Dopaminergic Autoreceptors Research Articles

Bell-shaped dose-response curve of antipsychotic drugs and dopaminergic auto-receptors: a hypothesis

Bell-shaped dose-response curve of antipsychotic drugs and dopaminergic auto-receptors: a hypothesis

Normative data of dopaminergic neurotransmission functions in substantia nigra measured with MRI and PET: Neuromelanin, dopamine synthesis, dopamine transporters, and dopamine D2 receptors

The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D2 receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[β-11C]DOPA, [18F]FE-PE2I and [11C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D2 receptor binding measured by PET in the substantia nigra. Although neuromelanin is synthesized from DOPA and dopamine in dopaminergic neurons, neuromelanin accumulation did not correlate with dopamine synthesis capacity in young healthy subjects. The role of dopamine transporters in the substantia nigra is considered to be the transport of dopamine into neurons, and therefore dopamine transporter binding might be related to neuromelanin accumulation; however, no significant correlation was observed between them. A positive correlation between dopamine D2 receptor binding and neuromelanin accumulation was observed, indicating a feedback mechanism by dopaminergic autoreceptors. Discrepancies in regional distribution between neuromelanin accumulation and dopamine synthesis capacity, dopamine transporter binding or dopamine D2 receptor binding were observed in the substantia nigra.

Regulatory Roles of Heterogeneous Nuclear Ribonucleoprotein M and Nova-1 Protein in Alternative Splicing of Dopamine D2 Receptor Pre-mRNA

The dopamine D2 receptor (D2R) plays a crucial role in the regulation of diverse key physiological functions, including motor control, reward, learning, and memory. This receptor is present in vivo in two isoforms, D2L and D2S, generated from the same gene by alternative pre-mRNA splicing. Each isoform has a specific role in vivo, underlining the importance of a strict control of its synthesis, yet the molecular mechanism modulating alternative D2R pre-mRNA splicing has not been completely elucidated. Here, we identify heterogeneous nuclear ribonucleoprotein M (hnRNP M) as a key molecule controlling D2R splicing. We show that binding of hnRNP M to exon 6 inhibited the inclusion of this exon in the mRNA. Importantly, the splicing factor Nova-1 counteracted hnRNP M effects on D2R pre-mRNA splicing. Indeed, mutations of the putative Nova-1-binding site on exon 6 disrupted Nova-1 RNA assembly and diminished the inhibitory effect of Nova-1 on hnRNP M-dependent exon 6 exclusion. These results identify Nova-1 and hnRNP M as D2R pre-mRNA-binding proteins and show their antagonistic role in the alternative splicing of D2R pre-mRNA.

Effects of (−)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

Benzodiazépines et schizophrénie, revue de la littérature

Benzodiazépines et schizophrénie, revue de la littérature

Effects of Prenatal Ethanol Exposure on the Excitability of Ventral Tegmental Area Dopamine Neurons in Vitro

Prenatal ethanol exposure leads to a persistent reduction in the number of spontaneously active dopaminergic (DA) neurons (DA neuron population activity) in the ventral tegmental area (VTA) in developing and adult animals. This effect might contribute to the dysfunction of the mesolimbic/cortical DA system and attention problems in children with fetal alcohol spectrum disorders. To characterize the underlying cellular mechanism for prenatal ethanol exposure-induced reduction in VTA DA neuron population activity, we used the whole-cell patch-clamp technique to study the membrane properties of putative VTA DA neurons in brain slices in 2- to 3-week-old control and prenatal ethanol-exposed animals. The results show that prenatal ethanol exposure did not impair the spontaneous pacemaker activity in putative VTA DA neurons but reduced the frequency of evoked action potentials. In addition, prenatal ethanol exposure led to a reduction in hyperpolarization-induced cation current (I(h)) and an up-regulation of somatodendritic DA autoreceptors. The above prenatal ethanol exposure-induced changes could decrease the excitability of VTA DA neurons. However, they do not seem to play a role in reduced VTA DA neuron population activity in vivo, an effect thought to be mediated by excessive excitation leading to depolarization inactivation. Taken together, the above results indicate that prenatal ethanol exposure-induced reduction in VTA DA neuron population activity in vivo is not caused by changes in the intrinsic pacemaker activity or other membrane properties and could instead be caused by altered inputs to VTA DA neurons.

Perinatal exposure to Δ 9-tetrahydrocannabinol increases presynaptic dopamine D 2 receptor sensitivity: a behavioral study in rats

The endogenous cannabinoid system is a relevant modulator of dopaminergic synapses in dorsal striatum. Perinatal exposure to cannabinoid receptor agonists has been described to affect the development of dopaminergic circuits in rat brain. The epigenetic alterations described affected both dopamine neurons and dopamine receptor-expressing neurons. The present work has been designed to explore the effects of maternal exposure to orally delivered Δ 9-tetrahydrocannabinol, (Δ 9-THC 0.1, 0.5, 2 mg/kg) on the behavioural responses to the dopamine receptor agonists apomorphine (0.1 mg/kg) and quinpirole (0.5 mg/kg), at doses that target presynaptic dopamine D2 receptors. Maternal exposure to Δ 9-THC affected both the developmental pattern of motor behaviours, and the behavioural responses to acute injections of apomorphine and quinpirole, tested in an open field. The effects were sex dimorphic, being more intense in male animals. Perinatal exposure to Δ 9-THC resulted in enhanced presynaptic dopamine D2 receptor mediated responses such as immobility and inhibition of locomotion. Additionally, postsynaptic dopamine D2 receptor agonist-induced stereotypes were reduced in the group exposed to the highest dose of Δ 9-THC (2 mg/kg). However, the late-onset pattern of behavioural activation observed after acute quinpirole exposure was equal in vehicle- and cannabinoid-treated animals. These effects suggest that perinatal exposure to Δ 9-THC affects the functionality of dopaminergic autoreceptors, inducing a greater sensitivity to the presynaptic actions of dopamine D 2 receptor agonists.

Apomorphine delays simple reaction time in Parkinsonian patients

Background. Parkinsonian patients have difficulty in the preparation and execution of movements, which translate into delayed performance of simple reaction time (SRT) paradigms. Objective. To examine short-term effects of an acute subcutaneous injection of the dopamine agonist apomorphine on the results of a SRT task. Methods. We studied a SRT paradigm in 26 non-fluctuating idiopathic Parkinsonian patients, before and 30, 60, 90 min after administration of apomorphine. Results. The reaction time (RT) was significantly delayed after apomorphine injection. We found no significant change in movement time (MT). Conclusion. Delay of RT and the lack of response of MT to apomorphine administration may result from the sedative effects of apomorphine, overstimulation of postsynaptic dopaminergic receptors with subsequent inhibition of prefrontal cholinergic neurotransmission, and at least partial binding of apomorphine to presynaptic dopaminergic autoreceptors, which cause inhibition of locomotor activity. We suggest that future studies testing the capacity for reaction in Parkinsonian patients should consider the exact timing of the delivery of dopamine substituting drugs prior to the test.

Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors.

An increase of extracellular dopamine (DA) concentration is a major neurobiological substrate of the addictive properties of drugs of abuse. In this article we investigated the contribution of the DA D2 receptor (D2R) in the control of this response. Extracellular DA levels were measured in the striatum of mice lacking D2R expression (D2R-/-) by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine. Interestingly, the increase in extracellular DA induced by both drugs was strikingly higher in D2R-/- than in wild-type littermates. This indicates that D2Rs play a key role in the modulation of DA release in response to drugs of abuse. Furthermore, this observation prompted us to investigate the dopaminergic autoreceptor function in the absence of D2 receptor in D2R-/- mice. Results obtained using complementary microdialysis and voltammetry analyses show that the autoreceptor function regulating DA release is totally abolished in the absence of D2R, despite unchanged DA uptake and basal DA efflux. Finally, we propose that the short isoform D2S receptor of the D2 receptors is the one controlling change in DA release induced by drugs of abuse. Indeed, the neurochemical effects of cocaine and morphine are unchanged in animals with a selective deletion of the long isoform D2L receptor. Thus, deregulated expression of D2R isoforms might be involved in the vulnerability of an individual to drug abuse.

Changes in Extracellular Dopamine Induced by Morphine and Cocaine: Crucial Control by D2 Receptors

An increase of extracellular dopamine (DA) concentration is a major neurobiological substrate of the addictive properties of drugs of abuse. In this article we investigated the contribution of the DA D2 receptor (D2R) in the control of this response. Extracellular DA levels were measured in the striatum of mice lacking D2R expression (D2R-/-) by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine. Interestingly, the increase in extracellular DA induced by both drugs was strikingly higher in D2R-/- than in wild-type littermates. This indicates that D2Rs play a key role in the modulation of DA release in response to drugs of abuse. Furthermore, this observation prompted us to investigate the dopaminergic autoreceptor function in the absence of D2 receptor in D2R-/- mice. Results obtained using complementary microdialysis and voltammetry analyses show that the autoreceptor function regulating DA release is totally abolished in the absence of D2R, despite unchanged DA uptake and basal DA efflux. Finally, we propose that the short isoform D2S receptor of the D2 receptors is the one controlling change in DA release induced by drugs of abuse. Indeed, the neurochemical effects of cocaine and morphine are unchanged in animals with a selective deletion of the long isoform D2L receptor. Thus, deregulated expression of D2R isoforms might be involved in the vulnerability of an individual to drug abuse.

Drugs used in the treatment of attention-deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action

Background: Current theories propose that low doses of catecholaminergic stimulants reduce symptoms in patients with attention-deficit/hyperactivity disorder by acting on autoreceptors to reduce catecholaminergic transmission; few data are available that directly address this hypothesis. Methods: We investigated the autoreceptor and postsynaptic receptor actions of systemically administered stimulants on dopaminergic systems in rats with single-unit recording in the substantia nigra pars compacta and globus pallidus, respectively. Results: Dose-response curves for rate indicated that the potencies of the indirect-acting agonists methylphenidate and d-amphetamine at dopaminergic autoreceptors were not greater than at postsynaptic receptors; in fact, d-amphetamine was more potent postsynaptically. In addition to effects on firing rate, spectral/wavelet analyses indicated that these drugs had prominent effects on postsynaptic multisecond oscillations. These oscillations were shifted by stimulants from baseline periods of ∼30 sec to periods of 5–10 sec. Effects on pattern were found at doses as low as 1.0 mg/kg (methylphenidate) and 0.2 mg/kg ( d-amphetamine). At this latter dose, d-amphetamine had little effect presynaptically. Conclusions: These and prior results demonstrate that there is no autoreceptor-preferring dose range of catecholaminergic stimulants; these drugs at low doses are unlikely to reduce motor activity by this mechanism. Nonetheless, they might affect attentive and cognitive processes by modulating multisecond temporal patterns of central activity.

The nucleus accumbens motor-limbic interface of the spontaneously hypertensive rat as studied in vitro by the superfusion slice technique

The behavioral disturbances of attention-deficit hyperactivity disorder (ADHD) have been attributed to dysfunction of the mesolimbic dopaminergic (DA) projection from the ventral tegmental area of the midbrain. DA released from terminals in the nucleus accumbens (interface between limbic and motor areas of the brain) draws attention to unexpected, behaviorally significant events and provides the motivational drive for reward-related behavior. An in vitro superfusion technique was used to show that depolarization (25 mM K +)-induced release of DA from nucleus accumbens slices of spontaneously hypertensive rats (SHR, animal model for ADHD) was significantly lower than that of Wistar-Kyoto controls (WKY). Evidence also suggested that DA autoreceptor efficacy was increased at low endogenous agoinst concentrations. D2 receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in the electrically stimulated release of DA from nucleus accumbens slices of SHR compared to WKY. This suggested that presynaptic regulation of DA release had been altered in SHR to cause down-regulation of the DA system. This could have occurred at an early stage of development in an attempt to compensate for abnormally high DA concentrations. The reduction in DA transmission could have left the adult SHR with impaired DA reward/reinforcement mechanisms, resulting in the behavioral disturbances characteristic of ADHD.

Loss of visual acuity under dopamine substitution therapy

Visual dysfunction is a well-known feature of Parkinson’s disease. Dopamine has been shown to be a functional modulator at many levels of the visual system. We report on a parkinsonian patient, suffering concurrently from various ophthalmological conditions including glaucoma and cataracts and displaying objectively measurable loss of visual acuity and blurring of vision while under medication with an MAO-B inhibitor and multiple ergolene-derived dopamine agonists. Various studies have investigated the effects of different D1- and D2-agonists and -antagonists on visual function and found that the presynaptic dopaminergic autoreceptor involved in the modulation of dopamine release in the retina displays characteristics of D2-receptors. We conclude that the observed phenomenon represents either an inhibition of dopamine release due to excessive stimulation of presynaptic D2-autoreceptors, leading to an insufficient stimulation of postsynaptic dopaminergic receptors and thus impeding retinal signal conduction, or a heretofore unclear interaction between the patient’s ophthalmological pathologies and dopaminergic therapy, possibly due to excessive stimulation of postsynaptic dopamine receptors, leading to faulty retinal information processing.

Absence of the dopamine D2 receptor leads to a decreased expression of GDNF and NT-4 mRNAs in restricted brain areas.

Neurotrophic factors (NTFs) control the metabolic and electrophysiological properties of dopaminergic neurons in the brain. At the level of the substantia nigra, NTFs have been proposed to control dopamine release by regulating the firing rate of dopaminergic cells. This function is normally controlled by presynaptic dopaminergic autoreceptors. Dopamine has also been proposed to regulate the expression of NTFs and their receptors in the nigrostriatal pathway. Thus, an interaction between the signalling cascades activated by NTFs and dopamine receptors might possibly influence the physiology of dopaminergic neurons. Among dopamine receptors, D2 receptors (D2R) are the most abundant on dopaminergic neurons, where they exert autoreceptor functions. To test for an interaction between the NTF and dopaminergic pathways we have analysed the expression of NTFs and their receptors in D2R-deficient (D2R -/-) mice. Our study shows that the mRNA levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 and their corresponding receptors are not modified in the dopaminergic system of D2R -/- adult mice compared with wild-type littermates. However, a marked reduction of glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4 (NT-4) mRNAs is observed in the striatum and parietal cortex of D2R -/- mice, respectively. These results implicate dopamine, acting through D2 receptors, in the local control of specific NTF expression. The down-regulation of GDNF and NT-4 expression might also contribute to the locomotor phenotype of D2R -/- mice.

2-[123I]-iodolisuride SPET visualizes dopaminergic loss in de-novo parkinsonian patients: is it a marker of striatal pre-synaptic degeneration?

The aim of this study was to assess the correlation between the functional integrity and density of striatal dopaminergic receptors and clinical data in 15 de-novo patients with idiopathic Parkinson's disease by single photon emission tomography (SPET) using 2-[123I]-iodolisuride (ILIS), a tracer based on the D2-dopamine receptor agonist lisuride. Deficient striatal uptake of ILIS correlated with the severity of the disorder, scored by the Unified Parkinson's Disease Rating Scale (UPDRS) (n = 15; ratio of ILIS uptake: basal ganglia/cerebellum [B/C] & UPDRS I-III, Spearman R = -0.562, P = 0.013), Beck's Depression Inventory (BDI) (n = 12; B/C & BDI, Spearman R = -0.825, P = 0.0009) and the ZUNG Depression Scale (ZDS) (n = 11; B/C & ZDS, Spearman R = -0.7425, P = 0.008). Experimental data indicate that lisuride shows a higher affinity for pre-synaptic dopaminergic autoreceptors than for post-synaptic D2-dopamine receptors under conditions of low applied ILIS concentrations as in this study. From the results of this study and these experimental data, we speculate that ILIS-SPET can visualize pre-synaptic striatal dopaminergic degeneration in Parkinson's disease.

Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine

Cataplexy in the narcoleptic canine may be modulated by systemic administration of monoaminergic compounds. In the present study, we have investigated the effects of monoaminergic drugs on cataplexy in narcoleptic canines when perfused locally via microdialysis probes in the amygdala, globus pallidus/putamen, basal forebrain, pontine reticular formation and ventral tegmental area of narcoleptic and control Doberman pinchers. Cataplexy was quantified using the Food-Elicited Cataplexy Test and analyzed by electroencephalogram, electrooculogram and electromyogram. Local perfusion with the monoaminergic agonist quinpirole, 7-OH-DPAT and BHT-920, into the ventral tegmental area produced a dose-dependent increase in cataplexy without significantly reducing basal muscle tone. Perfusion with the antagonist raclopride in the same structure produced a moderate reduction in cataplexy. Local perfusion with quinpirole, 7-OH-DPAT and BHT-920 into the globus pallidus/putamen also produced an increase, while raclopride produced a decrease, in cataplexy in narcoleptic canines. In control animals, none of the above drugs produced cataplexy or muscle atonia when perfused into either the ventral tegmental area or the globus pallidus/putamen. Other monoaminergic drugs tested in these two brain areas; prazosin, yohimbine, amphetamine, SKF 38393 and SCH 23390 had no effects on cataplexy. Local perfusion with each of the above listed drugs had no effect on cataplexy in any of the other brain regions examined. These findings show that cataplexy may be regulated by D2/D3 dopaminergic receptors in the ventral tegmental area and perhaps the globus pallidus/putamen. It is suggested that neurons in the mesolimbic dopamine system of narcoleptics are hypersensitive to dopaminergic autoreceptor agonists.

Common profile of D1 receptor antagonists and atypical antipstchotic drugs revealed by analysis of dopamine turnover

Heal, David J., Carole Czudek and W. Roger Buckett: Common Profile of D1 Receptor Antagonists and Atypical Antipsychotic Drugs Revealed by Analysis of Dopamine Turnover. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1994, 18 : 3 803–821. 1. Selective antagonists of dopamine D1 and D2 receptors enhanced 3-methoxytyramine (3-MT) accumulation in the striata and accumbens of tranylcypromine pretreated rats. Selective D1 and D2 agonists produced opposite effects. The smaller changes produced by the D1 agonists and antagonists were probably mediated by neuronal feedback, whereas the larger effects produced by the D2 ligands predominantly reflected pharmacological actions at prejunctional dopaminergic autoreceptors. 2. Atypical antipsychotics evoked small increases in 3-MT similar to the effects of the selective D1 inhibitors, whereas the mixed D1/D2 antagonists mimicked the selective D2 inhibitors by inducing much larger elevations in 3-MT. 3. γ-Butyrolactone, an inhibitor of dopaminergic neuronal firing, dose-dependently decreased 3-MT accumulation in both the striata and accumbens. 4. γ-Butyrolactone pretreatment abolished the small increases in 3-MT induced by the selective D1 antagonists and the atypical antipsychotics and also the large increases produced by the mixed D1/D2 antagonists. By contrast, γ-butyrolactone only partially reversed the marked elevation of 3-MT evoked by the selective D2 antagonists. 5. The above data suggest that in vivo the atypical antipsychotics behave predominantly as selective D1 antagonists.

2,5-Dimethoxy congeners of (+)-and (-)-3-(3-hydroxyphenyl)-N-n- propylpiperidine.

p-Dimethoxyaryl analogs of certain potent catechol-derived dopaminergic agonists show dopaminergic properties for which no structure-activity relationship has yet been defined. (S)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine (1, S-"3-PPP") is a dopaminergic autoreceptor agonist, and at high doses it also exhibits postsynaptic antagonism. (R)-1 is a postsynaptic agonist. In a continuation of studies of effects of the p-dimethoxy moiety at dopamine receptors, synthesis and resolution of the 2,5-dimethoxy analog 3 of 3-PPP was undertaken. The two enantiomers and the racemic modification showed cardiovascular effects consistent with actions at DA-2 receptors. The potency of all three compounds was much lower than that of 3-PPP, although they displayed approximately the same duration of action. Absolute configuration does not seem to be a major determinant of these compounds' ability to interact with DA-2 receptors.

Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains

The purpose of this study was to verify the dopamine-sensitizing behavioral effect of chronic antidepressant treatment in two selectively bred rat strains: the hypercholinergic Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL). Two antidepressants, desipramine HCl (DMI) and sertraline HC1, were injected IP in separate groups of FSL and FRL rats in a dose of 16.5 μmol/kg twice daily for 16 days. Twenty-four hours after withdrawal, locomotor and hypothermie responses to 0.2 mg/kg of apomorphine, SC, were examined. Attenuation of the effect of apomorphine was observed in the open field: FRLs withdrawn from sertraline were significantly less mobile than control FRLs, and the same trend was found in FSL rats. Chronic DMI resulted in similar changes in the locomotor activity. Sertraline treatment decreased apomorphine-induced hypothermia by almost half in FSLs, whereas slight hyperthermia was induced in FRL rats instead. The present results suggest that in these selectively bred strains, a serotonergic antidepressant such as sertraline may have sensitized dopaminergic autoreceptors and/or desensitized postsynaptic receptors. Apomorphine-induced hypothermia could be mediated by serotonergic neuron function that may have been altered by chronic sertraline but not DMI treatment.

Is depression a disorder of a receptor superfamily? A critical review of the receptor theory of depression and the appraisal of a new heuristic model

SummaryThe monoamine hypothesis of depression and its direct derivation, the receptor theory, have constituted for several years a frame of reference for researchers working in the field of biological psychiatry. Although most of the data are derived from animal findings and must be considered inconclusive in view of various controversies, some guidelines may be identified: these would suggest that changes in postsynaptic beta-adrenoreceptors, presynaptic alpha 2-adrenoreceptors, as well as in type 2 serotonin receptors and dopaminergic autoreceptors may be involved in the mode of action of antidepressant drugs and, consequently, in the pathophysiology of depression. Nowadays, any attempt to correlate depression with the dysfunction of a single neurotransmitter or receptor is no longer tenable, since it is clear that depression is a heterogeneous disorder which involves abnormalities in the interactive relationships between neurotransmitters and receptors. If, on the one hand, this new model has opened up new fields of research and has led to the investigation of new systems,egthe GABAergic and GABA B receptors, on the other hand, it has been strongly limited by the lack of research tools and reliable peripheral CNS models forin vivostudies. A possible approach to this unresolved dilemma may be provided by molecular biology techniques, which have permitted the identification of the genes and sequencing of the primary structure of several membrane receptors. It is now established that receptors may be grouped into four superfamilies; in depression, there exists compelling evidence of alterations mainly in receptors belonging to the G-protein-coupled family: it is plausible that depression may be related to a disorder of the G-protein-coupled receptor superfamily. Such an hypothesis would represent an attempt to unify the different receptor abnormalities found in depression or following antidepressant treatments, and to shift from the monoamine paradigm to a new heuristic model. In addition, it would accommodate the various dysfunctions likely to be encountered and would open up new theoretical perspectives in the treatment of depression.