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There is increasing evidence of functional lateralization within the rat brain. Here, we have examined the lateralization of dopamine (DA) function in the medial prefrontal cortex (PFC) in relation to memory consolidation in the novel object recognition test (NOR). Male Wistar rats received single bilateral or unilateral injections into prelimbic-PFC of agonists (SKF81297; 0.2 µg, quinpirole; 1 µg, SB277,011; 0.5 µg) and antagonists (SCH23390; 3 µg, L-741,626; 1 µg, 7-OH-DPAT; 3 µg) at DA D1, D2, or D3 receptors, immediately following the exposure trial in the NOR, and were tested either 1 or 24 h later for discrimination between a novel and a familiar object. As previously reported, bilateral injection of a D1 antagonist (SCH23390, 3 µg/side), a D2 antagonist (L-741,626, 1 µg/side) or a D3 agonist (7-OH-DPAT, 3 µg/side) impaired NOR at 1 h, while a D1 agonist (SKF81297, 0.2 µg/side), a D2 agonist (quinpirole, 1 µg/side) or a D3 antagonist (SB277,011, 0.5 µg/side) improved NOR at 24 h. The same effects were seen with left-sided unilateral injections. No effects were seen with right-sided unilateral injections. Endogenous DA release in the prelimbic-PFC promotes memory consolidation in the NOR, but only on the left side of the brain.

We have previously reported the effects of intracranial injections of dopamine D1, D2 and D3 ligands in animals subjected to the Novel Object Recognition (NOR) test following exposure to chronic mild stress (CMS) and chronic treatment with risperidone (RSP). Here, we present some molecular biological data from the same animals. It was predicted that brain-derived neurotrophic factor (BDNF) signalling in the prefrontal cortex (PFC) would reflect behavioural performance, implying an increase following acute administration of a D2 agonist or a D3 antagonist, blockade of this effect by CMS and its restoration by chronic RSP. In separate cohorts, animals were injected within the PFC or the hippocampus (HPC) with either the D1 agonist SKF-81297, the D2 agonist quinpirole or the D3 antagonist SB-277,011, following exposure to control conditions or CMS and chronic treatment with saline or RSP. Intracranial injections followed an exposure trial in the NOR test, with a retention trial 24 h later. Immediately afterwards, the animals were killed and expression of BDNF and TRKβ protein, and their respective mRNAs, was measured in PFC and HPC samples. CMS decreased the expression of TRKβ in both PFC and HPC. Several effects associated with intracranial injection were noted, but they were inconsistent and unrelated to CMS exposure. The effects of CMS on TRKβ are consistent with a decrease in BDNF signalling, albeit that expression of BDNF itself did not change significantly. There was no evidence for an involvement of the BDNF-TRKβ system in responses to RSP or dopamine ligands in animals exposed to CMS. However, there was a 24 h delay between the intracranial injection and tissue harvesting, meaning that brief early drug effects could have been missed.

Ketamine is the prototype of a new generation of antidepressant drugs, which is reported in clinical studies to be effective in treatment-resistant patients, with an effect that appears within hours and lasts for a few days. Chronic mild stress (CMS) is a well-established and widely used animal model of depression, in which anhedonia, anxiogenesis and cognitive dysfunction can be observed reliably. Studies using acute or brief ketamine treatment following withdrawal from CMS have replicated the clinical finding of a rapid onset of antidepressant action. However, there have been no CMS studies of chronic daily ketamine treatment or continued stress following ketamine treatment, which would have greater translational potential in relation to the long-term maintenance of antidepressant effects. Wistar rats were drug treated following an initial 2 weeks of CMS exposure, which continued alongside daily drug treatment. A first experiment tested a range of chronic (5 weeks) ketamine doses (5-30 mg/kg); a second compared the effects of subacute (3-5 days) and chronic (5 weeks) treatment. CMS-induced anhedonic, anxiogenic and dyscognitive effects, as measured, respectively, by decreased sucrose intake, avoidance of open arms in the elevated plus maze and loss of discrimination in the novel object recognition test. A sustained antidepressant-like effect of ketamine in the sucrose intake test was observed in both experiments, with an onset at around 1 week, faster than imipramine, and an optimum dose of 10 mg/kg. Anxiogenic and dyscognitive effects of CMS, in the elevated plus maze and novel object recognition test, respectively, were fully reversed by both subacute and chronic ketamine treatment. Daily treatment with ketamine in the CMS model causes sustained long-term antidepressant, anxiolytic and procognitive effects. The demonstration of a procognitive effect of ketamine may have particular translational value.

A recent review proposed four criteria for an animal model of treatment-resistant depression (TRD): a phenotypic resemblance to a risk factor for depression; enhanced response to stress; nonresponse to antidepressant drugs and response to treatments effective in TRD, such as deep brain stimulation (DBS) of the prefrontal cortex or ketamine. Chronic mild stress (CMS) provides a valid model of depression; the Wistar-Kyoto (WKY) rat is considered to be nonresponsive to antidepressant drugs. Here, we applied CMS to WKY rats. WKY and Wistar rats were exposed to CMS, then treated with saline, imipramine, citalopram or venlafaxine. After 5 weeks of CMS and 3 weeks of drug treatment, all WKY groups were implanted unilaterally with DBS electrodes in the prefrontal cortex, and examined in sucrose intake, elevated plus maze (EPM; decreased entries and time in the open arms) and novel object recognition (decreased exploration) tests, following 2×2 h of DBS. CMS decreased sucrose intake, open arm entries on the EPM, and object recognition. Relative to Wistars, WKY rats showed evidence of increased emotionality in the EPM and novel object recognition tests, and a greater impact of CMS on body weight gain and open arm entries. Wistars responded to drug treatment with an increase in sucrose intake but WKY were nonresponsive to drug treatment on all three behavioural tests. With one exception, DBS reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all groups of WKY rats. In a further experiment, subacute ketamine (10 mg/kg) also normalized behaviour on all three tests. We conclude that WKY rats subjected to CMS meet all four criteria for a valid model of TRD, and provide a basis for studying the mechanism of action of DBS.

Some animal models of depression, including the majority of the more recently introduced models, are better characterized as models of predisposition to depression. In the first part of this paper, we show that the basis for such a model could be either a procedure that increases the ease with which an analogue of major depression may be evoked, or a presentation analogous to dysthymia (chronic mild depression). We then consider how the concepts of predictive, face, and construct validity apply to such models. Next, we review the validity of the available models of predisposition to depression, which derive from genetics, genomics, developmental manipulations, and brain lesioning. Finally, we compare the performance of the different models, using a novel scoring system that formalizes the evaluation of animal models against each of the three sets of validation criteria.

The Questionnaire of Smoking Urges (QSU) was designed to measure cravings elicited by abstinence from cigarette smoking. In the present study, the sensitivity of the QSU both to brief periods of abstinence and to exposure to smoking-related cues was investigated. A progressive ratio (PR) operant procedure was also employed, in which behaviour was maintained either by primary reinforcement (puffs on a cigarette) or by secondary reinforcement (tokens exchanged later for puffs on a cigarette) in separate experiments. Dependent smokers, who were not abstinent or who were abstinent for either 2 or 4 h, were tested in both a cue-rich and a no-cue environment. The results indicated that the QSU was sensitive both to brief periods of abstinence and to exposure to smoking-related cues, but the effect of smoking-related cues on QSU scores was maximal in non-abstinent smokers. In contrast, neither abstinence nor exposure to smoking-related cues significantly influenced the number of reinforcers earned, or the number of responses made, in either PR task. However, there was a significant interaction between gender and degree of abstinence on PR performance under primary reinforcement, and correlations between PR and QSU measures that were dependent on a complex interaction between the presence/absence of smoking-related cues and the type of reinforcer used. These results suggest that the QSU is sensitive to subtle influences on subjective urges to smoke in dependent smokers and, although PR measures are relatively insensitive to these influences, there is some evidence that PR performance is related to subjective measures of the urge to smoke.

The effects of exposure to an alcohol-related cue (drinking low-alcohol beer) and a musical depression/elation mood induction procedure, on craving, motivation and liking for alcohol, were studied in male and female recreational drinkers. Alcohol craving was assessed using the multidimensional desires for alcohol questionnaire (DAQ), motivation for alcohol was assessed by performance on a progressive ratio (PR) task reinforced with small volumes (25 ml) of low-alcohol beer, and liking for the reinforcers earned in the PR task was assessed using a visual analogue scale. Consumption of a half-pint of low-alcohol beer increased alcohol craving in male subjects but had no effect or decreased craving in female subjects. Subsequent induction of a depressed mood increased craving scores, relative to elated or neutral mood groups, but these effects were confined to abstinent (non-cued) subjects, both male and female. Performance on the PR task correlated significantly with one of the four factors of the DAQ, negative reinforcement, and was increased by induction of a depressed mood in abstinent female and cued male subjects. Reinforcer liking was unchanged following mood induction in male subjects, but decreased in both groups of female subjects. To summarize, the cue of drinking low-alcohol beer increased alcohol craving in men but not in women, and induction of a depressed mood increased alcohol craving and motivation, but also decreased alcohol liking. These effects were present to different extents in different cue/gender subgroups, and were partially independent.

Social defeat in dominant male rats has previously been shown to result in a loss of rank, together with decreased consumption of a palatable sucrose solution, suggestive of a decrease in hedonic tone. The present study further investigated the effect of defeat on hedonic capacity using the conditioned place preference paradigm. Stable dominance hierarchies were determined in pairs of male PVG rats by repeated observation of agonistic behaviour at the onset of the dark phase of the dark-light cycle. Dominant animals and singly housed animals were then subjected to defeat by a male of the aggressive Tryon Maze Dull (TMD) strain, either 1 (singly housed animals only) 3 or 7 days prior to the first conditioning session. Each animal was tested for place conditioning with morphine (1 mg/kg i.p.) using one rewarded and one non-rewarded conditioning trial. In this paradigm, dominant animals as well as singly housed animals showed an increase in time spent in the drug-associated side but their submissive partners did not. Three days following the defeat of a dominant animal by a TMD, place conditioning to morphine was absent in the defeated animals, but was now present in their submissive partners. Seven days following defeat, conditioning was absent in defeated animals that were now submissive, but present in defeated animals that had maintained their dominant status. In isolated animals, place conditioning was absent 1 day following defeat, but was present 3 and 7 days post-defeat. These findings suggest that morphine-induced place conditioning is influenced by both the experience of defeat and the effects of defeat on social status.

This study used in-situ hybridization to examine D1 and D2 receptor mRNA expression in the brains of rats subjected to chronic mild stress and/or chronic treatment (5 weeks) with the antidepressant drugs imipramine and fluoxetine. As in previous studies using the chronic mild stress procedure, stress decreased the consumption of a palatable sucrose solution, and both antidepressants reversed this effect. In-situ hybridization to D1 and D2 receptor probes was studied in midbrain and forebrain sections. In the midbrain sections, stress decreased the D2 receptor message in the substantia nigra and in the lateral part of the ventral tegmental area (VTA), but not in the medial part of the VTA. Imipramine, but not fluoxetine, increased the D2 receptor message in the VTA, but only in the non-stressed group. In the basal ganglia, stress decreased the D2 receptor message in the nucleus accumbens (core and shell) and in the lateral, but not the medial, part of the caudate nucleus, in both control and stressed groups. Both imipramine and fluoxetine increased the D2 receptor message in the lateral, but not the medial, part of the caudate nucleus and in the shell, but not the core, of the nucleus accumbens. There were no significant changes in D1 receptor message. The results, which are consistent in some respects, and inconsistent in others, with predictions from earlier work, support the hypothesis that forebrain dopamine systems are involved in mediating the behavioural effects of chronic mild stress and their reversal by antidepressants.

Cigarette cravings were evaluated in a sample of moderately heavy smokers, using the Questionnaire on Smoking Urges (QSU), and a progressive-ratio (PR) operant procedure in which responding on a computer keyboard was reinforced by puffs on a cigarette, under a progressively increasing work requirement. Subjects were also exposed to musical mood-induction procedures: the induction and maintenance of depressed and elated mood states was confirmed by visual analogue scales and a mood questionnaire. Smoking did not alter mood state. However, relative to the elated condition, induction of a depressed mood caused increases in both QSU scores and measures of PR performance. The results provide the first experimental confirmation of a causal relationship between depressed mood and cigarette craving.

Previous studies have reported that DA receptor antagonists suppress most behaviours; however, a paradoxical increase in performance may be seen in tests of operant or consummatory behaviours maintained by very sweet rewards, which lie on the descending limb of the inverted U-shaped concentration-performance function (i.e., under conditions where performance decreases as sweetness increases). Despite the low performance levels associated with very sweet reinforcers, preference studies indicate that they are nonetheless more rewarding. In the present study, the hypothesis that reinforcer efficacy is monotonically related to reinforcer sweetness was tested using a geometric progressive ratio reinforcement schedule, in which increasing numbers of responses were required to earn successive reinforcers (1, 2, 4, 8,.); the amount of work the animal emits in order to obtain an increasingly infrequent reinforcer is assumed to provide a measure of the magnitude of its rewarding effect. Three groups of rats were trained on this schedule, using as reinforcers food pellets containing 1%, 10% and 95% sucrose, respectively. Under conditions of continuous sucrose-pellet reinforcement, the highest response rates were maintained by the 10% sucrose pellets. However, under the progressive ratio schedule, performance was monotonically related to sucrose concentration. The dopamine D2/D3 receptor antagonist raclopride dose-dependently suppressed progressive ratio performance in all three groups.

A runway was used to measure locomotor responses to quinpirole (200µg/kg), in rats. The locomotor stimulant effect of quinpirole increased progressively over successive trials at 3-day intervals. Animals administered quinpirole in the home cage were also sensitized, but to a lesser degree than animals tested in the runway following quinpirole injections. Exposure to an open field, following quinpirole injections, sensitized responsiveness in the runway to an extent comparable to that seen following runway exposure. Animals exposed to a movable running wheel, following quinpirole injections, were more sensitized to the effect of quinpirole in the runway than animals exposed to a locked running wheel. The results suggest that the extent of sensitization to quinpirole is determined by the behaviour elicited by the drug, rather than the environment in which it is administered. An operant conditioning model is proposed to account for these effects.