Jane Gosden

Mediation of the antidepressant-like effect of 8-OH-DPAT in mice by postsynaptic 5-HT1A receptors.

1 The 5‐hydroxytryptamine (5‐HT)1A agonist 8‐hydroxy‐2‐(dipropylamino)tetralin (8‐OH‐DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8‐OH‐DPAT‐induced response have also been determined. 2 8‐OH‐DPAT (0.3–10.0 mg kg−1, s.c.) dose‐dependently increased the mobility of mice in the Porsolt test. Other selective 5‐HT1A receptor ligands (0.3–30 mg kg−1, s.c.) either mimicked the 8‐OH‐DPAT response (ipsapirone, at 10 and 30 mg kg−1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (≤ 100 mg kg−1, p.o.) inhibited the response to 8‐OH‐DPAT (3 mg kg−1, s.c.) when given concurrently. 3 The putative 5‐HT1A antagonists, spiroxatrine (1–30 mg kg−1, p.o.), (±)‐pindolol (30 mg kg−1, p.o.) and methiothepin (3–10 mg kg−1, p.o.), each attenuated the 8‐OH‐DPAT (3 mg kg−1, s.c.)‐induced increase in mobility. 4 The dopamine D1 receptor antagonist, SCH 23390 (3–10 mg kg−1, p.o.), weakly reversed the 8‐OH‐DPAT response. Antagonists at 5‐HT1C/5‐HT2 receptors (ketanserin; 0.1–3.0 mg kg−1, p.o.), 5‐HT3 receptors (ondansetron; 0.03–10 mg kg−1, p.o.), α1‐adrenoceptors (prazosin; 1–3 mg kg−1, p.o.), α2‐adrenoceptors (idazoxan; 3–30 mg kg−1, p.o.), β1‐adrenoceptors (metoprolol; 1–30 mg kg−1, p.o.), β2‐adrenoceptors (ICI 118,551; 1–30 mg kg−1, p.o.), dopamine D2 receptors (sulpiride; 10–300 mg kg−1, p.o.) and opiate receptors (naloxone; 3–100 mg kg−1, p.o.) had no effect on the 8‐OH‐DPAT response. 5 Selective destruction of 5‐HT neurones with 5,7‐dihydroxytryptamine or inhibition of 5‐HT synthesis with p‐chlorophenylalanine did not change the 8‐OH‐DPAT response in the Porsolt test. This response was also unaltered by pretreatment with the noradrenergic neurotoxin, DSP‐4. 6 Administration of 8‐OH‐DPAT (3 mg kg−1, s.c.) twice‐daily for 10 days attenuated the hypothermia, but not the increased mobility, induced by 8‐OH‐DPAT (3 mg kg−1, s.c.). Similarly, repeated administration of amitriptyline (3–30 mg kg−1), desipramine (3–30 mg kg−1) or dothiepin (10–100 mg kg−1) also attenuated the former, but not the latter, response. 7 We conclude that 8‐OH‐DPAT produces an antidepressant‐like effect in the Porsolt test which is mediated via postsynaptic 5‐HT1A receptors.

A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine.

Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1–3 mg/kg PO) and methamphetamine (0.3–30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED50 values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10–100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [3H]-dopamine from preloaded rat striatal slices was not altered by 10−7–10−5 M concentrations of sibutramine, BTS 54 354, BTS 54 505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10−8–10−4 M) caused a significant concentration-dependent increase in [3H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 430 mg/kg PO) did not alter 3-methoxy-tyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3–10 mg/kg IP or 0.42–4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10–100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose. In a two-choice lever pressing model using rats trained to discriminated-amphetamine (0.5 mg/kg IP) from saline, sibutramine (0.3–3 mg/kg IP) generalised to the saline lever. Bupropion (3–30 mg/kg IP) generalised tod-amphetamine at the highest dose, while methamphetamine (0.1–5 mg/kg IP) generalised to this lever at doses as low as 0.3 mg/kg. Overall, the rank order of potency for enhancing central dopaminergic function is methamphetamine > bupropion >> sibutramine. The data therefore indicate that dopamine is unlikely to be an important pharmacological target for reuptake inhibition by sibutramine.

Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats

Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects.

Receptor binding and functional evidence suggest that postsynaptic α2-adrenoceptors in rat brain are of the α2D subtype

This study has determined the subtype(s) of postsynaptic α2-adrenoceptors in rat brain. This question has been addressed by using two separate approaches, i.e. ligand displacement of [3H]2-(2-methoxy)-1,4-benzodioxan-2-yl)-2-imidazoline ([3H]RX 821002) from membranes prepared from rat cortex after noradrenergic denervation and, secondly, by antagonism of clonidine-induced mydriasis. After rats had been lesioned using N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 100 mg/kg i.p., 30 min after zimeldine 10 mg/kg i.p.), noradrenaline was undetectable in the cortex 3 days later. Displacement of [3H]RX 821002 with a range of agonists and antagonists which distinguish between the known α2-adrenoceptor subtypes (α2A–2D) yielded pKi values which correlated very well with reported values for the α2D-adrenoceptor (r = 0.929; P < 0.001), but not the α2A (r = 0.450; P = 0.192), α2B (r = 0.280, P = 0.434) or α2C (r = 0.283; P = 0.460) subtypes. Similarly, the potencies of various α2-adrenoceptor antagonists to inhibit clonidine (0.03 mg/kg i.p.)-induced mydriasis in conscious rats correlated strongly with their pKi values for α2D-adrenoceptors (r = 0.899; P = 0.015) but not α2A- (r = 0.369; P = 0.472), α2B- (r = −0.224; P = 0.670) or α2C-adrenoceptors (r = 0.253; P = 0.584). These data are, therefore, consistent and argue strongly that postsynaptic α2-adrenoceptors in the rat cortex and Edinger-Westphal nucleus are of the α2D subtype.

Metabolic Consequences of Antipsychotic Therapy: Preclinical and Clinical Perspectives on Diabetes, Diabetic Ketoacidosis, and Obesity

Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics.

A comparison of various antidepressant drugs demonstrates rapid desensitisation of α2-adrenoceptors exclusively by sibutramine hydrochloride

The functional status of presynaptic and post-synaptic α2-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 mg/kg IP). Both responses were attenuated 24 h after 3 days of injection of sibutramine hydrochloride (3 mg/kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate α2-adrenoceptors rapidly: amitriptyline, doxepin, nomifensine, desipramine, amoxapine, fluoxetine, zimeldine, tranylcypromine and mianserin. When given for 3 or 5 days at the low dose of 3 mg/kg IP, none of the other antidepressants reduced clonidine-induced hypoactivity or mydriasis. Furthermore, increasing the dose of amitriptyline, doxepin, nomifensine, desipramine, amoxapine and tranylcypromine to 10 mg/kg IP did not enable these antidepressants to attenuate the α2-adrenoceptor-mediated responses after 3 days of treatment. An electroconvulsive shock (ECS; 200 V, 2 s) given once daily attenuated clonidine-induced mydriasis, but not hypoactivity, when administered for 3 days and both responses when administered for 5 days. In conclusion, this comparative study using antidepressant treatments with differing pharmacological modes of action demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic α2-adrenoceptors. ECS down-regulated postsynaptic α2-adrenoceptors when given for 3 days, but required 5 days to desensitise both α2-adrenoceptor populations.

Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats – possible relevance in the psychopathology and treatment of binge-eating disorder:

Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D1 receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors. There was no change in D1 receptor density in nucleus accumbens, medial prefrontal cortex or dorsolateral frontal cortex, striatal D2 receptors and dopamine reuptake transporter sites, or μ-opioid receptors in frontal cortex. There were no changes in ligand affinities. The concentrations of monoamines, metabolites and estimates of dopamine (dopamine/dihydroxyphenylacetic acid ratio) and serotonin/5-hydroxyindolacetic acid ratio turnover rates were unchanged in striatum and frontal cortex. However, turnover of dopamine and serotonin in the hypothalamus was increased ~20% and ~15%, respectively. Striatal transmission via D1 receptors is decreased in binge-eating rats while μ-opioid receptor signalling may be increased. These changes are consistent with the attenuation of binge-eating by lisdexamfetamine, which increases catecholaminergic neurotransmission, and nalmefene, a μ-opioid antagonist.