Role of the dorsal diencephalic conduction system in the brain reward circuitry.

Previous work with psychophysically based studies suggests that electrolytic lesion of the habenula, which lies in the dorsal diencephalic conduction system (DDC), degrades the intracranial self-stimulation (ICSS). This experiment was aimed at studying the importance of the DDC in brain stimulation reward, and its connections with other areas that support operant responding for brain stimulation. For this purpose, rats were implanted with stimulating electrodes at the dorsal raphe (DR) and lateral hypothalamus (LH), and lesioning electrodes in the medial forebrain bundle (MFB) and the DDC. Rats were trained to self-administer the stimulation at three different current intensities and were tested daily for changes in reward thresholds, defined as the pulse frequency required for half-maximal responding. The lesions were done at the DDC and the MFB, and were separated by two weeks interval during which the rats were tested for self-stimulation. At the end of the experiment, rats were transcardially perfused and their brains collected to determine the extent of the lesions and the locations of the stimulation sites. Results show that lesions at both the DDC and MFB produce larger and longer-lasting increases in the reward thresholds (upto 0.40 log10 units) than lesions at either pathway alone (upto 0.25 log10 units), and were more effective in attenuating the reward induced by the LH stimulation. These results suggest that there exist two parallel pathways, the MFB and the DDC, which could constitute a viable route for the reward signal triggered by ICSS.

Differential contribution of mesoaccumbens and mesohabenular dopamine to intracranial self-stimulation.

The contribution of mesoaccumbens dopamine transmission to intracranial self-stimulation is well-established. However, although the nucleus accumbens comprises two main subregions, the shell and the core, little is known of the contribution of each to this behaviour. Our first aim was to study the effects of d-amphetamine infusions into the shell and core in order to understand their relative importance to reward and operant responding. Our second aim was to examine the contribution of a lesser studied group of dopamine neurons, those within the mesohabenular pathway, to intracranial self-stimulation. Male Sprague-Dawley rats were implanted with bilateral cannulae in the nucleus accumbens shell, core or in the lateral habenula and a monopolar stimulation electrode in the posterior mesencephalon, a brain site that is sensitive to changes in dopamine transmission. Using curve-shift scaling, we measured the reward- and performance-enhancing effects of intra-accumbens (1-20 µg) and intra-habenular (10-40 µg) infusions of d-amphetamine or vehicle. Within the nucleus accumbens, the use of multiple doses and long test sessions allowed us to observe an interaction between drug effect and infusion site. We show, for the first time, differences in the minimal doses necessary to enhance rewarding effectiveness and operant responding, in the magnitude of these enhancements as well as in their duration. Conversely, regardless of dose, intra-habenular D-amphetamine did not alter rewarding effectiveness or operant rate, highlighting the differential contribution of mesoaccumbens and mesohabenular dopamine pathways to intracranial self-stimulation.

Individual phenotype predicts nicotine-haloperidol interaction in catalepsy: possible implication for the therapeutic efficacy of nicotine in Tourette's syndrome.

In individuals with Tourette's syndrome, the therapeutic efficacy of haloperidol can be augmented by nicotine. In laboratory rats, the dopamine antagonist haloperidol produces catalepsy and nicotine can potentiate it, although this effect is variable and not always observed. Our aim was to understand this variability. In rats, the locomotor response to a novel environment predicts the magnitude of the locomotor response to nicotine. Since the psychostimulant effect of nicotine might counter catalepsy, we hypothesized that rats with a high locomotor response to novelty would show reduced vulnerability to nicotine potentiation of haloperidol catalepsy. First, we administered haloperidol (0, 0.1 or 0.3mg/kg, ip) and found stronger catalepsy in rats with low reactivity to novelty. Second, we administered haloperidol (0.3mg/kg) or haloperidol plus nicotine (0.1mg/kg, ip) and found that nicotine indeed potentiated haloperidol catalepsy but only in rats with low reactivity to novelty. Nicotine did not induce catalepsy on its own. Thus, previously reported inconsistencies in the catalepsy potentiating effect of nicotine may have been due to differential vulnerability to its stimulant actions. As previously observed, the potentiation of haloperidol catalepsy was greatest 4h after injection. Given the short half-life of nicotine, the mechanism(s) underlying the delayed expression of its pro-cataleptic capacity remains obscure.

Lesions of the lateral habenula dissociate the reward-enhancing and locomotor-stimulant effects of amphetamine.

Midbrain dopamine neurons play a key role in goal-directed behaviour as well as in some psychiatric disorders. Recent studies have provided electrophysiological, anatomical and biochemical evidence that the lateral habenula (LHb) exerts strong inhibitory control over midbrain dopamine neurons. However, the behavioural relevance of this inhibitory input is poorly understood. Our aim was to examine the contribution of the LHb to dopamine-sensitive behaviour. Here, we characterized the locomotor-stimulant and reward-enhancing properties of amphetamine in rats with and without neurotoxic lesions of the LHb. Amphetamine-induced forward locomotion and reward were respectively measured in automated activity cages and with intracranial self-stimulation. Adult, male Sprague-Dawley rats were bilaterally infused with ibotenic acid in the LHb and allowed 7-10 days post-operative recovery. The locomotor-stimulant and reward-enhancing properties of amphetamine (0, 0.5 and 1.0 mg/kg, ip) were then tested in different groups of lesioned and sham-lesioned rats. Neurotoxic lesions of the LHb caused a significant enhancement of the locomotor-stimulant effect of amphetamine, an effect not seen following lesions of the medial habenula. Conversely, the reward-enhancing properties of amphetamine did not differ between lesioned and sham-lesioned rats responding for rewarding electrical stimulation of the posterior mesencephalon or the medial forebrain bundle. The dissociation between the locomotor-stimulant and reward-enhancing effects of amphetamine following LHb lesions suggests the contribution of two distinct substrates that are functionally dissociable and differentially sensitive to LHb modulation.

Trafficking of neurokinin-1 receptors in serotonin neurons is controlled by substance P within the rat dorsal raphe nucleus.

Substance P (SP) modulates serotonin neurotransmission via neurokinin-1 receptors (NK1rs), and exerts regulatory effects on mood through habenular afferents to the dorsal raphe nucleus (DRN). We have previously demonstrated that, in the caudal DRN of rat, some serotonin neurons are endowed with NK1rs that are mostly cytoplasmic, whereas these receptors are mostly membrane bound in non-serotonin neurons. Here, we first examined by double-labeling immunocytochemistry the relationships between SP axon terminals and these two categories of DRN neurons. Almost half of the SP terminals were synaptic and many were in close contact with serotonin dendrites, but never with non-serotonin dendrites. In additional double-immunolabeling experiments, most if not all dendrites bearing membranous NK1rs appeared to be GABAergic. Treatment with the selective neurokinin-1 antagonist RP67580 modified the subcellular distribution of NK1rs in serotonin neurons. At 1 h after administration of a single dose, the receptor distribution was unchanged in both dendritic types but, after daily administration for 7 or 21 days, the plasma membrane and cytoplasmic density of NK1rs were increased in serotonin dendrites, without any change in non-serotonin dendrites. These treatments also increased NK1r gene expression in the caudal DRN. Lastly, a marked increase in the membrane (but not cytoplasmic) density of NK1rs was measured in serotonin dendrites after bilateral habenular lesion. These results suggest that the trafficking of NK1rs represents a cellular mechanism in control of the modulation of serotonin neuron activity by SP in DRN.

Simultaneous anhedonia and exaggerated locomotor activation in an animal model of depression.

RATIONALE: Anhedonia, or hyposensitivity to normally pleasurable stimuli, is a cardinal symptom of depression. As such, reward circuitry may comprise a substrate with relevance to this symptom of depression. OBJECTIVES: Our aim was to characterize in the rat changes in the rewarding properties of a pharmacological and a natural stimulus following olfactory bulbectomy (OBX), a pre-clinical animal model of depression. METHODS: We measured amphetamine enhancement of brain stimulation reward, changes in sucrose intake, as well as striatal cAMP response element binding protein (CREB) activity, a molecular index previously associated with depressant-like behavior. Moreover, since alteration of psychomotor activity is also a common symptom of depression, and psychostimulant reward and locomotion are thought to share common neurobiology, we used the same treatment schedule of amphetamine to probe for changes in locomotion. RESULTS: Our findings show that OBX produces a behavioral phenotype characterized by both anhedonia and exaggerated locomotor activation. Thus, we observed a blunted response to the rewarding properties of amphetamine (1 mg/kg, 21 days post-lesion), a long-lasting reduction in sucrose intake and increased striatal CREB activity. In addition, the same dose of amphetamine, at a coincident time post-lesion, triggered an exaggerated response to its locomotor-stimulant actions. CONCLUSIONS: These paradoxical findings are not consistent with the notion that reward and locomotion are mediated by a common substrate; this dissociation may be useful in modeling psychiatric disorders such as mixed depressive states. In addition, our findings suggest that central reward circuitry may constitute a possible target for rationally designed therapeutics for depression.

Electrolytic lesions of the habenula attenuate brain stimulation reward.

The present experiment used electrolytic lesions in combination with curve-shift scaling to study the functional relation between the habenula and four different brain sites that support operant responding for brain stimulation reward. Rats were implanted with a monopolar stimulation electrode aimed at the lateral hypothalamus, ventral tegmental area, dorsal raphe or median raphe nuclei, and a lesioning electrode in the ipsilateral habenula. Operant nose poking resulted in self-administration of trains of electrical pulses to one of the above stimulation sites. Reward thresholds were derived from response-number curves and defined as the pulse number necessary for half-maximal responding. Rats were tested daily at each of three current intensities that were chosen from individual number-current trade-off functions and that yielded baseline reward thresholds of approximately 10, 20 and 40 pulses/train. Testing resumed 24h after lesioning the habenula (100 muA anodal current, 20-25s) and continued for 3-4 weeks. A total of 19 rats completed the experiment. In five of these, habenular lesions clearly reduced the rewarding effectiveness of the stimulation; reward thresholds increased by approximately 30-245% (0.12-0.54 log10 units). Generally, lesion effects were observed at low and medium current intensities, developed gradually and did not recover. Histological analysis revealed that in two rats the stimulation electrode was located in the posterior lateral hypothalamus, two in the anterior ventral tegmental area and one in the area of the dorsal raphe. These results strongly suggest that the habenula constitutes an important component of the neural circuitry important for brain stimulation reward.

Intracranial self-stimulation of the dorsal raphe sensitizes psychostimulant locomotion.

The authors hypothesized that repeated rewarding electrical stimulation of the dorsal raphe can produce behavioral sensitization to psychostimulants. Groups of male rats were implanted with a stimulation electrode and preexposed to brain stimulation at parameters set to equate rewarding effectiveness across rats. Control groups were implanted with an electrode but never stimulated, or not implanted at all. Twenty-four hours after the 12th self-stimulation session, all groups were challenged with amphetamine (0.5 mg/kg, ip), nicotine (0.2 mg/kg, sc), or saline, and locomotor activity was measured for 1 hr. Locomotor responses to amphetamine and to nicotine were significantly greater in rats preexposed to brain stimulation. These findings suggest at least partial overlap of underlying substrates. ((c) 2007 APA, all rights reserved).

Mesencephalic substrate of reward: lesion effects.

Psychophysical studies suggest that reward-relevant neurons in the posterior mesencephalon (PM) form a caudal extension of the axonal pathway that mediates the rewarding effectiveness of electrical stimulation of the medial forebrain bundle. The present study sought to further characterize the reward-relevant functional link between these two regions by assessing changes to the rewarding effectiveness of caudal medial forebrain bundle stimulation (ventral tegmental area, VTA) subsequent to electrolytic lesions of different PM sites. A total of 13 rats were tested, 11 of these at bilateral VTA stimulation sites. Overall, rewarding effectiveness was reduced in five rats and pontentiated in four. The presence and magnitude of the effects were site-, current- and time-dependent, and ranged from 0.1 to 0.4 log(10) unit shifts in reward magnitude, with most effects falling below 0.3 log(10) units. Generally, these effects became apparent approximately two weeks after the lesion. In addition to these effects, PM lesions placed on or close to the midline also produced small transient reductions in rewarding effectiveness immediately after the lesion, an effect that disappeared within three days. Conversely, lateral PM lesions were associated either with no immediate effects or with small transient potentiations of reward. The finding that lesions of the PM placed on the midline, just off the midline or laterally all altered the rewarding effectiveness of VTA stimulation suggests that the reward-relevant circuitry is distributed diffusely throughout the PM.

Mesencephalic substrate of reward: possible role for lateral pontine tegmental cells.

The present study was aimed at determining whether cells located in the lateral pontine tegmentum could constitute part of the neural circuitry that mediates the rewarding effect of mesencephalic electrical brain stimulation. Single action potentials were recorded from lateral pontine tegmental cells in urethane-anesthetized rats following antidromic activation from the ventral tegmental area and/or posterior mesencephalon. A total of 445 cells were recorded in 13 animals and of these, 44 were antidromically driven from the ventral tegmental area (n=13 ipsi-, n=5 contralateral), the posterior mesencephalon (n=8 ipsi-, n=5 midline), or from both sites (n=13). The occurrence of collision between ortho- and antidromic action potentials triggered by concurrent stimulation of both sites is consistent with psychophysical data obtained previously in behaving animals, and likewise suggests that the two sites are linked by uninterrupted axons. In five of the cells that were driven from both sites, the inter-electrode conduction time exceeded the difference in latencies, suggesting that stimulation of the ventral tegmental area and posterior mesencephalon triggered action potentials in different axonal branches of the same cell. Estimates of the end of the absolute refractory period ranged from 0.44 to 1.6 ms (ventral tegmental area) and from 0.3 to 2.0 ms (posterior mesencephalon), times that overlap with behaviorally derived estimates for mesencephalic reward-relevant neurons. These results suggest that cells originating in the lateral pontine tegmentum might constitute part of the directly-stimulated substrate responsible for the rewarding effect of mesencephalic electrical brain stimulation.

Evidence for sequence-dependent and reversible nonspecific effects of PS-capped antisense treatment after intracerebral administration.

Phosphorothioate (PS)-capped phosphodiester (PE) oligodeoxynucleotides (ODNs) were used to determine whether the dopamine-dependent locomotor-stimulant effect of nicotine is mediated via a4 subunit-containing nicotinic receptors. To this end, rats received direct intraventral tegmental area infusion of a4 antisense via osmotic minipump, and their locomotor response to nicotine (0.2 mg/kg, s.c.) was tested. Eight antisense ODNs were screened, but only one inhibited nicotine-induced locomotion. This inhibition was reversible and selective, insofar as basal (saline) activity was unaffected, and a mismatch ODN was without effect. However, antisense treatment also caused sequence-dependent toxic effects, including neuronal degeneration in the ventral tegmental area, dopaminergic denervation, and weight loss. We conclude that despite previous reports, PS-capped PE-ODNs can cause severe neurotoxicity on chronic infusion into brain tissue. Moreover, sequence dependence and temporal reversibility, two generally accepted criteria of antisense action, may sometimes reflect the occurrence of toxic effects and resultant functional compensation.