Ann E. K. Kosobud

Mice genetically selected for differences in open-field activity after ethanol

Starting from a population of genetically heterogeneous mice, selective breeding is being used to develop lines differing in sensitivity to ethanol-induced open-field activity. Mice are tested twice for 4 min in an open field. The first test is between min 2-6 after injection of saline. Twenty-four hr later, a similar test is performed after injection of ethanol (1.5 g/kg). Two independent FAST lines are being selected for ethanol-induced increases in activity, and two independent SLOW lines are being selected for ethanol-induced decreases. After four generations of selection, the lines have diverged significantly. These lines should be useful for exploring the neuropharmacological basis for the activating and rewarding properties of ethanol.

Alcohol‐Related Olfactory Cues Activate the Nucleus Accumbens and Ventral Tegmental Area in High‐Risk Drinkers: Preliminary Findings

BACKGROUND The mesocorticolimbic dopamine system is implicated in motivation and reward and may be involved in the development of alcoholism. METHODS We used functional magnetic resonance imaging to study the blood oxygen level-dependent (BOLD) response to alcohol-related olfactory stimuli (AROS; odors of beer and whiskey) and non-alcohol-related olfactory stimuli (NAROS; odors of grass and leather) in 10 high-risk (HR) drinkers (average drinks per week, 19.99; SD, 6.99; all with > or = 2 first- or second-degree alcoholic relatives) and 5 low-risk (LR) social drinking controls (drinks per week, 2.82; SD, 2.87; 1 subject had 1 second-degree alcoholic relative). Data were analyzed with SPM99 and random effects analysis by using regions of interest and corrected cluster statistics (p < 0.05) to focus on the nucleus accumbens (NAc) and ventral tegmental area (VTA). RESULTS In HR subjects, there was a greater BOLD signal increase in the NAc during AROS than during clean air. BOLD signal increases during AROS were also greater in the NAc than the signal increases induced by NAROS. The AROS signal was significantly greater than the NAROS signal in a small number of voxels in the VTA. Finally, the AROS/NAROS difference signal was larger in HR drinkers in both the NAc and VTA. CONCLUSIONS Alcoholic olfactory cues may invoke the dopaminergic mesocorticolimbic system to a greater degree than nonalcoholic odors and could be effective tools in exploring the role of the dopamine system in susceptibility to alcoholism.

Drugs of abuse can entrain circadian rhythms.

Circadian rhythms prepare organisms for predictable events during the Earths 24-h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.

Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task

Motor-control models of basal ganglia function have emphasized disinhibition through reduction of tonic, inhibitory output. Although these models have shed important light on basal ganglia operations, evidence emerging from electrophysiological studies of behaving primates suggests that disinhibition alone may not adequately explain the role of the basal ganglia in movement. To assess this role in the rat, the most frequently used subject in studies of basal ganglia function, we recorded neuronal activity in the primary output nucleus, the substantia nigra pars reticulata, during an operant task. After rats were trained to nosepoke into an illuminated hole for access to a 10% sucrose solution delivered through a spout, single- and multiple-unit activity was recorded during 60-120 nosepoke trials. Compared to the period 60 s before the start of the first trial in the task, 110 of 225 reticulata units increased firing >200% while 17 of 225 decreased to 40% of baseline. Of these 225 units, >60% responded coincident with specific task events such as nosepokes and spout licking. Most nosepoke-responsive units showed either excitation (>50%) or a combination of excitation and inhibition (>25%) rather than inhibition alone (>20%). Increases in firing were also common during approach and licking at the spout, with inhibitions alone comprising 30% of responses. In some units, there was evidence of reward-related responding, with changes occurring in anticipation of reward delivery or during the delivery of sucrose, but not the persistent licking that continued for several seconds after its offset. While 70% of units responded during both nosepokes and spout licking, changes in firing were typically unique depending on the motor behavior required (i.e. nosepoking vs. licking). Our results, which indicate a prominent role for increases in nigra reticulata activity during movement, add to growing evidence that although inhibitions may allow desired motor responses to emerge, excitations may help shape behavioral output by suppressing competing motor programs.

Circadian activity precedes daily methamphetamine injections in the rat.

Scheduled daily injections of methamphetamine (MA) produced locomotor activity that preceded and followed the usual time of injection in rats housed under conditions of constant, moderately dim light and temporally distributed feeding. A circadian basis for pre-injection time activity was supported by its anticipatory timing in the apparent absence of reliable preceding external cues and by its persistence on a test day on which the rats remained undisturbed. Post-injection time locomotor activity also persisted on the test day, occurring from 24 to 29 h after the final MA injection. These results indicate that MA injections engage circadian processes underlying locomotor activity, and they raise the possibility that intake of drugs of abuse by humans may facilitate drug taking or relapse at times of day related to previous drug use.

Strain differences in pituitary β-endorphin and ACTH content in inbred mice

Abstract The whole pituitary contents of β-endorphin and ACTH were found to vary widely among 5 inbred strains of mice. β-endorphin values were 2.5-fold different and ACTH values 1.5-fold. Strains low in β-endorphin were also low in ACTH. The existence of genetic differences raises the possibility that there exist, or can be developed, strains with extremely low or high levels of these peptides that would aid research directed at elucidating the physiology of opioid peptides.

Pre-and post-nicotine circadian activity rhythms can be differentiated by a paired environmental cue

Previous studies have shown that addictive drugs presented daily at fixed times produce circadian (oscillator-driven) anticipatory and evoked activity rhythms in rats. Other studies have shown that environmental cues paired with addictive drugs produce tolerance to drug effects and elicit craving behavior when presented without the drug. The present study tested these circadian entrainment and paired-cue conditioning effects together. This study compared the ability of daily nicotine and saline injections at different fixed times to entrain pre-injection (anticipatory) and post-injection (evoked) circadian activity rhythms in two groups of female Sprague-Dawley rats. One group (Paired) had an environmental cue (a tone) paired with the effects of the nicotine injection, and the second group (Unpaired) had the tone paired with the effects of the saline injection. The rats were housed singly for 56 days in chambers with attached wheels under constant dim light and rate-limited food access. During three separate injection phases, nicotine and saline were administered daily at different fixed times, and the tone was presented at the second injection time. Three multi-day test phases examined circadian activity (a) without injections or tone, (b) with the tone alone at normal and novel times, and (c) with the tone absent and with injections occurring at normal and at novel times. The results showed that nicotine entrained both pre- and post-injection circadian oscillators, and the nicotine-paired tone interfered with pre-injection anticipatory activity.

Effects of ethanol on rat somatosensory cortical neurons

In this study, we characterized the local effects of ethanol (EtOH) on postsynaptic potentials (PSPs) and membrane properties of layer II-III (L2-3) and layer V (L5) somatosensory cortical neurons. Intracellular recordings were done using the in vitro slice preparation of rat somatosensory cortex. Our results show that EtOH exerts local effects on cortical cell membrane at physiologically relevant concentrations. A predominant effect of EtOH was to reduce excitability of L2-3 and L5 neurons by increasing the rheobase, decreasing input resistance and repetitive firing, reducing PSPs amplitude and the probability of evoking action potentials. Early (6 ms) and late (18 ms) PSP components were affected differentially by EtOH, the late components being more suppressed. Overall, EtOH-mediated suppression of PSPs was stronger in L5 neurons. Cortical neurons were divided into three subtypes: regular spiking adapting (RS-A), regular spiking non-adapting (RS-NA) and bursting (D-IB) neurons. PSPs evoked in RS-A neurons were more sensitive to EtOH suppressant effects. EtOH effects on input resistance were distributed differentially among the three groups of neurons. These results support the notion that EtOH disrupts higher processing of somatosensory information via a differential alteration of cortical neurons membrane properties and synaptic transmission.

Amphetamine inhibits behavior-related neuronal responses in substantia nigra pars reticulata of rats working for sucrose reinforcement

Changes in activity of basal ganglia neurons, especially those in the striatum, are thought to underlie the characteristic behavioral patterns produced by d-amphetamine (AMPH). To study the role of the substantia nigra pars reticulata (SNr), a major basal ganglia output nucleus, we recorded from SNr neurons before and after a behaviorally activating dose of AMPH (0.5 mg/kg) in rats trained to nosepoke for sucrose reinforcement. Before AMPH, task-related behaviors were associated primarily with increases or both increases and decreases in SNr firing. Although these same behavior-related patterns persisted after AMPH, their relative magnitude was significantly attenuated. Units unresponsive during task events were unaffected by AMPH. Thus, rather than change the overall level of SNr firing, a behaviorally active dose of AMPH exerts context-dependent effects on the activity of SNr neurons.

Long T methamphetamine schedules produce circadian ensuing drug activity in rats.

Eight female Sprague-Dawley rats were housed in isolated continuous 24-h/day environments under conditions of constant dim light and a rate-limited feeding schedule. Following 2 months of free-running activity, all animals were administered methamphetamine (MA) i.p. (2 mg/kg) once every 31 h for 24 injection cycles. Average wave forms of wheel-running activity showed that animals did not anticipate the 31-h schedule of MA injections, but rather displayed circadian ensuing drug activity (CEDA) between 24 and 28 h following the injections. Post-injection meals failed to meet reliably the threshold necessary to achieve food-engendered anticipatory or ensuing activity. Cosinor analysis showed that the intensity of CEDA was strongly influenced by the relative phase of the free-running rhythm. CEDA was moderately influenced by the size of the post-injection bout of activity. Because injection times rotated daily throughout local time without repeating a time of day, CEDA resulting from a long T schedule of MA administration appeared to be based on one-trial resetting of a circadian-related mechanism by a major drug of abuse.