) and (±)TCP treatment enhanced monoamine overflow subsequent to nicotine. Together, our data suggests TCP enhancement of nicotine self-administration are mediated through mechanisms independent of MAO inhibition, including nicotine-paired cues and monoamine uptake inhibition.