To determine responsivity to antidepressant medication of Sprague-Dawley rats bred for low activity in the swim test [Swim Low-Active (SwLo) rats], these animals were given different antidepressant drugs via subcutaneously implanted minipumps for 1, 12, or 26 days, and then were tested for activity in the swim test and 2 days later in the open field. Antidepressant drugs given were amitriptyline, imipramine, desipramine (tricyclics), phenelzine (monoamine oxidase inhibitor (MAOI)], fluoxetine [selective serotonin reuptake inhibitor (SSRI)], venlafaxine, and bupropion (atypical). To assess specificity of response, the nonantidepressant drugs amphetamine, caffeine, and haloperidol were also tested. For comparison, several drugs were also tested in rats bred for high activity in the swim test [Swim High-Active (SwHi) rats]. When administered for 14 and/or 28 days (but not for 1 day), imipramine, desipramine, venlafaxine, phenelzine, and bupropion significantly increased struggling behavior of SwLo rats in swim test. No nonantidepressant drug significantly elevated struggling activity. Long-term administration of phenelzine and bupropion also significantly decreased floating behavior in the swim test, although amphetamine also had this effect at all times of administration. No significant effects of antidepressants were seen in SwHi rats. Amitriptyline and fluoxetine were ineffective in altering either struggling or floating in SwLo rats; however, a high dose of an SSRI (sertraline) did reduce floating, but this type of effect is probably not indicative of antidepressant action. Behavior in the open field was not consistently affected by any drug type. It is concluded that, based on pharmacological response profile in the swim test, SwLo rats represent depression that is responsive to potent norepinephrine reuptake-blocking antidepressants and also MAOIs; atypical depression may fit this profile.