Voluntary Exercise and Sucrose Consumption Enhance Cannabinoid CB1 Receptor Sensitivity in the Striatum

The endogenous cannabinoid system is involved in the regulation of the central reward pathway. Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction. In this study, we investigated whether running wheel or sucrose consumption altered the sensitivity of striatal synapses to the activation of cannabinoid CB1 receptors. We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations. In contrast, the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors. The sensitization of cannabinoid CB1 receptor-mediated responses was slowly reversible after the discontinuation of running wheel or sucrose consumption, and was also detectable following the mobilization of endocannabinoids by metabotropic glutamate receptor 5 stimulation. Finally, we found that the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress.     

Analgesic effects of mGlu1 and mGlu5 receptor antagonists in the rat formalin test

mGlu1 and mGlu5 receptors have been implicated in pain associated with inflammation. In the present study, the formalin test was used to measure sustained pain with components of tissue injury. The aims of the present study were to assess: (i) the role of mGlu1 and mGlu5 receptors in inflammatory pain using selective antagonist EMQMCM, 1.25-5 mg/kg, as the mGlu1 receptor antagonist, and MPEP or MTEP, 2.5-10 mg/kg, as mGlu5 receptor antagonist; (ii) the possible interaction between mGlu1 and mGlu5 receptor antagonists and morphine; and (iii) whether tolerance develops to the analgesic effects of these antagonists after prolonged treatment. EMQMCM, MTEP and MPEP significantly reduced the manifestation of both phases of formalin response. However, all these mGlu receptor antagonists did not affect the withdrawal latencies in a model of acute pain (Hargreaves test), which has a different underlying mechanism. In the present study, the suppressive effect on formalin-induced pain behaviour was much stronger when mGlu1 and mGlu5 receptor antagonists were co-injected compared to administration of a single antagonist, but this effect was not seen when mGlu receptor antagonist was co-administered with morphine. This is in contrast to the pronounced inhibitory effects after co-treatment with morphine and the uncompetitive NMDA receptor antagonist memantine. The present study also provides the first direct in vivo evidence that prolonged administration of MTEP (5 mg/kg) over 7 days leads to the development of tolerance to its antinociceptive effects. Such tolerance was not observed when EMQMCM (5 mg/kg) was administered in the same manner. In conclusion, these results provide additional arguments for the role of group I mGlu receptors in pain with inflammatory conditions.     

Neurotensin reduces glutamatergic transmission in the dorsolateral striatum via retrograde endocannabinoid signaling

Neurotensin is a peptide that has been suggested to mimic the actions of antipsychotics, but little is known about how it affects synaptic transmission in the striatum, the major input nucleus of the basal ganglia. In this study we measured the effects of neurotensin on EPSCs from medium spiny projection neurons in the sensorimotor striatum, a region implicated in habit formation and control of motor sequences. We found that bath-applied neurotensin reduced glutamate release from presynaptic terminals, and that this effect required retrograde endocannabinoid signaling, as it was prevented by the CB1 cannabinoid receptor antagonist AM251. Neurotensin-mediated inhibition of striatal EPSCs was also blocked by antagonists of D2-like dopamine receptors and group I metabotropic glutamate receptors, as well as by intracellular calcium chelation and phospholipase C inhibition. These results suggest that neurotensin can indirectly engage an endocannabinoid-mediated negative feedback signal to control glutamatergic input to the basal ganglia.     

Somatostatin increases rat locomotor activity by activating sst2 and sst4 receptors in the striatum and via glutamatergic involvement

The involvement of striatal somatostatin receptors (sst₁, sst₂ and sst₄) in locomotor activity was investigated. Male Sprague–Dawley rats, 280–350 g, received in the striatum bilateral infusions of saline, somatostatin, and selective sst₁, sst₂, and sst₄ ligands. Spontaneous locomotor activity was recorded for 60 min. The involvement of excitatory amino acid receptors (AMPA and NMDA) on somatostatin’s actions was also examined. Western blot analysis was employed for the identification of somatostatin receptors in striatal membranes. Somatostatin, sst₂ and sst₄, but not sst₁, selective ligands increased rat locomotor activity in a dose-dependent manner. Blockade of AMPA and NMDA receptors reversed somatostatin’s actions. In conclusion, striatal somatostatin receptor activation differentially influence rat locomotor activity, while glutamatergic actions underlie the behavioral actions of somatostatin.     

Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome

Tic disorders produce substantial morbidity, but their pathophysiology remains poorly understood. Convergent evidence suggests that dysregulation of the cortico-basal ganglia circuitry is central to the pathogenesis of tics. Tourette syndrome (TS), the most severe end of the continuum of tic disorders, is substantially genetic, but causative mutations have been elusive. We recently described a mouse model, the histidine decarboxylase (Hdc) knockout mouse, that recapitulates a rare, highly penetrant mutation found in a single family; these mice exhibit TS-like phenomenology. These animals have a global deficit in brain histamine and a consequent dysregulation of DA in the basal ganglia. Histamine modulation of DA effects is increasingly appreciated, but the mechanisms underlying this modulation remain unclear; the consequences of modest DA elevation in the context of profound HA deficiency are difficult to predict, but understanding them in the Hdc knockout mouse may provide generalizable insights into the pathophysiology of TS. Here we characterized signaling pathways in striatal cells in this model system, at baseline and after amphetamine challenge. In vivo microdialysis confirms elevated DA in Hdc-KO mice. We find dephosphorylation of Akt and its target GSK3β and activation of the MAPK signaling cascade and its target rpS6; these are characteristic of the effects of DA on D2- and D1-expressing striatal neurons, respectively. Strikingly, there is no alteration in mTOR signaling, which can be regulated by DA in both cell types. These cellular effects help elucidate striatal signaling abnormalities in a uniquely validated mouse model of TS and move towards the identification of new potential therapeutic targets for tic disorders.     

Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent

The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.     

Gene expression of opioid and dopamine systems in mouse striatum: effects of CB1 receptors, age and sex

RATIONALE: Endocannabinoid, opioid, and dopamine systems interact to exhibit cannabinoid receptor neuromodulation of opioid peptides and D(4) dopamine receptor gene expression in CB(1)-cannabinoid-deficient mouse striatum. OBJECTIVE: Using CB(1)-transgenic mice, we examine primary age-sex influences and interactions on opioid and dopamine system members' gene expression in striatum. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction was used to analyze gene expression of opioid peptides [preproenkephalin (PPENK); preprodynorphin (PPDYN)], opioid receptors [delta-opioid receptor (delta-OR); mu-opioid receptor (micro-OR)] and dopamine receptor subtypes (D(1) through D(5)) in male/female CB(1)(+/+)/CB(1)(-/-) mice striata at two adult ages [young (60-90 days); old (140-300 days)]. RESULTS: (1) Increased PPENK and PPDYN, owing to genotype [CB(1)(+/+) vs. CB(1)(-/-)], depended on sex. When genotype-independent, they depended on sex (PPENK) or age (PPDYN). (2) delta-OR was age-dependent (higher in old). (3) micro-OR, owing to genotype, was age-dependent [higher in old CB(1)(-/-) males]. When genotype-independent, it depended on sex (higher in females). (4) Female D(1) was genotype-independent and age-dependent, while male D(1) was higher in old over young CB(1)(+/+) mice. (5) D(5), owing to genotype, was sex-dependent [higher in young female CB(1)(-/-) mice]. (6) D(2), genotype-independent, was higher in old over young male mice. (7) Young female D(3) was higher in CB(1)(-/-) over CB(1)(+/+) mice. Male D(3) was age-dependent (higher in old mice). (8) D(4), owing to genotype, was sex-dependent [higher in CB(1)(-/-) over CB(1)(+/+) females]. Genotype-independent D(4) was sex-dependent in young mice (higher in females) and age-dependent in males (higher in old). CONCLUSIONS: Greater striatal expression is genotype-dependent in females (opioid-peptides, D(3), D(4), D(5)) and genotype-independent in both females (PPENK, mu-OR, D(4)) and old males (PPDYN, delta-OR, D(2), D(3), D(4)).     

Intermittent ethanol consumption depresses endocannabinoid-signaling in the dorsolateral striatum of rat

Recent research suggests that adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long-term changes in behavior by altering synaptic function and plasticity. In this study, endocannabinoid (eCB) signaling in the dorsolateral striatum, a brain region vital for habit formation, was evaluated in acutely isolated brain slices from ethanol (EtOH)-consuming rats and control rats. EtOH-consuming rats had free access to a 20% EtOH solution for three 24 hour sessions a week during seven weeks and consumed an average of 3.4 g/kg per session. eCB-mediated long-lasting disinhibition (DLL) of population spike (PS) amplitude induced by moderate frequency stimulation was impaired in EtOH-consuming rats, and was not restored by the muscarinic receptor antagonist scopolamine (10 μM). The lack of DLL could be linked to a reduced GABA_A receptor tone, since bicuculline-mediated disinhibition of striatal output was significantly reduced in slices from EtOH-consuming rats. However, eCB signaling induced by high frequency stimulation (HFS) was also impaired in slices from EtOH-consuming rats and isolated control rats. Activation of presynaptic cannabinoid 1 receptors (CB1R) with WIN55,212-2 (250 nM, 1 μM) significantly modulated PS amplitude in slices from age-matched control rats while slices from EtOH-consuming rats remained unaffected, indicating that eCB signaling is inhibited at a level that is downstream from CB1R activation. Intermittent alcohol intake for seven weeks might thus be sufficient to modulate a presynaptic mechanism that needs to be synergized with CB1R activation for induction of long-term depression (LTD). In conclusion, alcohol consumption inhibits striatal eCB signaling in a way that could be of importance for understanding the neurological underpinnings of addictive behavior.This article is part of a Special Issue entitled ‘Synaptic Plasticity and Addiction’.     

Activation of somatostatin receptors in the globus pallidus increases rat locomotor activity and dopamine release in the striatum

Rationale  Somatostatin and its receptors have been localized in brain nuclei implicated in motor control, such as the striatum, nucleus accumbens, ventral pallidum, and globus pallidus (GP). Objectives  The objective of this study was to investigate the role of somatostatin receptors (sst_1,2,4) in the GP on dopamine (DA)-mediated behaviors, such as locomotor activity, and to examine the GP–striatum circuitry by correlating the effect of somatostatin in the GP with the release of DA in the striatum. Materials and methods  Animals received saline, somatostatin (60, 120, 240 ng/0.5 μl per side) or the following selective ligands: L-797,591 (sst₁ analog, 60, 120, 240 ng/0.5 μl per side), L-779,976 (sst₂ analog, 120, 240, 480 ng/0.5 μl per side), L-803,087 (sst₄ analog; 120, 240, 480 ng/0.5 μl per side), L-796,778 (sst₃ analog, 240 ng/0.5 μl per side), SRA-880 (sst₁ selective antagonist + somatostatin, 120 ng/0.5 μl per side), CYN154806 (sst₂ selective antagonist + somatostatin, 120 ng/0.5 μl per side) bilaterally in the GP of the rat. Locomotor activity was measured for 60 min. The effect of somatostatin, administered intrapallidally, on the extracellular concentrations of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the striatum was also studied in the behaving rat using in vivo microdialysis methodology. Results  Somatostatin increased the locomotor activity of the rat in a dose-dependent manner. This effect was mediated by activation of the sst₁, sst₂, and sst₄ receptors. Selective sst agonists increased locomotor activity in a statistical significant manner, while selective sst₁ and sst₂ antagonists reversed the somatostatin-mediated locomotor activity to control levels. DA levels increased in the striatum after intrapallidal infusion of somatostatin (240 ng/side). Conclusions  These data provide behavioral and neurochemical evidence of the functional role of somatostatin receptors in the GP–striatum circuitry. We announce with great sorrow that our colleague and friend Prof. Christina Spyraki passed away on September 2, 2006.     

Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics

Rational Clinical studies in patients with schizophrenia suggest that atypical neuroleptics are more effective than typical neuroleptics in reducing negative symptoms including apathy and anhedonia. Dysfunction of the dopaminergic reward system may contribute to negative symptoms in schizophrenia.Objective We used functional magnetic resonance imaging to assess the blood oxygen level dependency response in the ventral striatum of medicated schizophrenics and healthy control subjects during reward anticipation.Methods Twenty schizophrenics [ten medicated with typical (e.g., haloperidol) and ten with atypical (e.g., olanzapine and risperidone) neuroleptics] and ten age-matched healthy volunteers participated in an incentive monetary delay task in which visual cues predicted that a rapid response to a subsequent target stimulus would result either in monetary gain or no consequence.Results Healthy volunteers and schizophrenics treated with atypical neuroleptics showed ventral striatal activation in response to reward-indicating cues, but schizophrenics treated with typical neuroleptics did not. In patients treated with typical neuroleptics, decrease in activation of the left ventral striatum was correlated with the severity of negative symptoms.Conclusions Failure to activate the ventral striatum during reward anticipation was previously associated with the severity of negative symptoms in schizophrenia and was also found in schizophrenics treated with typical neuroleptics in this study. Significant blunting of ventral striatal activation was not observed in patients treated with atypical neuroleptics, which may reflect the improved efficacy of these drugs in treating negative symptoms.Georg Juckel and Florian Schlagenhauf contributed equally to this work.     

Local modulation of the 5-HT release in the dorsal striatum of the rat: an in vivo microdialysis study

Using in vivo microdialysis in freely moving rats, we examined the involvement of major striatal transmitters on the local modulation of the 5-HT release. Tetrodotoxin reduced the striatal 5-HT output to 15–20% of baseline. The selective 5-HT_1B receptor agonist CP 93129 (50 μM) reduced (50%) and the 5-HT_2A/2C receptor agonist DOI (1–100 μM) increased (220%) the 5-HT output. Neither GABA nor baclofen (100 nM–100 μM) altered the 5-HT output. The glutamate reuptake inhibitor -trans-PDC (1–4 mM) raised 5-HT to 280% of baseline. This effect was not antagonized by the NMDA receptor antagonist MK-801 (0.5 mg/kg i.p.). Local MK-801 (10–100 μM) did not significantly alter the 5-HT output. Finally, neither carbachol (10–100 μM) nor quipirole (10 μM–1 mM) affected 5-HT. These data suggest that the striatal 5-HT release is influenced by local serotonergic and glutamatergic (but not GABAergic) inputs.     

Behavioral and convulsant effects of the (S) enantiomer of the group I metabotropic glutamate receptor agonist 3,5-DHPG in mice

The purpose of the present studies was to investigate the behavioral and convulsant effects produced by the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Administered i.c.v. to mice, (S)-3,5-DHPG produced a behavioral syndrome consisting of scratching and/or facial grooming, tremors, slow forelimb clonus, rearing, and falling that increased over the dose range of 10-400 nmol. The full syndrome, produced by 400 nmol of (S)-3,5-DHPG, was antagonized by the selective mGlu1 receptor antagonist LY456236 but not by the mGlu5 receptor antagonist MPEP or the mGlu2/3 receptor antagonist LY341495. The behaviors induced by the 400 nmol dose were not blocked by the NMDA receptor antagonist MK-801, but were attenuated by the non-NMDA receptor antagonists GYKI 52466 and NBQX, and the Ca2+ mobilization inhibitor dantrolene, but at motor-impairing doses. The scratching behaviors produced by 30 nmol of (S)-3,5-DHPG were antagonized by LY456236 but not by MPEP, LY341495 or MK-801. GYKI 52466 and dantrolene, but not NBQX, inhibited scratching at motor-impairing doses. Both 400 and 30 nmol of (S)-3,5-DHPG produced a generalized seizure as recorded by surface EEG electrodes. LY456236 blocked the seizures produced by 30 nmol but not by 400 nmol; dantrolene was ineffective in blocking seizures produced by either dose. The present findings suggest that (S)-3,5-DHPG produces an increase in excitation that is mediated by mGlu1 and non-NMDA receptors.     

Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: dependence on cholinergic nicotinic and dopaminergic D1 receptors

We used an intracranial self-administration (ICSA) procedure to assess the involvement of the ventral tegmental area (VTA) nicotinic receptors in the rewarding effects of nicotine. We then challenged intra-VTA nicotine self-administration via systemic or local injections of dopamine (DA)-D1 and nicotinic receptor antagonists. C57BL/6J mice were stereotaxically implanted unilaterally with a guide cannula above the VTA. After 1 week of recovery, mice were allowed to discriminate between two arms of a Y-maze over seven daily sessions, one arm being reinforced by intracranial nicotine microinjection. Mice exhibited nicotine self-administration at both doses tested, i.e. 10 ng (21.6 pmol) and 100 ng (216 pmol)/50-nl injection. In contrast, mice receiving a 216-pmol nicotine dose 0.8 mm above VTA performed at chance level. Once the ICSA response was acquired, systemic pretreatment with the DA-D1 receptor antagonist SCH 23390 (25 μg/kg i.p.) or co-infusion of the nAChR antagonist DHβE with nicotine disrupted ICSA. Replacement of SCH 23390 by vehicle, or withdrawal of DHβE from nicotine/DHβE mixed solutions led to recovery of intra-VTA nicotine self-administration. We conclude that nicotinic receptors in the VTA, presumably 4β2 nAChRs are critically to mediate the rewarding effects of nicotine and that DA-D1 receptors are also directly implicated.     

Intracranial self-administration of MDMA into the ventral striatum of the rat: differential roles of the nucleus accumbens shell, core, and olfactory tubercle

Rationale Behavioral and anatomical data suggest that the ventral striatum, consisting of the nucleus accumbens and olfactory tubercle, is functionally heterogeneous. Cocaine and d-amphetamine appear to be more rewarding when administered into the medial olfactory tubercle or medial accumbens shell than into their lateral counterparts, including the accumbens core. Objectives We sought to determine whether rats self-administer the popular recreational drug (±)-3,4-methylenedioxymethamphetamine (MDMA) into ventrostriatal subregions and whether the medial olfactory tubercle and medial accumbens shell mediate MDMA’s positive reinforcing effects more effectively than their lateral counterparts. Results Rats receiving 30 mM MDMA into the medial olfactory tubercle, medial accumbens shell, or accumbens core, but not the lateral tubercle or lateral shell, showed higher self-administration rates than rats receiving vehicle. The medial shell supported more vigorous self-administration of MDMA at higher concentrations than the core or medial olfactory tubercle. In addition, intra-medial shell MDMA self-administration was disrupted by co-administration of the D1 or D2 receptor antagonists SCH 23390 (1–3 mM) or raclopride (3–10 mM). Conclusions Our data suggest that the ventral striatum is functionally heterogeneous. The medial accumbens shell appears to be more important than other ventrostriatal subregions in mediating the positive reinforcing effects of MDMA via both D1- and D2-type receptors. Together with previous data, our data also suggest that unidentified actions of MDMA interfere with the positive reinforcing effects of dopamine in the medial olfactory tubercle.     

Adenosine A<Subscript>2A</Subscript> receptor antagonism reverses the effects of dopamine receptor antagonism on instrumental output and effort-related choice in the rat: implications for studies of psychomotor slowing

Rationale Organisms frequently make effort-related decisions based upon assessments of motivational value and response costs. Energy-related dysfunctions such as psychomotor slowing and apathy are critically involved in some clinical syndromes. Dopamine (DA), particularly in the nucleus accumbens, regulates effort-related processes. Dopamine antagonism and accumbens dopamine depletions cause rats performing on choice tasks to reallocate their behavior away from food-reinforced tasks that have high response requirements. Objective There is evidence of a functional interaction between DA and adenosine A_2A receptors in the neostriatum and nucleus accumbens. The present experiments were conducted to determine if adenosine A_2A receptor antagonism could reverse the effects of dopamine receptor antagonism on instrumental behavior and effort-related choice. Materials and methods The adenosine A_2A receptor antagonist MSX-3 was investigated for its ability to reverse the effects of the dopamine receptor antagonist haloperidol (0.1 mg/kg) on fixed ratio 5 instrumental lever-pressing and on response allocation using a concurrent lever-pressing/chow-feeding choice task. Results Haloperidol significantly suppressed fixed ratio 5 responding, and with rats responding on the concurrent choice task, it altered choice behavior, significantly reducing lever-pressing for food and increasing chow intake. Injections of MSX-3 (0.5–2.0 mg/kg) produced a dose-related attenuation of the effects of 0.1 mg/kg haloperidol on both tasks. The high dose of MSX-3, when administered in the absence of haloperidol, did not significantly affect responding on either task. Conclusions Adenosine and dopamine systems interact to regulate instrumental behavior and effort-related processes, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia.     

Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats

The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB₁ cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03–3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3–1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3–1 mg/kg), suggesting that it was accounted for by the stimulation of CB₁ receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA. Received: 14 March 1997 / Final version: 28 July 1997     

Role of 5-HT(1) receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn

BACKGROUND AND PURPOSE

5-HT receptor agonists have variable nociceptive effects within the spinal cord. While there is some evidence for 5-HT_1A spinally-mediated analgesia, the role of other 5-HT₁ receptor subtypes remains unclear. In the present study, we examined the spinal actions of a range of 5-HT₁ agonists, including sumatriptan, on acute pain, plus their effect on afferent-evoked synaptic transmission onto superficial dorsal horn neurons.

EXPERIMENTAL APPROACH

For in vivo experiments, 5-HT agonists were injected via chronically implanted spinal catheters to examine their effects in acute mechanical and thermal pain assays using a paw pressure analgesymeter and a Hargreave''s device. For in vitro experiments, whole-cell patch-clamp recordings of primary afferent-evoked glutamatergic EPSC were made from lamina II neurons in rat lumbar spinal slices.

KEY RESULTS

Intrathecal (i.t.) delivery of the 5-HT_1A agonist R ± 8-OH-DPAT (30–300 nmol) produced a dose-dependent thermal, but not mechanical, analgesia. Sumatriptan and the 5-HT_1B, 5-HT_1D, 5-HT_1F agonists CP93129, PNU109291 and {"type":"entrez-nucleotide","attrs":{"text":"LY344864","term_id":"1257802930","term_text":"LY344864"}}LY344864 (100 nmol) had no effect on either acute pain assay. R ± 8-OH-DPAT (1 µM) and sumatriptan (3 µM) both reduced the amplitude of the evoked EPSC. In contrast, CP93129, PNU109291 and {"type":"entrez-nucleotide","attrs":{"text":"LY344864","term_id":"1257802930","term_text":"LY344864"}}LY344864 (0.3–3 µM) had no effect on the evoked EPSC. The actions of both R ± 8-OH-DPAT and sumatriptan were abolished by the 5-HT_1A antagonist WAY100635 (3 µM).

CONCLUSIONS AND IMPLICATIONS

These findings indicate that the 5-HT_1A receptor subtype predominantly mediates the acute antinociceptive and cellular actions of 5-HT₁ ligands within the rat superficial dorsal horn.     

Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease

Current drugs used in the treatment of Parkinson''s disease (PD), for example, L-DOPA and dopamine agonists, are very effective at reversing the motor symptoms of the disease. However, they do little to combat the underlying degeneration of dopaminergic neurones in the substantia nigra pars compacta (SNc) and their long-term use is associated with the appearance of adverse effects such as L-DOPA-induced dyskinesia. Much emphasis has therefore been placed on finding alternative non-dopaminergic drugs that may circumvent some or all of these problems. Group III metabotropic glutamate (mGlu) receptors were first identified in the basal ganglia a decade ago. One or more of these receptors (mGlu4, mGlu7 or mGlu8) is found on pre-synaptic terminals of basal ganglia pathways whose overactivity is implicated not only in the generation of motor symptoms in PD, but also in driving the progressive SNc degeneration. The finding that drugs which activate group III mGlu receptors can inhibit transmission across these overactive synapses has lead to the proposal that group III mGlu receptors are promising targets for drug discovery in PD. This paper provides a comprehensive review of the role and target potential of group III mGlu receptors in the basal ganglia. Overwhelming evidence obtained from in vitro studies and animal models of PD supports group III mGlu receptors as potentially important drug targets for providing both symptom relief and neuroprotection in PD.