Apparent seasonal rhythms in hypothalamic neuropeptides in rats without photoperiod changes.

An apparent seasonal or circannual rhythm in the hypothalamic content of CRF, TRH, neurotensin, and neuromedin N has been observed in 12 separate monthly coherts (n = 10@ or 130 total) adult, male Sprague-Dawley rats obtained at the same time each month from a single commercial supplier and held under constant (12:12) photoperiod conditions since birth. Both annual and 4-month (terannual) harmonics can be statistically discerned in these apparent rhythms, which exhibit cycles containing concentration changes up to 3-fold the lowest levels across the year (CRF increases 390%, TRH increases 173%, neurotensin increases 136%, and neuromedin N increases 150%). Hypothalamic somatostatin did not exhibit these statistically significant robust rhythms nor did any peptide in regions outside the hypothalamus. These data indicate that a mechanism allowing enhanced or diminished physiological availability of these regulatory neuropeptides at different times of the year may exist and may display distinct cycles even in the absence of normal photoperiod cues. Possible regulatory responses of pituitary receptor populations for these hypothalamic peptides must be considered. As certain of these neuropeptides also appear to be altered in the cerebrospinal fluid of patients with major depression or schizophrenia, similar hypothalamic cyclic changes may underly psychiatric symptoms with seasonal periodicity.

Chronic continuous or intermittent infusion of cocaine differentially alter the concentration of neurotensin-like immunoreactivity in specific rat brain regions.

Neurotensin (NT) is an endogenous brain tridecapeptide that exhibits selective anatomic and neurochemical interactions with rat brain dopaminergic systems. Because modulation of dopaminergic neurotransmission may underlie many of the behavioral properties of cocaine, the effects of both acute and chronic administration of cocaine on the concentration of NT-like immunoreactivity (NT-LI) in specific brain regions was determined. Adult male rats were treated with cocaine for 14 days at a dose of 40 mg/kg/day (0.118 mmoles/kg/day) administered as either 1 subcutaneous injection per day, or infused continuously using subcutaneously implanted minipumps. Neurotensin-like immunoreactivity in specific brain regions was then measured 24 hours or 8 days following drug administration. After 24 hours of withdrawal from daily subcutaneous injection, the concentration of NT-LI was significantly increased in the substantia nigra (SN) and frontal cortex. After 24 hours of withdrawal from continuous infusion with cocaine, NT-LI was increased only in the SN. After 8 days of withdrawal, NT-LI was increased in the SN of rats treated with daily subcutaneous infections of cocaine, but not in the group treated with continuous infusion. Twenty-four hours following a single acute injection of 40 mg/kg of cocaine, NT-LI was increased in the SN and nucleus accumbens. These results provide evidence consistent with a neuroanatomically selective involvement of NT systems in the behavioral and/or addictive properties of cocaine.

Effects of haloperidol, quinelorane, and lithium on regional neurotensin/neuromedin N concentrations: further evidence for neurotensin/neuromedin N-dopamine interactions.

In order to further characterize the pharmacologic mechanisms that mediate the antipsychotic drug-induced increase in neurotensin (NT) in nucleus accumbens and striatum, the effects of three weeks treatment with psychotherapeutic levels of lithium alone or in conjunction with haloperidol were compared to the ability of haloperidol alone to alter NT and neuromedin N (NMN) regional brain concentrations in rats. A separate experiment examined the ability of a selective dopamine D2 receptor agonist, quinelorane, to alter NT/NMN regional concentrations after three weeks of treatment as compared to haloperidol, a D2 receptor antagonist. Haloperidol (1 mg/kg) increased both NT and NMN concentrations in several brain regions and these parallel peptide increases were highly correlated. Lithium chloride (0.4 mM) had no effect, either alone or with haloperidol, on NT/NMN concentrations. Quinelorane (1 mg/kg), however, effectively increased both NT and NMN concentrations in the caudate nucleus and nucleus accumbens, as did haloperidol (2 mg/kg). These data indicate that the induction of NT and NMN, whose adjacent sequences are contained in a pro-hormone product of a single gene, occurs in tandem and remains proportional, as well as demonstrating that putative D2 receptor agonists can produce effects on NT/NMN systems that are similar to D2 receptor antagonists.