Athanasios P. Zis

Feeding and drinking deficits after 6-hydroxydopamine administration in the rat: similarities to the lateral hypothalamic syndrome

Summary The role of catecholamines in the behavioral changes observed after lateral hypothalamic (LH) lesions was assessed by comparing LH lesioned animals with animals subjected to various treatments with 6-hydroxydopamine (6-OHDA). In agreement with previous reports, bilateral electrolytic lesions of the lateral hypothalamus (LH lesioned), intraventricular administration of 6-OHDA in monoamine oxidase inhibited animals (6-OHDA + tranylcypromine) or bilateral injections of 6-OHDA into the substantia nigra (nigral 6-OHDA) produced aphagia and adipsia. Recovery of food and water intake occurred in most animals within 10 days. Some of the nigral 6-OHDA injected animals did not, however, recover during the 3 months of the experiment. Intraventricular injections of 6-OHDA did not produce these effects unless monoamine oxidase was first inhibited. After recovery of food and water intake, the intraventricular 6-OHDA + tranylcypromine and the nigral 6-OHDA groups showed the same deficits in water regulation as were found in the LH lesioned animals: decreased daily water intake, prandial drinking, increased finickiness to quinine adulteration of drinking water, and a lack of drinking in response to hypertonic saline injections. Changes in regulation of food intake were also evident. Amphetamine anorexia was reduced in the LH lesioned and the nigral 6-OHDA groups. Amphetamine anorexia was abolished in the intraventricular 6-OHDA + MAOI animals. In contrast, the anorectic properties of fenfluramine were augmented in these groups. The results suggest that the lateral hypothalamic syndrome may to a large extent reflect the interruption of the dopaminergic nigro-striatal system. Based on tyrosine hydroxylase measures in the striatum, hypothalamus and midbrain, however, it is suggested that damage to this system cannot account for the magnitude of the behavioral changes seen after LH lesions and that other as yet unknown factors may also contribute to this syndrome.

Ascending catecholamine pathways and amphetamine-induced locomotor activity: importance of dopamine and apparent non-involvement of norepinephrine.

Stereotaxically placed intracerebral microinjections of 6-hydroxydopamine (6-OHDA) were used to produce selective and extensive lesions of either the dopaminergic nigro-neostriatal bundle or the dorsal and ventral noradrenergic projections in the rat. The extensive damage of the noradrenergic pathways which is typically obtained after intranigral 6-OHDA injections was completely prevented by pretreatment with desipramine. Extensive depletions (85-95%) of norepinephrine (NE) in the hypothalamus, cerebral cortices and hippocampi failed to influence either spontaneous or D-amphetamine-induced locomotor activity. Neither the time course of the amphetamine response as measured by photocell cages nor the qualitative nature of the response as determined by direct observation was significantly altered by these lesions. In contrast, selective depletion (92%) of neostriatal dopamine (DA) after intranigral 6-OHDA injections severly reduced but did not abolish amphetamine-induced hyperkinesia. At the highest dose studied (2.0 mg/kg) these animals showed an initial increase in activity but, unlike controls, failed to maintain this level. This response was probably mediated by the small remaining stores of DA in the neostriatum. Pimozide (0.5 mg/kg) also severely attenuated but did not abolish amphetamine-induced locomotor activity. These data are consistent with the view that ascending DA projections are a critical substrate for amphetamine-induced hyperkinesia. They furthermore suggest that ascending NE systems do not play a role in this response.

Haloperidol-induced disruption of conditioned avoidance responding: Attenuation by prior training or by anticholinergic drugs

Rats injected daily with haloperidol (0.15 mg/kg) failed to acquire a one-way avoidance response over a 9 day period (10 trails/day). When these animals were subsequently tested without haloperidol, on the first drug-free day they preformed as well as animals given saline throughout the training period and significantly better than naive saline-treated animals on the first day of training. The performance of rats which were trained for two days before receiving haloperidol was only partly blocked by the drug, while animals trained for 9 days before drug administration were immune to the disruptive effects. Three anticholinergic (muscarinic) drugs, atropine (10 mg/kg), scopolamine (1 mg/kg) and benztropine (2 mg/kg) significantly reversed the effect of haloperidol on the acquisition of the nigroneostriatal projection and support the view that this system is critically involved in the acquistion of learned instrumental responses. The nature of the avoidance deficit produced by these treatments is discussed with reference to the possibility that they selectively block the initiation of boluntary motor responses. According to this hypothesis, the failure of these teratments to disrupt escape responding may be due to the fact that the unconditioned stimulus generates reflexive motor responses (flinch, jump, etc.) which are sufficient to begin the motoric sequences that cannot be initiated voluntarily in response to the conditioned stimulus.

Deficits in instrumental responding after 6-hydroxydopamine lesions of the nigro-neostriatal dopaminergic projection

Abstract Rats subjected to bilateral injections of 6-hydroxydopamine (8 μg) into the zona compacta of the substantia nigra completely failed to learn either a one-way active avoidance response or a simple approach response for food reinforcement. The neurotoxic lesions reduced striatal dopamine and tyrosine hydroxylase activity to less than 10 percent of control levels. A significant loss of hypothalamic norepinephrine was also produced by these lesions suggesting that this procedure also destroyed part of the ventral noradrenergic bundle. When bilateral lesions of the latter pathway were made caudal to the substantia nigra, so that similar losses were produced in hypothalamic norepinephrine levels without reducing striatal tyrosine hydroxylase activity, normal acquisition of both avoidance and appetitive responses were observed. In another experiment, almost complete retention of avoidance responding was obtained if the animals were overtrained on this response prior to the bilateral nigral lesions. These results suggest that the nigro-neostriatal dopaminergic projection may play an important role in the acquisition of learned instrumental responses.

Weight gain with antidepressants and lithium

Undesired weight gain is a common complaint of patients receiving pharmacological treatment for major affective disorders. It has been found to jeopardize patient compliance and may pose additional health hazards. A review of the literature on weight gain associated with tricyclic antidepressants, monoamine oxidase inhibitors, and lithium was carried out with the aim of deriving practical management strategies. Tricyclic antidepressants were found to stimulate appetite, carbohydrate craving, and a dose-dependent continuous weight gain of 0.57 to 1.37 kg per month of treatment. Proposed mechanisms include noradrenergic or antihistaminic inhibition of satiety and decreased metabolic rate. Novel serotonergic and dopaminergic antidepressants were found to be anorectic. Monoamine oxidase inhibitors may stimulate appetite and potentiate insulin-induced hypoglycemia. Lithium maintenance therapy stimulates weight gains of over 10 kg in 20% of patients. Documented mechanisms include insulin-like actions on carbohydrate and fat metabolism, polydipsia, and sodium retention. Recommendations regarding choice of antidepressant drug as well as dietary and behavioral strategies to prevent excessive weight gain are presented. Potential adjunctive drug approaches to severe weight gain are reviewed.

Reversal by L-Dopa of Impaired Learning Due to Destruction of the Dopaminergic Nigro-Neostriatal Projection

Rats receiving bilateral stereotaxic injections of 6-hydroxydopamine into the zona compacta of the substantia nigra failed to learn a one-way active avoidance response. Small doses of L-dopa (1.5 milligrams per kilogram of body weight) in combination with a peripheral decarboxylase inhibitor reversed this impairment. Animals with lesions which acquired the avoidance response during L-dopa administration retained this response when drug treatment was discontinued. These experiments suggest that the dopaminergic nigro-neostriatal projection serves a critical function in the acquisition of learned instrumental responses.

Morphine inhibits cortisol and stimulates prolactin secretion in man

The role of opioids in endocrine regulation has been the subject of numerous studies. Surprisingly, however, the acute endocrine effects of morphine on basal hormonal levels in man have not been adequately documented. We report here the effects of intravenous morphine (5 mg) on plasma cortisol and prolactin. Fourteen healthy volunteers (nine male, five female) received morphine at 0930 hr. Blood samples were collected immediately before and 30, 60, 90, 120 and 180 min after the injection. In six of the male subjects the procedure was repeated with a placebo (normal saline) injection. Morphine stimulated prolactin release. There was a trend for a greater response in females compared to male subjects. Cortisol secretion was markedly suppressed by morphine. In sharp contrast to the results obtained with placebo, cortisol levels following morphine declined progressively at a rate consistent with the half-life of cortisol. This downward trend of cortisol values continued uninterrupted for the duration of the experiment in all 14 subjects. These results are consistent with the presence of an inhibitory opioid mechanism in the human hypothalamo-pituitary-adrenal axis.

A controlled study of light therapy in women with late luteal phase dysphoric disorder

Previous studies suggest that light therapy, as used to treat seasonal affective disorder, may be beneficial for pre-menstrual depressive disorders. We conducted a six-menstrual cycle randomized, double-blind, counter-balanced, crossover study of dim vs. bright light therapy in women with late luteal phase dysphoric disorder (LLPDD). Fourteen women who met DSM-III-R criteria for LLPDD completed two menstrual cycles of prospective baseline monitoring of pre-menstrual symptoms, followed by two cycles of each treatment. During the 2-week luteal phase of each treatment cycle, patients were randomized to receive 30 min of evening light therapy using: (1) 10000 lx cool-white fluorescent light (active condition); or (2) 500 lx red fluorescent light (placebo condition), administered by a light box at their homes. After two menstrual cycles of treatment, patients were immediately crossed over to the other condition for another two cycles. Outcome measures were assessed at the mid-follicular and luteal phases of each cycle. Results showed that the active bright white light condition significantly reduced depression and pre-menstrual tension scores during the symptomatic luteal phase, compared to baseline, while the placebo dim red light condition did not. These results suggest that bright light therapy is an effective treatment for LLPDD.

Platelet alpha2 adrenoreceptors are decreased in number after antidepressant therapy

Specific binding of 3H-clonidine to alpha 2 adrenoreceptors upon human blood platelet membranes is increased in patients with major depressive disorder (endogenous depression). Specific binding of 3H-yohimbine to the platelet adrenoreceptor is not altered in endogenously depressed patients. Other psychiatric disorders are not associated with alterations in the specific binding of either 3H-clonidine or 3H-yohimbine. In patients with severe congestive heart failure or with symptomatic coronary artery disease the number of platelet alpha 2 adrenoreceptors is actually decreased. Treatment of endogenously depressed patients with tricyclic antidepressants, lithium salts or electroconvulsive therapy results in a decrease in the number of alpha 2 adrenoreceptors on blood platelet membranes. These studies suggest that a supersensitivity of the alpha 2 adrenoreceptor might exist in patients with endogenous depression and that effective forms of therapy lead to a decrease in the number of neural alpha 2 adrenoreceptors which is reflected by a decrease in the number of these receptors upon blood platelet membranes.

Neuroleptic-induced deficits in food and water regulation: Similarities to the lateral hypothalamic syndrome

The role of central dopaminergic mechanisms in the regulation of food and water intake was assessed by examining the effects of haloperidol and pimozide on various measures of feeding and drinking in rats. Haloperidol (0.20 mg/kg) or pimozide (0.45 mg/kg) did not significantly affect 1-hr water intake in response to 24 hrs of water deprivation, nor did they influence 2-hr food intake after 24 hrs of food deprivation. However both pimozide and haloperidol significantly reduced drinking in response to injections of hypertonic saline. In addition, animals pretreated with these drugs drank less than controls in the absence of food (a measure of “non-prandial” drinking), and drank less than controls when the water was adulterated with quinine (a measure of “finickiness”). These drugs also significantly reduced food intake in response to injections of insulin and attenuated amphetamine anorexia. These deficits are similar to those observed after electrolytic lesions of the lateral hypothalamus or after 6-hydroxydopamine lesions of the substantia nigra. Because haloperidol and pimozide block central dopaminergic receptor sites, the present findings are consistent with the hypothesis that part of the lateral hypothalamic syndrome is the result of damage to the dopaminergic nigro-neostriatal projection. Finally, the data suggest that the changes in feeding and drinking induced by haloperidol and pimozide reflect genuine homeostatic deficits rather than being due to a neuroleptic-induced motor dysfunction.